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Sample records for variant creuzfeldt-jakob disease

  1. Modelling BSE trend over time in Europe, a risk assessment perspective

    NARCIS (Netherlands)

    Ducrot, C.; Sala, C.; Ru, G.; Koeijer, de A.A.; Sheridan, H.; Saegerman, C.; Selhorst, T.; Arnold, M.; Polak, M.P.; Calavas, D.

    2010-01-01

    BSE is a zoonotic disease that caused the emergence of variant Creuzfeldt-Jakob disease in the mid 1990s. The trend of the BSE epidemic in seven European countries was assessed and compared, using Age-Period-Cohort and Reproduction Ratio modelling applied to surveillance data 2001-2007. A strong

  2. TREM2 Variants in Alzheimer's Disease

    Science.gov (United States)

    Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

    2013-01-01

    BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

  3. Genetic variants in periodontal health and disease

    Energy Technology Data Exchange (ETDEWEB)

    Dumitrescu, Alexandrina L [Tromsoe Univ. (Norway). Inst. of Clinical Dentistry; Kobayashi, Junya [Kyoto Univ. (Japan). Dept. of Genome Repair Dynamics

    2010-07-01

    Periodontitis is a complex, multifactorial disease and its susceptibility is genetically determined. The present book systematically reviews the evidence of the association between the genetic variants and periodontitis progression and/or treatment outcomes. Genetic syndromes known to be associated with periodontal disease, the candidate gene polymorphisms investigated in relation to periodontitis, the heritability of chronic and aggressive periodontitis, as well as common guidelines for association studies are described. This growing understanding of the role of genetic variation in inflammation and periodontal chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. The book represents a new concept in periodontology with its pronounced focus on understanding through knowledge rather than presenting the presently valid answers. Connections between genetics and periodontology are systematically reviewed and covered in detail. (orig.)

  4. Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants

    DEFF Research Database (Denmark)

    Spratley, Samantha J; Hill, Chris H; Viuff, Agnete H

    2016-01-01

    different mutations have been identified in GALC that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full-length human GALC and used these to monitor the trafficking and processing of GALC variants in cell-based assays...

  5. Variant Creutzfeldt-Jakob Disease (vCJD)

    Science.gov (United States)

    ... Form Controls Cancel Submit Search the CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

  6. Diverse Functional Properties of Wilson Disease ATP7B Variants

    Science.gov (United States)

    Huster, Dominik; Kühne, Angelika; Bhattacharjee, Ashima; Raines, Lily; Jantsch, Vanessa; Noe, Johannes; Schirrmeister, Wiebke; Sommerer, Ines; Sabri, Osama; Berr, Frieder; Mössner, Joachim; Stieger, Bruno; Caca, Karel; Lutsenko, Svetlana

    2012-01-01

    BACKGROUND & AIMS Wilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. METHODS We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells. Protein function was analyzed by measuring catalytic activity and copper (64Cu) transport into vesicles. We studied intracellular localization of variants of ATP7B that had measurable transport activities and were tagged with green fluorescent protein in mammalian cells using confocal laser scanning microscopy. RESULTS Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor-intermediate formation or had partial losses of activity. In mammalian cells, transport-competent variants differed in stability and subcellular localization. CONCLUSIONS Variants in ATP7B associated with Wilson disease disrupt the protein’s transport activity, result in its mislocalization, and reduce its stability. Single assays are insufficient to accurately predict the effects of ATP7B variants the function of its product and development of Wilson disease. These findings will contribute to our understanding of genotype–phenotype correlation and mechanisms of disease pathogenesis. PMID:22240481

  7. Clear Speech Variants: An Acoustic Study in Parkinson's Disease

    Science.gov (United States)

    Lam, Jennifer; Tjaden, Kris

    2016-01-01

    Purpose: The authors investigated how different variants of clear speech affect segmental and suprasegmental acoustic measures of speech in speakers with Parkinson's disease and a healthy control group. Method: A total of 14 participants with Parkinson's disease and 14 control participants served as speakers. Each speaker produced 18 different…

  8. Attenuated Variants of Lesch-Nyhan Disease

    Science.gov (United States)

    Jinnah, H. A.; Ceballos-Picot, Irene; Torres, Rosa J.; Visser, Jasper E.; Schretlen, David J.; Verdu, Alfonso; Larovere, Laura E.; Chen, Chung-Jen; Cossu, Antonello; Wu, Chien-Hui; Sampat, Radhika; Chang, Shun-Jen; de Kremer, Raquel Dodelson; Nyhan, William; Harris, James C.; Reich, Stephen G.; Puig, Juan G.

    2010-01-01

    Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the…

  9. Late onset Pompe disease- new genetic variant: Case report ...

    African Journals Online (AJOL)

    The patient was not given enzyme replacement therapy due to cost but received high protein therapy and Oxygen supplementation using Oxygen extractor machine. She is worsening due to respiratory failure. Conclusion: This is a new genetic variant isolated of late-onset Pompe disease which presents with almost pure ...

  10. Disintegrating perineal disease: A variant of watering-can perineum

    African Journals Online (AJOL)

    N. Abrol

    www.ees.elsevier.com/afju · www.sciencedirect.com. Case report. Disintegrating perineal disease: A variant of watering-can perineum. N. Abrol. ∗. , A. Devasia. Department of Urology, Christian Medical College, Vellore, India. Received 11 January 2014; received in revised form 11 January 2014; accepted 11 March 2014.

  11. Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease

    Directory of Open Access Journals (Sweden)

    Laura Ibanez

    2018-04-01

    Full Text Available Background: The prevalence of dementia in Parkinson disease (PD increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP, Presenilin 1 and 2 (PSEN1, PSEN2, and Granulin (GRN genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES data by single variant and gene base (SKAT-O and burden tests analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE or the Montreal Cognitive Assessment (MoCA. The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status.Results: Known AD pathogenic mutations in the PSEN1 (p.A79V and PSEN2 (p.V148I genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10−4, independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site.Conclusions: Pathogenic mutations in

  12. Human genomic disease variants: a neutral evolutionary explanation.

    Science.gov (United States)

    Dudley, Joel T; Kim, Yuseob; Liu, Li; Markov, Glenn J; Gerold, Kristyn; Chen, Rong; Butte, Atul J; Kumar, Sudhir

    2012-08-01

    Many perspectives on the role of evolution in human health include nonempirical assumptions concerning the adaptive evolutionary origins of human diseases. Evolutionary analyses of the increasing wealth of clinical and population genomic data have begun to challenge these presumptions. In order to systematically evaluate such claims, the time has come to build a common framework for an empirical and intellectual unification of evolution and modern medicine. We review the emerging evidence and provide a supporting conceptual framework that establishes the classical neutral theory of molecular evolution (NTME) as the basis for evaluating disease- associated genomic variations in health and medicine. For over a decade, the NTME has already explained the origins and distribution of variants implicated in diseases and has illuminated the power of evolutionary thinking in genomic medicine. We suggest that a majority of disease variants in modern populations will have neutral evolutionary origins (previously neutral), with a relatively smaller fraction exhibiting adaptive evolutionary origins (previously adaptive). This pattern is expected to hold true for common as well as rare disease variants. Ultimately, a neutral evolutionary perspective will provide medicine with an informative and actionable framework that enables objective clinical assessment beyond convenient tendencies to invoke past adaptive events in human history as a root cause of human disease.

  13. ABCA7 rare variants and Alzheimer disease risk.

    Science.gov (United States)

    Le Guennec, Kilan; Nicolas, Gaël; Quenez, Olivier; Charbonnier, Camille; Wallon, David; Bellenguez, Céline; Grenier-Boley, Benjamin; Rousseau, Stéphane; Richard, Anne-Claire; Rovelet-Lecrux, Anne; Bacq, Delphine; Garnier, Jean-Guillaume; Olaso, Robert; Boland, Anne; Meyer, Vincent; Deleuze, Jean-François; Amouyel, Philippe; Munter, Hans Markus; Bourque, Guillaume; Lathrop, Mark; Frebourg, Thierry; Redon, Richard; Letenneur, Luc; Dartigues, Jean-François; Pasquier, Florence; Rollin-Sillaire, Adeline; Génin, Emmanuelle; Lambert, Jean-Charles; Hannequin, Didier; Campion, Dominique

    2016-06-07

    To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting. We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)). These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants. © 2016 American Academy of Neurology.

  14. CEACAM6 gene variants in inflammatory bowel disease.

    Science.gov (United States)

    Glas, Jürgen; Seiderer, Julia; Fries, Christoph; Tillack, Cornelia; Pfennig, Simone; Weidinger, Maria; Beigel, Florian; Olszak, Torsten; Lass, Ulrich; Göke, Burkhard; Ochsenkühn, Thomas; Wolf, Christiane; Lohse, Peter; Müller-Myhsok, Bertram; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

    2011-04-29

    The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

  15. CEACAM6 gene variants in inflammatory bowel disease.

    Directory of Open Access Journals (Sweden)

    Jürgen Glas

    Full Text Available BACKGROUND: The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6 acts as a receptor for adherent-invasive E. coli (AIEC and its ileal expression is increased in patients with Crohn's disease (CD. Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD. METHODOLOGY: In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC, and 1,350 healthy, unrelated controls was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839. In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. CONCLUSIONS: This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

  16. [Clinical and morphological variants of diverticular disease in colon].

    Science.gov (United States)

    Levchenko, S V; Lazebnik, L B; Potapova, V B; Rogozina, V A

    2013-01-01

    Our own results of two-stage research are presented in the article. The first stage contains the retrospective analysis of 3682 X-ray examining of large bowel which were conducted in 2002-2004 to define the structure of colon disease and to determine gender differences. The second stage is prospective research which took place from 2003 to 2012 and 486 patients with diverticular disease were regularly observed. Following parameters were estimated: dynamics of complaints, life quality, clinical symptoms. Multiple X-ray and endoscopic examining were done with estimation of quantity and size of diverticula, changes of colon mucosa, comparison of X-ray and endoscopic methods in prognosis of complications. Two basic clinical morphological variants of diverticular disease (DD) of colon are made out as a result of our research. There are IBD-like and DD with ischemic component. The variants differ by pain characteristics, presence of accompanying diseases, life quality parameters and description of colon mucosa morphological research. We suppose that different ethiopathogenetic factors of development of both variants mentioned above influence the disease prognosis and selection of treatment.

  17. Modelling BSE trend over time in Europe, a risk assessment perspective.

    Science.gov (United States)

    Ducrot, Christian; Sala, Carole; Ru, Giuseppe; de Koeijer, Aline; Sheridan, Hazel; Saegerman, Claude; Selhorst, Thomas; Arnold, Mark; Polak, Miroslaw P; Calavas, Didier

    2010-06-01

    BSE is a zoonotic disease that caused the emergence of variant Creuzfeldt-Jakob disease in the mid 1990s. The trend of the BSE epidemic in seven European countries was assessed and compared, using Age-Period-Cohort and Reproduction Ratio modelling applied to surveillance data 2001-2007. A strong decline in BSE risk was observed for all countries that applied control measures during the 1990s, starting at different points in time in the different countries. Results were compared with the type and date of the BSE control measures implemented between 1990 and 2001 in each country. Results show that a ban on the feeding of meat and bone meal (MBM) to cattle alone was not sufficient to eliminate BSE. The fading out of the epidemic started shortly after the complementary measures targeted at controlling the risk in MBM. Given the long incubation period, it is still too early to estimate the additional effect of the ban on the feeding of animal protein to all farm animals that started in 2001. These results provide new insights in the risk assessment of BSE for cattle and Humans, which will especially be useful in the context of possible relaxing BSE surveillance and control measures.

  18. Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Pfeiffer Ronald F

    2010-04-01

    Full Text Available Abstract Background Mitochondrial function is impaired in Parkinson's disease (PD and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. Methods We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. Results The frequency of affected mothers of the proband with PD (83/167, 49.4% was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4% (Odds Ratio 1.22; 95%CI 0.83 - 1.81. After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. Conclusions These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic m

  19. Meta-analyses of HFE variants in coronary heart disease.

    Science.gov (United States)

    Lian, Jiangfang; Xu, Limin; Huang, Yi; Le, Yanping; Jiang, Danjie; Yang, Xi; Xu, Weifeng; Huang, Xiaoyan; Dong, Changzheng; Ye, Meng; Zhou, Jianqing; Duan, Shiwei

    2013-09-15

    HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P=0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values>0.05). In addition, the results of our case-control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. Our meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. [Multicentric hyaline vascular Castleman's disease. A POEMS type variant].

    Science.gov (United States)

    Gracia-Ramos, Abraham Edgar; Cruz-Domínguez, María del Pilar; Vera-Lastra, Olga Lidia

    2013-01-01

    Castleman's disease is an atypical lymphoproliferative disorder which may be compatible with paraneoplastic manifestations of POEMS syndrome. a 53 year old man with a history of type 2 diabetes, hypothyroidism and Addison's disease presented with numbness and weakness in limbs, dyspnea, skin hardening, Raynaud's phenomenon, weight loss and fatigue. A physical exam showed tachypnea, generalized cutaneous hyperpigmentation and skin hardening of extremities, muscle weakness, hypoesthesia and hyporeflexia. Laboratory showed hyperprolactinemia, low testosterone, hypothyroidism and Addison's disease. Electrophoresis of proteins showed polyclonal hypergammaglobulinemia. Somatosensory evoked potentials reported peripheral neuropathy and severe axonal polyneuropathy by electromyography. Chest X-rays showed bilateral reticular infiltrates and mediastinal widening. An echocardiogram displayed moderate pulmonary hypertension. Skin biopsy had no evidence of scleroderma. CT reported axillar, mediastinal and retroperitoneal nodes. The mediastinal lesion biopsy reported hyaline vascular Castleman's disease, multicentric variety. He was treated with rituximab. the case meet criteria for multicentric hyaline vascular Castleman's disease, POEMS variant, treated with rituximab.

  1. Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

    Science.gov (United States)

    Balendra, Rubika; Uphill, James; Collinson, Claire; Druyeh, Ronald; Adamson, Gary; Hummerich, Holger; Zerr, Inga; Gambetti, Pierluigi; Collinge, John; Mead, Simon

    2016-04-07

    Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

  2. Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 genomes project dataset.

    Directory of Open Access Journals (Sweden)

    Tjaart A P de Beer

    Full Text Available The 1000 Genomes Project data provides a natural background dataset for amino acid germline mutations in humans. Since the direction of mutation is known, the amino acid exchange matrix generated from the observed nucleotide variants is asymmetric and the mutabilities of the different amino acids are very different. These differences predominantly reflect preferences for nucleotide mutations in the DNA (especially the high mutation rate of the CpG dinucleotide, which makes arginine mutability very much higher than other amino acids rather than selection imposed by protein structure constraints, although there is evidence for the latter as well. The variants occur predominantly on the surface of proteins (82%, with a slight preference for sites which are more exposed and less well conserved than random. Mutations to functional residues occur about half as often as expected by chance. The disease-associated amino acid variant distributions in OMIM are radically different from those expected on the basis of the 1000 Genomes dataset. The disease-associated variants preferentially occur in more conserved sites, compared to 1000 Genomes mutations. Many of the amino acid exchange profiles appear to exhibit an anti-correlation, with common exchanges in one dataset being rare in the other. Disease-associated variants exhibit more extreme differences in amino acid size and hydrophobicity. More modelling of the mutational processes at the nucleotide level is needed, but these observations should contribute to an improved prediction of the effects of specific variants in humans.

  3. Estimating the contribution of genetic variants to difference in incidence of disease between population groups.

    Science.gov (United States)

    Moonesinghe, Ramal; Ioannidis, John P A; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

    2012-08-01

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

  4. Estimating the contribution of genetic variants to difference in incidence of disease between population groups

    Science.gov (United States)

    Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

    2012-01-01

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal. PMID:22333905

  5. Identifying noncoding risk variants using disease-relevant gene regulatory networks.

    Science.gov (United States)

    Gao, Long; Uzun, Yasin; Gao, Peng; He, Bing; Ma, Xiaoke; Wang, Jiahui; Han, Shizhong; Tan, Kai

    2018-02-16

    Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.

  6. Fine-mapping inflammatory bowel disease loci to single-variant resolution

    NARCIS (Netherlands)

    Huang, Hailiang; Fang, Ming; Jostins, Luke; Umićević Mirkov, Maša; Boucher, Gabrielle; Anderson, Carl A; Andersen, Vibeke; Cleynen, Isabelle; Cortes, Adrian; Crins, François; D'Amato, Mauro; Deffontaine, Valérie; Dmitrieva, Julia; Docampo, Elisa; Elansary, Mahmoud; Farh, Kyle Kai-How; Franke, Andre; Gori, Ann-Stephan; Goyette, Philippe; Halfvarson, Jonas; Haritunians, Talin; Knight, Jo; Lawrance, Ian C; Lees, Charlie W; Louis, Edouard; Mariman, Rob; Meuwissen, Theo; Mni, Myriam; Momozawa, Yukihide; Parkes, Miles; Spain, Sarah L; Théâtre, Emilie; Trynka, Gosia; Satsangi, Jack; van Sommeren, Suzanne; Vermeire, Severine; Xavier, Ramnik J; Weersma, Rinse K; Duerr, Richard H; Mathew, Christopher G; Rioux, John D; McGovern, Dermot P B; Cho, Judy H; Georges, Michel; Daly, Mark J; Barrett, Jeffrey C

    2017-01-01

    Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we

  7. Fine-mapping inflammatory bowel disease loci to single-variant resolution

    DEFF Research Database (Denmark)

    Huang, Hailiang; Fang, Ming; Jostins, Luke

    2017-01-01

    Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here w...

  8. Behavioral variant of frontotemporal dementia mimicking Huntington's disease

    DEFF Research Database (Denmark)

    Nielsen, T Rune; Bruhn, Peter; Nielsen, Jørgen E

    2010-01-01

    Behavioral changes and cognitive decline are the core clinical manifestations in the behavioral variant of frontotemporal dementia (bv-FTD). The behavioral changes may include characteristic stereotypic movements. These movements, although without clear purpose, are not involuntary. Involuntary...

  9. The UK10K project identifies rare variants in health and disease

    DEFF Research Database (Denmark)

    Walter, Klaudia; Min, Josine L.; Huang, Jie

    2015-01-01

    -marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive...

  10. Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases.

    Science.gov (United States)

    Hitomi, Yuki; Tokunaga, Katsushi

    2017-01-01

    Human genome variation may cause differences in traits and disease risks. Disease-causal/susceptible genes and variants for both common and rare diseases can be detected by comprehensive whole-genome analyses, such as whole-genome sequencing (WGS), using next-generation sequencing (NGS) technology and genome-wide association studies (GWAS). Here, in addition to the application of an NGS as a whole-genome analysis method, we summarize approaches for the identification of functional disease-causal/susceptible variants from abundant genetic variants in the human genome and methods for evaluating their functional effects in human diseases, using an NGS and in silico and in vitro functional analyses. We also discuss the clinical applications of the functional disease causal/susceptible variants to personalized medicine.

  11. OligoPVP: Phenotype-driven analysis of individual genomic information to prioritize oligogenic disease variants

    KAUST Repository

    Boudellioua, Imene; Kulmanov, Maxat; Schofield, Paul N; Gkoutos, Georgios V; Hoehndorf, Robert

    2018-01-01

    patient phenotypes to databases of gene-phenotype associations observed in clinical research can provide useful information and improve variant prioritization for Mendelian diseases. Additionally, background knowledge about interactions between genes can

  12. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

    Science.gov (United States)

    Blair, David R; Lyttle, Christopher S; Mortensen, Jonathan M; Bearden, Charles F; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H; Grossman, Robert L; Cox, Nancy J; White, Kevin P; Rzhetsky, Andrey

    2013-09-26

    Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

    NARCIS (Netherlands)

    Ellinghaus, David; Zhang, Hu; Zeissig, Sebastian; Lipinski, Simone; Till, Andreas; Jiang, Tao; Stade, Bjoern; Bromberg, Yana; Ellinghaus, Eva; Keller, Andreas; Rivas, Manuel A.; Skieceviciene, Jurgita; Doncheva, Nadezhda T.; Liu, Xiao; Liu, Qing; Jiang, Fuman; Forster, Michael; Mayr, Gabriele; Albrecht, Mario; Haesler, Robert; Boehm, Bernhard O.; Goodall, Jane; Berzuini, Carlo R.; Lee, James; Andersen, Vibeke; Vogel, Ulla; Kupcinskas, Limas; Kayser, Manfred; Krawczak, Michael; Nikolaus, Susanna; Weersma, Rinse K.; Ponsioen, Cyriel Y.; Sans, Miquel; Wijmenga, Cisca; Strachan, David P.; McAardle, Wendy L.; Vermeire, Severine; Rutgeerts, Paul; Sanderson, Jeremy D.; Mathew, Christopher G.; Vatn, Morten H.; Wang, Jun; Noethen, Markus M.; Duerr, Richard H.; Buening, Carsten; Brand, Stephan; Glas, Juergen; Winkelmann, Juliane; Illig, Thomas; Latiano, Anna; Annese, Vito; Halfvarson, Jonas; D'Amato, Mauro; Daly, Mark J.; Nothnagel, Michael; Karlsen, Tom H.; Subramani, Suresh; Rosenstiel, Philip; Schreiber, Stefan; Parkes, Miles; Franke, Andre

    BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through

  14. Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

    NARCIS (Netherlands)

    Ellinghaus, David; Zhang, Hu; Zeissig, Sebastian; Lipinski, Simone; Till, Andreas; Jiang, Tao; Stade, Björn; Bromberg, Yana; Ellinghaus, Eva; Keller, Andreas; Rivas, Manuel A.; Skieceviciene, Jurgita; Doncheva, Nadezhda T.; Liu, Xiao; Liu, Qing; Jiang, Fuman; Forster, Michael; Mayr, Gabriele; Albrecht, Mario; Häsler, Robert; Boehm, Bernhard O.; Goodall, Jane; Berzuini, Carlo R.; Lee, James; Andersen, Vibeke; Vogel, Ulla; Kupcinskas, Limas; Kayser, Manfred; Krawczak, Michael; Nikolaus, Susanna; Weersma, Rinse K.; Ponsioen, Cyriel Y.; Sans, Miquel; Wijmenga, Cisca; Strachan, David P.; McArdle, Wendy L.; Vermeire, Séverine; Rutgeerts, Paul; Sanderson, Jeremy D.; Mathew, Christopher G.; Vatn, Morten H.; Wang, Jun; Nöthen, Markus M.; Duerr, Richard H.; Büning, Carsten; Brand, Stephan; Glas, Jürgen; Winkelmann, Juliane; Illig, Thomas; Latiano, Anna; Annese, Vito; Halfvarson, Jonas; D'Amato, Mauro; Daly, Mark J.; Nothnagel, Michael; Karlsen, Tom H.; Subramani, Suresh; Rosenstiel, Philip; Schreiber, Stefan; Parkes, Miles; Franke, Andre

    2013-01-01

    Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed

  15. IL10 low-frequency variants in Behçet's disease patients.

    Science.gov (United States)

    Matos, Mafalda; Xavier, Joana M; Abrantes, Patrícia; Sousa, Inês; Rei, Nádia; Davatchi, Fereydoun; Shahram, Farhad; Jesus, Gorete; Barcelos, Filipe; Vedes, Joana; Salgado, Manuel; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Moraes-Fontes, Maria Francisca; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Vaz Patto, José; Crespo, Jorge; Oliveira, Sofia A

    2017-05-01

    To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7 kb genomic region encompassing the complete IL10 gene, 0.9 kb upstream and 2 kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  16. Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes.

    Science.gov (United States)

    Astuti, Galuh D N; van den Born, L Ingeborgh; Khan, M Imran; Hamel, Christian P; Bocquet, Béatrice; Manes, Gaël; Quinodoz, Mathieu; Ali, Manir; Toomes, Carmel; McKibbin, Martin; El-Asrag, Mohammed E; Haer-Wigman, Lonneke; Inglehearn, Chris F; Black, Graeme C M; Hoyng, Carel B; Cremers, Frans P M; Roosing, Susanne

    2018-01-10

    Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 ( SNRNP200 ) and Zinc Finger Protein 513 ( ZNF513 ), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 ( DHX32 ) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.

  17. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

    NARCIS (Netherlands)

    Robak, L.A.; Jansen, I.E.; Rooij, J van; Uitterlinden, A.G.; Kraaij, R.; Jankovic, J.; Heutink, P.; Shulman, J.M.; Bloem, B.; Post, B.; Scheffer, H.; Warrenburg, B.P.C. van de; et al.,

    2017-01-01

    Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The

  18. The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features

    NARCIS (Netherlands)

    Ossenkoppele, R.; Pijnenburg, Y.A.L.; Perry, D.C.; Cohn-Sheehy, B.I.; Scheltens, N.M.E.; Vogel, J.W.; Kramer, J.H.; van der Vlies, A.E.; La Joie, R.; Rosen, H.J.; van der Flier, W.M.; Grinberg, L.T.; Rozemuller, A.J.M.; Huang, E.J.; van Berckel, B.N.M.; Miller, B.L.; Barkhof, F.; Jagust, W.J.; Scheltens, P.; Seeley, W.W.; Rabinovici, G.D.

    2015-01-01

    A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical,

  19. GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

    Science.gov (United States)

    Jesús, Silvia; Huertas, Ismael; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

    2016-01-01

    The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

  20. GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

    Science.gov (United States)

    Jesús, Silvia; Huertas, Ismael; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

    2016-01-01

    The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants. PMID:28030538

  1. GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Silvia Jesús

    Full Text Available The presence of mutations in glucocerebrosidase (GBA gene is a known factor increasing the risk of developing Parkinson's disease (PD. Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021, earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013, as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

  2. Efficient utilization of rare variants for detection of disease-related genomic regions.

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2010-12-01

    Full Text Available When testing association between rare variants and diseases, an efficient analytical approach involves considering a set of variants in a genomic region as the unit of analysis. One factor complicating this approach is that the vast majority of rare variants in practical applications are believed to represent background neutral variation. As a result, analyzing a single set with all variants may not represent a powerful approach. Here, we propose two alternative strategies. In the first, we analyze the subsets of rare variants exhaustively. In the second, we categorize variants selectively into two subsets: one in which variants are overrepresented in cases, and the other in which variants are overrepresented in controls. When the proportion of neutral variants is moderate to large we show, by simulations, that the both proposed strategies improve the statistical power over methods analyzing a single set with total variants. When applied to a real sequencing association study, the proposed methods consistently produce smaller p-values than their competitors. When applied to another real sequencing dataset to study the difference of rare allele distributions between ethnic populations, the proposed methods detect the overrepresentation of variants between the CHB (Chinese Han in Beijing and YRI (Yoruba people of Ibadan populations with small p-values. Additional analyses suggest that there is no difference between the CHB and CHD (Chinese Han in Denver datasets, as expected. Finally, when applied to the CHB and JPT (Japanese people in Tokyo populations, existing methods fail to detect any difference, while it is detected by the proposed methods in several regions.

  3. Common genetic variants associated with thyroid function may be risk alleles for Hashimoto's disease and Graves' disease.

    Science.gov (United States)

    Campbell, Purdey; Brix, Thomas H; Wilson, Scott G; Ward, Lynley C; Hui, Jennie; Beilby, John P; Hegedüs, Laszlo; Walsh, John P

    2015-02-14

    Recent studies have identified common genetic variants associated with TSH, free T4 and thyroid peroxidase antibodies, but it is unclear whether these differ between patients with Hashimoto's disease and Graves' disease. To examine whether 11 common genetic variants differ between Graves' disease and Hashimoto's disease. We genotyped 11 common variants in a discovery cohort of 203 Australian patients with autoimmune thyroid disease (AITD). Two variants with significant or suggestive associations were analysed in a replication cohort of 384 Danish patients. For rs753760 (PDE10A), the minor allele frequency in Graves' disease and Hashimoto's disease was 0·38 vs. 0·23, respectively, (P = 6·42 × 10 -4 ) in the discovery cohort, 0·29 vs. 0·24 (P = 0·147) in the replication cohort and 0·32 vs. 0·24 in combined analysis (P = 0·0021; all analyses adjusted for sex). In healthy controls from Busselton, the frequency was 0·29, significantly different from Hashimoto's disease but not Graves' disease. For rs4889009 (MAF gene region), the frequency of the minor G-allele in Graves' disease and Hashimoto's disease was 0·48 vs. 0·36 (P = 0·0156) in the discovery cohort, 0·48 vs. 0·34 (P = 1·83 × 10 -4 ) in the replication cohort and 0·48 vs. 0·35 in the combined analysis (P = 7·53 × 10 -6 ); in controls, the frequency was 0·38, significantly different from Graves' disease but not Hashimoto's disease. After further adjustment for smoking, associations with rs4889009 remained significant, whereas those with rs753760 were not. Common variants in PDE10A and MAF gene regions may influence whether patients with AITD develop Graves' disease or Hashimoto's disease. © 2015 John Wiley & Sons Ltd.

  4. OligoPVP: Phenotype-driven analysis of individual genomic information to prioritize oligogenic disease variants

    KAUST Repository

    Boudellioua, Imene

    2018-05-02

    Purpose: An increasing number of Mendelian disorders have been identified for which two or more variants in one or more genes are required to cause the disease, or significantly modify its severity or phenotype. It is difficult to discover such interactions using existing approaches. The purpose of our work is to develop and evaluate a system that can identify combinations of variants underlying oligogenic diseases in individual whole exome or whole genome sequences. Methods: Information that links patient phenotypes to databases of gene-phenotype associations observed in clinical research can provide useful information and improve variant prioritization for Mendelian diseases. Additionally, background knowledge about interactions between genes can be utilized to guide and restrict the selection of candidate disease modules. Results: We developed OligoPVP, an algorithm that can be used to identify variants in oligogenic diseases and their interactions, using whole exome or whole genome sequences together with patient phenotypes as input. We demonstrate that OligoPVP has significantly improved performance when compared to state of the art pathogenicity detection methods. Conclusions: Our results show that OligoPVP can efficiently detect oligogenic interactions using a phenotype-driven approach and identify etiologically important variants in whole genomes.

  5. A Nondegenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

    DEFF Research Database (Denmark)

    Blair, David R.; Lyttle, Christopher S.; Mortensen, Jonathan M.

    2013-01-01

    Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to c...... of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases....

  6. Unusual Phenotype of the Brownell-Oppenheimer Variant of Sporadic Creutzfeldt-Jakob Disease

    Directory of Open Access Journals (Sweden)

    Dronacharya Lamichhane

    2016-03-01

    Full Text Available Creutzfeldt-Jakob disease is a rare, transmissible, neurodegenerative disease caused by conformationally changed abnormal prion protein. Most patients present with cognitive impairment, myoclonus, ataxia, visual impairment alone or in combination. Patients who present with ataxia only at the onset are said to have Brownell-Oppenheimer variant of the disease. However, here we present a case where visual symptoms preceded the clinical presentation and hallucinations accompanied the ataxia at the onset of the disease.

  7. Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia

    NARCIS (Netherlands)

    Cuyvers, Elise; Bettens, Karolien; Philtjens, Stephanie; Van Langenhove, Tim; Gijselinck, Ilse; van der Zee, Julie; Engelborghs, Sebastiaan; Vandenbulcke, Mathieu; Van Dongen, Jasper; Geerts, Nathalie; Maes, Githa; Mattheijssens, Maria; Peeters, Karin; Cras, Patrick; Vandenberghe, Rik; De Deyn, Peter P.; Van Broeckhoven, Christine; Cruts, Marc; Sleegers, Kristel

    Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOE epsilon 4. We

  8. Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease

    NARCIS (Netherlands)

    Yull, H.M.; Ritchie, D.L.; Langeveld, J.P.M.; Zijderveld, van F.G.; Bruce, M.E.; Ironside, J.W.; Head, M.W.

    2006-01-01

    Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably

  9. Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Douet, Jean Yves; Zafar, Saima; Perret-Liaudet, Armand; Lacroux, Caroline; Lugan, Séverine; Aron, Naima; Cassard, Herve; Ponto, Claudia; Corbière, Fabien; Torres, Juan Maria; Zerr, Inga; Andreoletti, Olivier

    2014-01-01

    We report the presence of infectivity in erythrocytes, leukocytes, and plasma of 1 person with variant Creutzfeldt-Jakob disease and in the plasma of 2 in 4 persons whose tests were positive for sporadic Creutzfeldt-Jakob disease. The measured infectivity levels were comparable to those reported in various animals with transmissible spongiform encephalopathies.

  10. Celiac disease : moving from genetic associations to causal variants

    NARCIS (Netherlands)

    Hrdlickova, B.; Westra, H-J; Franke, L.; Wijmenga, C.

    Genome-wide association studies are providing insight into the genetic basis of common complex diseases: more than 1150 genetic loci [2165 unique single nucleotide polymorphisms (SNPs)] have recently been associated to 159 complex diseases. The hunt for genes contributing to immune-related diseases

  11. Thyroid papillary carcinoma and histologic variants linked to Hashimoto disease

    OpenAIRE

    Neves Junior, Murilo Pedreira; Camandaroba, Marcos Pedro Guedes; Almeida, Marco Antônio Cardoso de; Miranda, Julia Souto

    2009-01-01

    INTRODUÇÃO E OBJETIVO: A associação entre o carcinoma papilífero da tireoide e suas variantes e a tireoidite de Hashimoto (TH) é bastante questionada no meio científico, pois compartilham diversos aspectos morfológicos, imuno-histoquímicos e biomoleculares. Os tumores da tireoide representam mais de 90% de todos os cânceres endócrinos e são caracterizados por alterações genéticas, entre as quais envolvem RET (rearranjos) e BRAS, RAS, P53 (mutações). Já a TH é uma doença autoimune, caracteriza...

  12. Identification of genetic variants associated with Huntington's disease progression

    DEFF Research Database (Denmark)

    Hensman Moss, Davina J; Pardiñas, Antonio F; Langbehn, Douglas

    2017-01-01

    indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers...... in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression......BACKGROUND: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate...

  13. Estimating the total number of susceptibility variants underlying complex diseases from genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Hon-Cheong So

    2010-11-01

    Full Text Available Recently genome-wide association studies (GWAS have identified numerous susceptibility variants for complex diseases. In this study we proposed several approaches to estimate the total number of variants underlying these diseases. We assume that the variance explained by genetic markers (Vg follow an exponential distribution, which is justified by previous studies on theories of adaptation. Our aim is to fit the observed distribution of Vg from GWAS to its theoretical distribution. The number of variants is obtained by the heritability divided by the estimated mean of the exponential distribution. In practice, due to limited sample sizes, there is insufficient power to detect variants with small effects. Therefore the power was taken into account in fitting. Besides considering the most significant variants, we also tried to relax the significance threshold, allowing more markers to be fitted. The effects of false positive variants were removed by considering the local false discovery rates. In addition, we developed an alternative approach by directly fitting the z-statistics from GWAS to its theoretical distribution. In all cases, the "winner's curse" effect was corrected analytically. Confidence intervals were also derived. Simulations were performed to compare and verify the performance of different estimators (which incorporates various means of winner's curse correction and the coverage of the proposed analytic confidence intervals. Our methodology only requires summary statistics and is able to handle both binary and continuous traits. Finally we applied the methods to a few real disease examples (lipid traits, type 2 diabetes and Crohn's disease and estimated that hundreds to nearly a thousand variants underlie these traits.

  14. Coffee, Genetic Variants, and Parkinson's Disease: Gene–Environment Interactions

    OpenAIRE

    Yamada-Fowler, Naomi; Söderkvist, Peter

    2015-01-01

    Studies of gene–environment interactions may help us to understand the disease mechanisms of common and complex diseases such as Parkinson's disease (PD). Sporadic PD, the common form of PD, is thought to be a multifactorial disorder caused by combinations of multiple genetic factors and environmental or life-style exposures. Since one of the most extensively studied life-style factors in PD is coffee/caffeine intake, here, the studies of genetic polymorphisms with life-style interactions of ...

  15. Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry.

    Science.gov (United States)

    Corradin, Olivia; Cohen, Andrea J; Luppino, Jennifer M; Bayles, Ian M; Schumacher, Fredrick R; Scacheri, Peter C

    2016-11-01

    SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs. Additionally, the clinical risk associated with GWAS SNPs is considerably modified by the genotype of outside variants. Collectively, these findings suggest a potential model in which outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability for complex traits.

  16. Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-01-01

    BACKGROUND Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. METHODS To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute

  17. Prions in the urine of patients with variant Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-08-07

    Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrP(Sc)). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt-Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt-Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. To investigate whether PrP(Sc) can be detected in the urine of patients with variant Creutzfeldt-Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrP(Sc), enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt-Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. PrP(Sc) was detectable only in the urine of patients with variant Creutzfeldt-Jakob disease and had the typical electrophoretic profile associated with this disease. PrP(Sc) was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt-Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrP(Sc) concentration in urine calculated by means of quantitative PMCA was estimated at 1×10(-16) g per milliliter, or 3×10(-21) mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrP(Sc) per milliliter of urine. Urine samples obtained from patients with variant Creutzfeldt-Jakob disease contained minute quantities of PrP(Sc). (Funded by the

  18. Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease

    DEFF Research Database (Denmark)

    Paludan-Müller, Christian; Ahlberg, Gustav; Ghouse, Jonas

    2017-01-01

    BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study...... sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database. METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias...... trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in Ex...

  19. The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease.

    Science.gov (United States)

    Duran, Raquel; Mencacci, Niccolo E; Angeli, Aikaterini V; Shoai, Maryam; Deas, Emma; Houlden, Henry; Mehta, Atul; Hughes, Derralynn; Cox, Timothy M; Deegan, Patrick; Schapira, Anthony H; Lees, Andrew J; Limousin, Patricia; Jarman, Paul R; Bhatia, Kailash P; Wood, Nicholas W; Hardy, John; Foltynie, Tom

    2013-02-01

    Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. Copyright © 2012 Movement Disorders Society.

  20. Peripheral Tissue Involvement in Sporadic, Iatrogenic, and Variant Creutzfeldt-Jakob Disease

    Science.gov (United States)

    Head, Mark W.; Ritchie, Diane; Smith, Nadine; McLoughlin, Victoria; Nailon, William; Samad, Sazia; Masson, Stephen; Bishop, Matthew; McCardle, Linda; Ironside, James W.

    2004-01-01

    Human prion diseases are rare fatal neurodegenerative conditions that occur as acquired, familial, or idiopathic disorders. A key event in their pathogenesis is the accumulation of an altered form of the prion protein, termed PrPSc, in the central nervous system. A novel acquired human prion disease, variant Creutzfeldt-Jakob disease, is thought to result from oral exposure to the bovine spongiform encephalopathy agent. This disease differs from other human prion diseases in its neurological, neuropathological, and biochemical phenotype. We have used immunohistochemistry and Western blot techniques to analyze the tissue distribution and biochemical properties of PrPSc in peripheral tissues in a unique series of nine cases of variant Creutzfeldt-Jakob disease. We have compared this with the distribution and biochemical forms found in all of the major subtypes of sporadic Creutzfeldt-Jakob disease and in a case of iatrogenic Creutzfeldt-Jakob disease associated with growth hormone therapy. The results show that involvement of the lymphoreticular system is a defining feature of variant Creutzfeldt-Jakob disease, but that the biochemical isoform of PrPSc found is influenced by the cell type in which it accumulates. PMID:14695328

  1. Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.

    Directory of Open Access Journals (Sweden)

    Katrina Soderquest

    2017-02-01

    Full Text Available The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21 specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

  2. Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.

    Science.gov (United States)

    Farfel, Jose M; Yu, Lei; Buchman, Aron S; Schneider, Julie A; De Jager, Philip L; Bennett, David A

    2016-08-02

    To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies. This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia. Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies. © 2016 American Academy of Neurology.

  3. Vitamin D Receptor Gene Variants in Parkinson's Disease Patients

    African Journals Online (AJOL)

    Rokhsareh Meamar

    2016-09-22

    Sep 22, 2016 ... c Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran ... polymorphisms, no significant difference in genotype or allele distribution was found between PD patients ... Parkinson's Disease Brain Bank criteria [16]. Then ... PD patients and 53 age-sex matched controls were chosen.

  4. Vitamin D receptor gene variants in Parkinson's disease patients ...

    African Journals Online (AJOL)

    Background: Vitamin D plays an important role in neurodegenerative disorders as a crucial neuro-immunomodulator. Accumulating data provide evidences that vitamin D receptor (VDR) gene is a candidate gene for susceptibility to Parkinson's disease (PD). Aim: To find out whether the risk of the development of sporadic ...

  5. Common and Rare Variant Association Study for Plasma Lipids and Coronary Artery Disease.

    Science.gov (United States)

    Tada, Hayato; Kawashiri, Masa-aki; Konno, Tetsuo; Yamagishi, Masakazu; Hayashi, Kenshi

    2016-01-01

    Blood lipid levels are highly heritable and modifiable risk factors for coronary artery disease (CAD), and are the leading cause of death worldwide. These facts have motivated human genetic association studies that have the substantial potential to define the risk factors that are causal and to identify pathways and therapeutic targets for lipids and CAD.The success of the HapMap project that provided an extensive catalog of human genetic variations and the development of microarray based genotyping chips (typically containing variations with allele frequencies > 5%) facilitated common variant association study (CVAS; formerly termed genome-wide association study, GWAS) identifying disease-associated variants in a genome-wide manner. To date, 157 loci associated with blood lipids and 46 loci with CAD have been successfully identified, accounting for approximately 12%-14% of heritability for lipids and 10% of heritability for CAD. However, there is yet a major challenge termed "missing heritability problem," namely the observation that loci detected by CVAS explain only a small fraction of the inferred genetic variations. To explain such missing portions, focuses in genetic association studies have shifted from common to rare variants. However, it is challenging to apply rare variant association study (RVAS) in an unbiased manner because such variants typically lack the sufficient number to be identified statistically.In this review, we provide a current understanding of the genetic architecture mostly derived from CVAS, and several updates on the progress and limitations of RVAS for lipids and CAD.

  6. Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

    Science.gov (United States)

    Lubbe, S J; Escott-Price, V; Brice, A; Gasser, T; Pittman, A M; Bras, J; Hardy, J; Heutink, P; Wood, N M; Singleton, A B; Grosset, D G; Carroll, C B; Law, M H; Demenais, F; Iles, M M; Bishop, D T; Newton-Bishop, J; Williams, N M; Morris, H R

    2016-12-01

    A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis

    DEFF Research Database (Denmark)

    Yazdanyar, Shiva; Weischer, Maren; Nordestgaard, Børge

    2009-01-01

    BACKGROUND: Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. METHODS: We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally...

  8. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

    NARCIS (Netherlands)

    Butterworth, A.S.; Braund, P.S.; Hardwick, R.J.; Saleheen, D.; Peden, J.F.; Soranzo, N.; Chambers, J.C.; Kleber, M.E.; Keating, B.; Qasim, A.; Klopp, N.; Erdmann, J.; Basart, H.; Baumert, J.H.; Bezzina, C.R.; Boehm, B.O.; Brocheton, J.; Bugert, P.; Cambien, F.; Collins, R.; Couper, D.; Jong, J.S. de; Diemert, P.; Ejebe, K.; Elbers, C.C.; Elliott, P.; Fornage, M.; Frossard, P.; Garner, S.; Hunt, S.E.; Kastelein, J.J.; Klungel, O.H.; Kluter, H.; Koch, K.; Konig, I.R.; Kooner, A.S.; Liu, K.; McPherson, R.; Musameh, M.D.; Musani, S.; Papanicolaou, G.; Peters, A.; Peters, B.J.; Potter, S.; Psaty, B.M.; Rasheed, A.; Scott, J.; Seedorf, U.; Sehmi, J.S.; Sotoodehnia, N.; Stark, K.; Stephens, J.; Schoot, C.E. van der; Schouw, Y.T. van der; Harst, P. van der; Vasan, R.S.; Wilde, A.A.; Willenborg, C.; Winkelmann, B.R.; Zaidi, M.; Zhang, W.; Ziegler, A.; Koenig, W.; Matz, W.; Trip, M.D.; Reilly, M.P.; Kathiresan, S.; Schunkert, H.; Hamsten, A.; Hall, A.S.; Kooner, J.S.; Thompson, S.G.; Thompson, J.R.; Watkins, H.; Danesh, J.; Barnes, T.; Rafelt, S.; Codd, V.; Bruinsma, N.; Dekker, L.R.; Henriques, J.P.; Koch, K.T.; Winter, R.J. de; Alings, M.; Allaart, C.F.; Gorgels, A.P.; Verheugt, F.W.A.; Mueller, M.; Meisinger, C.; DerOhannessian, S.; Mehta, N.N.; Ferguson, J.; Hakonarson, H.; Matthai, W.; Wilensky, R.; Hopewell, J.C.; Parish, S.; Linksted, P.; Notman, J.; Gonzalez, H.; Young, A.; Ostley, T.; Munday, A.; Goodwin, N.; Verdon, V.; Shah, S.; Edwards, C.; Mathews, C.; Gunter, R.; Benham, J.; Davies, C.; Cobb, M.; Cobb, L.; Crowther, J.; Richards, A.; Silver, M.; Tochlin, S.; Mozley, S.; Clark, S.; Radley, M.; Kourellias, K.; Olsson, P.; Barlera, S.; Tognoni, G.; Rust, S.; Assmann, G.; Heath, S.; Zelenika, D.; Gut, I.; Green, F.; Farrall, M.; Goel, A.; Ongen, H.; Franzosi, M.G.; Lathrop, M.; Clarke, R.; Aly, A.; Anner, K.; Bjorklund, K.; Blomgren, G.; Cederschiold, B.; Danell-Toverud, K.; Eriksson, P.; Grundstedt, U.; Heinonen, M.; Hellenius, M.L.; Hooft, F. van 't; Husman, K.; Lagercrantz, J.; Larsson, A.; Larsson, M.; Mossfeldt, M.; Malarstig, A.; Olsson, G.; Sabater-Lleal, M.; Sennblad, B.; Silveira, A.; Strawbridge, R.; Soderholm, B.; Ohrvik, J.; Zaman, K.S.; Mallick, N.H.; Azhar, M.; Samad, A.; Ishaq, M.; Shah, N.; Samuel, M.; Kathiresan, S.C.; Assimes, T.L.; Holm, H.; Preuss, M.; Stewart, A.F.; Barbalic, M.; Gieger, C.; Absher, D.; Aherrahrou, Z.; Allayee, H.; Altshuler, D.; Anand, S.; Andersen, K.; Anderson, J.L.; Ardissino, D.; Ball, S.G.; Balmforth, A.J.; Barnes, T.A.; Becker, L.C.; Becker, D.M.; Berger, K.; Bis, J.C.; Boekholdt, S.M.; Boerwinkle, E.; Brown, M.J.; Burnett, M.S.; Buysschaert, I.; Carlquist, J.F.; Chen, L.; Davies, R.W.; Dedoussis, G.; Dehghan, A.; Demissie, S.; Devaney, J.; Do, R.; Doering, A.; El Mokhtari, N.E.; Ellis, S.G.; Elosua, R.; Engert, J.C.; Epstein, S.; Faire, U. de; Fischer, M.; Folsom, A.R.; Freyer, J.; Gigante, B.; Girelli, D.; Gretarsdottir, S.; Gudnason, V.; Gulcher, J.R.; Tennstedt, S.; Halperin, E.; Hammond, N.; Hazen, S.L.; Hofman, A.; Horne, B.D.; Illig, T.; Iribarren, C.; Jones, G.T.; Jukema, J.W.; Kaiser, M.A.; Kaplan, L.M.; Khaw, K.T.; Knowles, J.W.; Kolovou, G.; Kong, A.; Laaksonen, R.; Lambrechts, D.; Leander, K.; Li, M.; Lieb, W.; Lettre, G.; Loley, C.; Lotery, A.J.; Mannucci, P.M.; Martinelli, N.; McKeown, P.P.; Meitinger, T.; Melander, O.; Merlini, P.A.; Mooser, V.; Morgan, T.; Muhleisen T.W., .; Muhlestein, J.B.; Musunuru, K.; Nahrstaedt, J.; Nothen, Markus; Olivieri, O.; Peyvandi, F.; Patel, R.S.; Patterson, C.C.; Qu, L.; Quyyumi, A.A.; Rader, D.J.; Rallidis, L.S.; Rice, C.; Roosendaal, F.R.; Rubin, D.; Salomaa, V.; Sampietro, M.L.; Sandhu, M.S.; Schadt, E.; Schafer, A.; Schillert, A.; Schreiber, S.; Schrezenmeir, J.; Schwartz, S.M.; Siscovick, D.S.; Sivananthan, M.; Sivapalaratnam, S.; Smith, A.V.; Smith, T.B.; Snoep, J.D.; Spertus, J.A.; Stefansson, K.; Stirrups, K.; Stoll, M.; Tang, W.H.; Thorgeirsson, G.; Thorleifsson, G.; Tomaszewski, M.; Uitterlinden, A.G.; Rij, A.M. van; Voight, B.F.; Wareham, N.J.; AWells, G.; Wichmann, H.E.; Witteman, J.C.; Wright, B.J.; Ye, S.; Cupples, L.A.; Quertermous, T.; Marz, W.; Blankenberg, S.; Thorsteinsdottir, U.; Roberts, R.; O'Donnell, C.J.; Onland-Moret, N.C.; Setten, J. van; Bakker, P.I. de; Verschuren, W.M.; Boer, J.M.; Wijmenga, C.; Hofker, M.H.; Maitland-van der Zee, A.H.; Boer, A. de; Grobbee, D.E.; Attwood, T.; Belz, S.; Cooper, J.; Crisp-Hihn, A.; Deloukas, P.; Foad, N.; Goodall, A.H.; Gracey, J.; Gray, E.; Gwilliams, R.; Heimerl, S.; Hengstenberg, C.; Jolley, J.; Krishnan, U.; Lloyd-Jones, H.; Lugauer, I.; Lundmark, P.; Maouche, S.; Moore, J.S.; Muir, D.; Murray, E.; Nelson, C.P.; Neudert, J.; Niblett, D.; O'Leary, K.; Ouwehand, W.H.; Pollard, H.; Rankin, A.; Rice, C.M.; Sager, H.; Samani, N.J.; Sambrook, J.; Schmitz, G.; Scholz, M.; Schroeder, L.; Syvannen, A.C.; Wallace, C.

    2011-01-01

    Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants.

  9. The UK10K project identifies rare variants in health and disease

    NARCIS (Netherlands)

    K. Walter (Klaudia); J.L. Min (Josine L.); J. Huang (Jie); L. Crooks (Lucy); Y. Memari (Yasin); S. McCarthy (Shane); J.R.B. Perry (John); C. Xu (Changjiang); M. Futema (Marta); D. Lawson (Daniel); V. Iotchkova (Valentina); S. Schiffels (Stephan); A.E. Hendricks (Audrey E.); P. Danecek (Petr); R. Li (Rui); J. Floyd (James); L.V. Wain (Louise); I.E. Barroso (Inês); S.E. Humphries (Steve); M.E. Hurles (Matthew); E. Zeggini (Eleftheria); J.C. Barrett (Jeffrey); V. Plagnol (Vincent); J.B. Richards (Brent); C.M.T. Greenwood (Celia); N.J. Timpson (Nicholas); R. Durbin (Richard); S. Bala (Senduran); P. Clapham (Peter); G. Coates (Guy); T. Cox (Tony); A. Daly (Allan); Y. Du (Yuanping); T. Edkins (Ted); P. Ellis (Peter); P. Flicek (Paul); X. Guo (Xiaosen); X. Guo (Xueqin); L. Huang (Liren); D.K. Jackson (David K.); C. Joyce (Chris); T. Keane (Thomas); A. Kolb-Kokocinski (Anja); C. Langford (Cordelia); Y. Li (Yingrui); J. Liang (Jieqin); H. Lin (Hong); R. Liu (Ryan); J. Maslen (John); D. Muddyman (Dawn); M.A. Quail (Michael A.); J. Stalker (Jim); J. Sun (Jianping); J. Tian (Jing); G. Wang (Guangbiao); J. Wang (Jun); Y. Wang (Yu); K. Wong (Kim); P. Zhang (Pingbo); E. Birney (Ewan); C. Boustred (Chris); L. Chen (Lu); G. Clement (Gail); M. Cocca (Massimiliano); G.D. Smith; I.N.M. Day (Ian N.M.); A.G. Day-Williams (Aaron); T. Down (Thomas); D.M. Dunham (David); D.M. Evans (David M.); T.R. Gaunt (Tom); M. Geihs (Matthias); D. Hart (Deborah); B. Howie (Bryan); T. Hubbard (Tim); P.G. Hysi (Pirro); Y. Jamshidi (Yalda); K.J. Karczewski (Konrad); J.P. Kemp (John); G. Lachance (Genevieve); M. Lek (Monkol); M.C. Lopes (Margarida); D.G. MacArthur (Daniel G.); J. Marchini (Jonathan); M. Mangino (Massimo); I. Mathieson (Iain); S. Metrustry (Sarah); A. Moayyeri (Alireza); K. Northstone (Kate); K. Panoutsopoulou (Kalliope); L. Paternoster (Lavinia); L. Quaye (Lydia); S. Ring (Susan); G.R.S. Ritchie (Graham R.S.); H.A. Shihab (Hashem A.); S.-Y. Shin (So-Youn); K.S. Small (Kerrin); M.S. Artigas; N. Soranzo (Nicole); L. Southam (Lorraine); T.D. Spector (Timothy); B. St Pourcain (Beate); G. Surdulescu (Gabriela); I. Tachmazidou (Ioanna); M.D. Tobin (Martin); A.M. Valdes; P.M. Visscher (Peter); K. Ward (Kirsten); S.G. Wilson (Scott); J. Yang (Joanna); F. Zhang (Feng); H.-F. Zheng (Hou-Feng); R. Anney (Richard); M. Ayub (Muhammad); D.H.R. Blackwood (Douglas); P.F. Bolton (Patrick F.); G. Breen (Gerome); D.A. Collier (David); N.J. Craddock (Nick); S. Curran (Sarah); D. Curtis (David); L. Gallagher (Louise); D. Geschwind (Daniel); H. Gurling (Hugh); P.A. Holmans (Peter A.); I. Lee (Irene); J. Lönnqvist (Jouko); P. McGuffin (Peter); A.M. McIntosh (Andrew); A.G. McKechanie (Andrew G.); A. McQuillin (Andrew); J. Morris (James); M.C. O'donovan (Michael); M.J. Owen (Michael); A. Palotie (Aarno); J.R. Parr (Jeremy R.); T. Paunio (Tiina); O.P.H. Pietiläinen (Olli); K. Rehnström (Karola); S.I. Sharp (Sally I.); D. Skuse (David); D. St. Clair (David); J. Suvisaari (Jaana); J.T. Walters (James); H.J. Williams (Hywel J.); E. Bochukova (Elena); R. Bounds (Rebecca); A. Dominiczak (Anna); I.S. Farooqi (I. Sadaf); J. Keogh (Julia); G. Marenne (Gaëlle); A.D. Morris (Andrew); S. O'Rahilly (Stephen); D.J. Porteous (David J.); B.H. Smith (Blair); E. Wheeler (Eleanor); S.H. Al Turki (Saeed); C. Anderson (Carl); D. Antony (Dinu); P.L. Beales (Philip); J. Bentham (Jamie); S. Bhattacharya (Shoumo); M. Calissano (Mattia); K. Carss (Keren); K. Chatterjee (Krishna); S. Cirak (Sebahattin); C. Cosgrove (Catherine); D.R. Fitzpatrick (David R.); A.R. Foley (A. Reghan); C.S. Franklin (Christopher S.); D. Grozeva (Detelina); H.M. Mitchison (Hannah M.); F. Muntoni; A. Onoufriadis (Alexandros); V. Parker (Victoria); F. Payne (Felicity); F.L. Raymond (F. Lucy); N. Roberts (Nicola); D.B. Savage (David); P.J. Scambler (Peter); M. Schmidts (Miriam); N. Schoenmakers (Nadia); R.K. Semple (Robert K.); E. Serra (Eva); O. Spasic-Boskovic (Olivera); E. Stevens (Elizabeth); M. Van Kogelenberg (Margriet); P. Vijayarangakannan (Parthiban); K.A. Williamson (Kathleen); C. Wilson (Crispian); T. Whyte (Tamieka); A. Ciampi (Antonio); K. Oualkacha (Karim); M. Bobrow (Martin); H. Griffin (Heather); J. Kaye (Jane); K. Kennedy (Karen); A. Kent (Alastair); C. Smee (Carol); R. Charlton (Ruth); R. Ekong (Rosemary); F. Khawaja (Farrah); L.R. Lopes (Luis R.); N. Migone (Nicola); S.J. Payne (Stewart J.); R.C. Pollitt (Rebecca C.); S. Povey (Sue); C.K. Ridout (Cheryl K.); R.L. Robinson (Rachel L.); R.H. Scott (Richard H.); A. Shaw (Adam); P. Syrris (Petros); R. Taylor (Rohan); A.M. Vandersteen (Anthony M.); A. Amuzu (Antoinette); J.P. Casas (Juan); J.C. Chambers (John); G.V. Dedoussis (George); G. Gambaro (Giovanni); P. Gasparini (Paolo); A. Isaacs (Aaron); J. Johnson (Jon); M.E. Kleber (Marcus); J.S. Kooner (Jaspal S.); C. Langenberg (Claudia); J. Luan; G. Malerba (Giovanni); W. März (Winfried); A. Matchan (Angela); R. Morris (Richard); B.G. Nordestgaard (Børge); M. Benn (Marianne); R.A. Scott (Robert); D. Toniolo (Daniela); M. Traglia (Michela); A. Tybjaerg-Hansen; C.M. van Duijn (Cornelia); E.M. van Leeuwen (Elisa); A. Varbo (Anette); P.H. Whincup (Peter); G. Zaza (Gianluigi); W. Zhang (Weihua)

    2015-01-01

    textabstractThe contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In

  10. Common variants in mendelian kidney disease genes and their association with renal function

    NARCIS (Netherlands)

    A. Parsa (Afshin); C. Fuchsberger (Christian); A. Köttgen (Anna); C.M. O'Seaghdha (Conall); C. Pattaro (Cristian); M. de Andrade (Mariza); D.I. Chasman (Daniel); A. Teumer (Alexander); K. Endlich (Karlhans); M. Olden (Matthias); M-H. Chen (Ming-Huei); A. Tin (Adrienne); Y-J. Kim (Yong-Jin); D. Taliun (Daniel); M. Li (Man); M.F. Feitosa (Mary Furlan); M. Gorski (Mathias); Q. Yang (Qiong); C. Hundertmark (Claudia); M.C. Foster (Michael); N. Glazer (Nicole); A.J. Isaacs (Aaron); M. Rao (Madhumathi); G.D. Smith; J.R. O´Connell; M.V. Struchalin (Maksim); T. Tanaka (Toshiko); G. Li (Guo); S.J. Hwang; E.J. Atkinson (Elizabeth); K. Lohman (Kurt); M. Cornelis (Marilyn); A. Johansson (Åsa); A. Tönjes (Anke); A. Dehghan (Abbas); V. Couraki (Vincent); E.G. Holliday (Elizabeth); R. Sorice; Z. Kutalik (Zoltán); T. Lehtimäki (Terho); T. Esko (Tõnu); H. Deshmukh (Harshal); S. Ulivi (Shelia); A.Y. Chu (Audrey); D. Murgia (Daniela); S. Trompet (Stella); M. Imboden (Medea); B. Kollerits (Barbara); G. Pistis (Giorgio); T.B. Harris (Tamara); L.J. Launer (Lenore); T. Aspelund (Thor); G. Eiriksdottir (Gudny); B.D. Mitchell (Braxton); E.A. Boerwinkle (Eric); H. Schmidt (Helena); E. Hofer (Edith); F.B. Hu (Frank); A. Demirkan (Ayşe); B.A. Oostra (Ben); S.T. Turner (Stephen); J. Ding (Jingzhong); J.S. Andrews (Jeanette); B.I. Freedman (Barry); F. Giulianini (Franco); W. Koenig (Wolfgang); T. Illig (Thomas); A. Döring (Angela); H.E. Wichmann (Heinz Erich); L. Zgaga (Lina); T. Zemunik (Tatijana); M. Boban (Mladen); C. Minelli (Cosetta); H.E. Wheeler (Heather); W. Igl (Wilmar); G. Zaboli (Ghazal); S.H. Wild (Sarah); A.F. Wright (Alan); H. Campbell (Harry); D. Ellinghaus (David); U. Nöthlings (Ute); G. Jacobs (Gunnar); R. Biffar (Reiner); F.D.J. Ernst (Florian); G. Homuth (Georg); H.K. Kroemer (Heyo); M. Nauck (Matthias); S. Stracke (Sylvia); U. Vol̈ker (Uwe); H. Völzke (Henry); P. Kovacs (Peter); M. Stumvoll (Michael); R. Mägi (Reedik); A. Hofman (Albert); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); Y.S. Aulchenko (Yurii); O. Polasek (Ozren); N. Hastie (Nick); V. Vitart (Veronique); C. Helmer (Catherine); J.J. Wang (Jie Jin); B. Stengel (Bernd); D. Ruggiero; S.M. Bergmann (Sven); M. Kähönen (Mika); J. Viikari (Jorma); T. Nikopensius (Tiit); M.A. Province (Mike); H.M. Colhoun (H.); A.S.F. Doney (Alex); A. Robino (Antonietta); B.K. Krämer (Bernhard); L. Portas (Laura); I. Ford (Ian); B.M. Buckley (Brendan M.); M. Adam (Martin); G.-A. Thun (Gian-Andri); B. Paulweber (Bernhard); M. Haun (Margot); C. Sala (Cinzia); P. Mitchell (Paul); M. Ciullo; P. Vollenweider (Peter); O. Raitakari (Olli); A. Metspalu (Andres); C.N.A. Palmer (Colin); P. Gasparini (Paolo); M. Pirastu (Mario); J.W. Jukema (Jan Wouter); N.M. Probst-Hensch (Nicole M.); F. Kronenberg (Florian); D. Toniolo (Daniela); V. Gudnason (Vilmundur); A.R. Shuldiner (Alan); J. Coresh (Josef); R. Schmidt (Reinhold); L. Ferrucci (Luigi); C.M. van Duijn (Cornelia); I.B. Borecki (Ingrid); S.L.R. Kardia (Sharon); Y. Liu (YongMei); G.C. Curhan (Gary); I. Rudan (Igor); U. Gyllensten (Ulf); J.F. Wilson (James); A. Franke (Andre); P.P. Pramstaller (Peter Paul); R. Rettig (Rainer); I. Prokopenko (Inga); J.C.M. Witteman (Jacqueline); C. Hayward (Caroline); P.M. Ridker (Paul); M. Bochud (Murielle); I.M. Heid (Iris); D.S. Siscovick (David); C.S. Fox (Caroline); W.H.L. Kao (Wen); C.A. Böger (Carsten)

    2013-01-01

    textabstractMany common genetic variants identified by genome-wide association studies for complex traitsmap to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with

  11. Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer's disease

    NARCIS (Netherlands)

    A. Hafkemeijer (Anne); C. Möller (Christiane); E.G.P. Dopper (Elise); L.C. Jiskoot (Lize); T.M. Schouten (Tijn M.); J.C. van Swieten (John); W.M. van der Flier (Wiesje); H. Vrenken (Hugo); Y. Pijnenburg (Yolande); F. Barkhof (Frederik); P. Scheltens (Philip); J. van der Grond (Jeroen); S.A.R.B. Rombouts (Serge)

    2015-01-01

    textabstractIntroduction: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. Early differentiation between both types of dementia may be challenging due to heterogeneity and overlap of symptoms. Here, we apply resting

  12. Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

    Science.gov (United States)

    Green, Nancy S.; Ender, Katherine L.; Pashankar, Farzana; Driscoll, Catherine; Giardina, Patricia J.; Mullen, Craig A.; Clark, Lorraine N.; Manwani, Deepa; Crotty, Jennifer; Kisselev, Sergey; Neville, Kathleen A.; Hoppe, Carolyn; Barral, Sandra

    2013-01-01

    Background Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. Methodology/Principal Findings In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. Conclusions/Significance These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease. PMID:23409025

  13. Common and Rare Genetic Variants Associated With Alzheimer's Disease.

    Science.gov (United States)

    Marei, Hany E; Althani, Asmaa; Suhonen, Jaana; El Zowalaty, Mohamed E; Albanna, Mohammad A; Cenciarelli, Carlo; Wang, Tengfei; Caceci, Thomas

    2016-07-01

    Alzheimer's disease (AD) is one of the most devastating disorders. Despite the continuing increase of its incidence among aging populations, no effective cure has been developed mainly due to difficulties in early diagnosis of the disease before damaging of the brain, and the failure to explore its complex underlying molecular mechanisms. Recent technological advances in genome-wide association studies (GWAS) and high throughput next generation whole genome, and exome sequencing had deciphered many of AD-related loci, and discovered single nucleotide polymorphisms (SNPs) that are associated with altered AD molecular pathways. Highlighting altered molecular pathways linked to AD pathogenesis is crucial to identify novel diagnostic and therapeutic AD targets. © 2015 Wiley Periodicals, Inc.

  14. Database for Parkinson Disease Mutations and Rare Variants

    Science.gov (United States)

    2016-09-01

    up to 26 candidate genes (June 2016). These searches have been time consuming and will continue past the end date of this award. As more data becomes...PD development. Learning Objectives: Define areas of new neuroscience knowledge and research Understand Clinicopathologic (CPC) correlations of...neurologic disease Illuminate areas of practice-based improvement within the neurosciences based on advancing scientific research or Practice- based

  15. Evidence of trem2 variant associated with triple risk of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Zainularifeen Abduljaleel

    Full Text Available Alzheimer's disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer's disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His. The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD simulation under salvation, the results confirmed that native form of the variant (Arg47His might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns, which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to "immunoglobulin V-set" and "immunoglobulin-like folds". Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer's disease.

  16. Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease

    DEFF Research Database (Denmark)

    Wittrup, Hans H; Andersen, Rolf V; Tybjaerg-Hansen, Anne

    2006-01-01

    Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD).......Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD)....

  17. Evaluation of the role of SNCA variants in survival without neurological disease.

    Directory of Open Access Journals (Sweden)

    Michael G Heckman

    Full Text Available A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease.We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33-99 years and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk.There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021, from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025. A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD.In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.

  18. Magnetic resonance in Pelizaeus Merzbacher disease: findings in three brothers presenting the connatal variant

    International Nuclear Information System (INIS)

    Saez, J.; Perez, F.; Fuster, M.J.; Marti, L.

    1997-01-01

    Pelizaeus Merzbacher disease is a rare hereditary disorder of the white matter that is characterized by nystagmic eye movements, head shaking and severe psychomotor retardation. We report the MR findings in three brothers presenting the connatal variant of the disease, which is characterized by a diffuse increase in signal intensity on T2-weighted sequences, involving the white matter of the CNS. (Author) 10 refs

  19. Splice Variant Biomarkers for Parkinson’s Disease

    Science.gov (United States)

    2014-05-01

    10.1210/en.2009-0996. Gupta, R.K., Kaestner, K.H. 2004. HNF-4alpha: from MODY to late-onset type 2 diabetes . Trends Mol Med 10(11), 521-4. doi...the common molecular pathways involved with PD and type 2 diabetes (T2DM). Using these networks, we identified APP, HNF4A and SOD2 mRNAs as blood...12-15 Santiago, J.A and Potashkin, J.A. Integrative network analysis unveils convergent molecular pathways in Parkinson’s disease and diabetes

  20. Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants.

    Directory of Open Access Journals (Sweden)

    Steven C Bagley

    2016-04-01

    Full Text Available Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford, and compared to a large database of published disease-associated genetic variants (VARIMED; data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups.

  1. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

    Science.gov (United States)

    Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong; Schaffner, Adam; Pankratz, Nathan; Hsu, Nai-Yun; Chuang, Ling-Shiang; Carmi, Shai; Villaverde, Nicole; Li, Xianting; Rivas, Manual; Levine, Adam P; Bao, Xiuliang; Labrias, Philippe R; Haritunians, Talin; Ruane, Darren; Gettler, Kyle; Chen, Ernie; Li, Dalin; Schiff, Elena R; Pontikos, Nikolas; Barzilai, Nir; Brant, Steven R; Bressman, Susan; Cheifetz, Adam S; Clark, Lorraine N; Daly, Mark J; Desnick, Robert J; Duerr, Richard H; Katz, Seymour; Lencz, Todd; Myers, Richard H; Ostrer, Harry; Ozelius, Laurie; Payami, Haydeh; Peter, Yakov; Rioux, John D; Segal, Anthony W; Scott, William K; Silverberg, Mark S; Vance, Jeffery M; Ubarretxena-Belandia, Iban; Foroud, Tatiana; Atzmon, Gil; Pe'er, Itsik; Ioannou, Yiannis; McGovern, Dermot P B; Yue, Zhenyu; Schadt, Eric E; Cho, Judy H; Peter, Inga

    2018-01-10

    Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10 -10 ) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10 -8 ). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  2. Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease

    Science.gov (United States)

    Chen, Haoyan; Hayashi, Genki; Lai, Olivia Y.; Dilthey, Alexander; Kuebler, Peter J.; Wong, Tami V.; Martin, Maureen P.; Fernandez Vina, Marcelo A.; McVean, Gil; Wabl, Matthias; Leslie, Kieron S.; Maurer, Toby; Martin, Jeffrey N.; Deeks, Steven G.; Carrington, Mary; Bowcock, Anne M.; Nixon, Douglas F.; Liao, Wilson

    2012-01-01

    An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis. PMID:22577363

  3. Magnetic resonance spectroscopic abnormalities in sporadic and variant Creutzfeldt-Jakob disease

    International Nuclear Information System (INIS)

    Pandya, H.G.; Coley, S.C.; Wilkinson, I.D.; Griffiths, P.D.

    2003-01-01

    AIM: To study the proton MR spectroscopic findings in Creutzfeldt-Jakob disease (CJD) (sporadic and variant). MATERIALS AND METHODS: MR imaging and proton MR spectra were acquired in two patients with sporadic CJD (biopsy proven) and one patient with variant CJD. RESULTS: The two patients with sporadic CJD demonstrated MR signal change within the basal ganglia and thalami and reduced N-acetylaspartate (NAA):creatine ratios. The patient with variant CJD showed characteristic signal change within the pulvinar of the thalami and a markedly reduced N-acetylaspartate:creatine ratio. CONCLUSION: All three patients with CJD demonstrated evidence of reduced N-acetylaspartate: creatine ratios on MR spectroscopy. These changes imply that neuronal loss and/or dysfunction is a consistent finding in established CJD. Pandya H. G., et al (2003) Clinical Radiology58, 148--153

  4. Magnetic resonance spectroscopic abnormalities in sporadic and variant Creutzfeldt-Jakob disease

    Energy Technology Data Exchange (ETDEWEB)

    Pandya, H.G.; Coley, S.C.; Wilkinson, I.D.; Griffiths, P.D

    2003-02-01

    AIM: To study the proton MR spectroscopic findings in Creutzfeldt-Jakob disease (CJD) (sporadic and variant). MATERIALS AND METHODS: MR imaging and proton MR spectra were acquired in two patients with sporadic CJD (biopsy proven) and one patient with variant CJD. RESULTS: The two patients with sporadic CJD demonstrated MR signal change within the basal ganglia and thalami and reduced N-acetylaspartate (NAA):creatine ratios. The patient with variant CJD showed characteristic signal change within the pulvinar of the thalami and a markedly reduced N-acetylaspartate:creatine ratio. CONCLUSION: All three patients with CJD demonstrated evidence of reduced N-acetylaspartate: creatine ratios on MR spectroscopy. These changes imply that neuronal loss and/or dysfunction is a consistent finding in established CJD. Pandya H. G., et al (2003) Clinical Radiology58, 148--153.

  5. Frontal variant of Alzheimer's disease and typical Alzheimer's disease: a comparative study

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    Bernardino Fernández-Calvo

    2013-01-01

    Full Text Available Clinical heterogeneity is one of the characteristics of Alzheimer's disease (AD. Hence, the atypical frontal or dysexecutive presentation is becoming increasingly well-known, although the underlying factors are still unknown. In this study, the neuropsychological performance of two groups of patients with AD (frontal variant--ADfv--and typical--TAD were compared. The ADfv group (n = 13 was selected due to the existence of frontal hypoperfusion on a simple photon emission computer tomography (SPECT. The results revealed that the ADfv group displayed a severe dysexecutive disorder, more severe neuropsychiatric symptomatology (disinhibition and apathy, more functional impairment, and it generated a higher caregiver overload than the TAD group without frontal impairment (n = 47. Despite the facts that the ADfv group's performance was poorer in all the neuropsychological tests, significant group differences were only found in the processing speed and visuoconstruction tasks. Logistic regression analysis revealed that the processing speed and mental flexibility scores significantly predicted a diagnosis of ADfv. The existence of the grasp reflex, anosognosia, and the absence of apolipoprotein E epsilon 4 allele (APOE e4 were also more prevalent in the ADfv group. This group had a predominance of males and it was more likely to have a positive family history of AD. To conclude, the study suggests that ADfv represents a subtype of AD that seems to have different clinical, neuropsychological, and genetic characteristics from TAD.

  6. A naturally occurring variant of the human prion protein completely prevents prion disease.

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    Asante, Emmanuel A; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D F; Collinge, John

    2015-06-25

    Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

  7. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3

    Science.gov (United States)

    Murthy, Aditya; Li, Yun; Peng, Ivan; Reichelt, Mike; Katakam, Anand Kumar; Noubade, Rajkumar; Roose-Girma, Merone; Devoss, Jason; Diehl, Lauri; Graham, Robert R.; van Lookeren Campagne, Menno

    2014-02-01

    Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.

  8. Genetic epidemiology of motor neuron disease-associated variants in the Scottish population.

    Science.gov (United States)

    Black, Holly A; Leighton, Danielle J; Cleary, Elaine M; Rose, Elaine; Stephenson, Laura; Colville, Shuna; Ross, David; Warner, Jon; Porteous, Mary; Gorrie, George H; Swingler, Robert; Goldstein, David; Harms, Matthew B; Connick, Peter; Pal, Suvankar; Aitman, Timothy J; Chandran, Siddharthan

    2017-03-01

    Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Genetic variants of CD209 associated with Kawasaki disease susceptibility.

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    Ho-Chang Kuo

    Full Text Available BACKGROUND: Kawasaki disease (KD is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209 in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. METHODS: A total of 948 subjects (381 KD and 567 controls were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804 were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL and intravenous immunoglobulin (IVIG treatment outcomes were collected for analysis. RESULTS: Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240 and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61 and G/A/G haplotype (P = 0.0365, OR = 1.52 had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. CONCLUSION: CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness.

  10. Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

    Science.gov (United States)

    Kuo, Ho-Chang; Huang, Ying-Hsien; Chien, Shu-Chen; Yu, Hong-Ren; Hsieh, Kai-Sheng; Hsu, Yu-Wen; Chang, Wei-Chiao

    2014-01-01

    Background Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. Methods A total of 948 subjects (381 KD and 567 controls) were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Results Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240) and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61) and G/A/G haplotype (P = 0.0365, OR = 1.52) had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. Conclusion CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness. PMID:25148534

  11. Evaluation of Parkinson disease risk variants as expression-QTLs.

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    Jeanne C Latourelle

    Full Text Available The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26 and controls (N = 24 by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for cis-acting effects on all probes within 250 kb of each locus. Trans-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of cis-acting SNP effects, several SNPs in the MAPT region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene LOC644246 and the duplicated genes LRRC37A and LRRC37A2, and a third uncorrelated probe targeting the gene DCAKD. Significant cis-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine trans effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8 × 10(-8 including SNPs from the SNCA, MAPT and RIT2 regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations.

  12. Exonic variants associated with development of aspirin exacerbated respiratory diseases.

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    Seung-Woo Shin

    Full Text Available Aspirin-exacerbated respiratory disease (AERD is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA, and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1 were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC of the receiver operating characteristic (ROC curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10-8 in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954 showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21, with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be "probably damaging" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

  13. Evaluation of Parkinson disease risk variants as expression-QTLs.

    Science.gov (United States)

    Latourelle, Jeanne C; Dumitriu, Alexandra; Hadzi, Tiffany C; Beach, Thomas G; Myers, Richard H

    2012-01-01

    The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for cis-acting effects on all probes within 250 kb of each locus. Trans-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of cis-acting SNP effects, several SNPs in the MAPT region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene LOC644246 and the duplicated genes LRRC37A and LRRC37A2, and a third uncorrelated probe targeting the gene DCAKD. Significant cis-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine trans effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8 × 10(-8)) including SNPs from the SNCA, MAPT and RIT2 regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations.

  14. Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.

    Science.gov (United States)

    Carrasquillo, Minerva M; Crook, Julia E; Pedraza, Otto; Thomas, Colleen S; Pankratz, V Shane; Allen, Mariet; Nguyen, Thuy; Malphrus, Kimberly G; Ma, Li; Bisceglio, Gina D; Roberts, Rosebud O; Lucas, John A; Smith, Glenn E; Ivnik, Robert J; Machulda, Mary M; Graff-Radford, Neill R; Petersen, Ronald C; Younkin, Steven G; Ertekin-Taner, Nilüfer

    2015-01-01

    We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

    Science.gov (United States)

    Nicolas, G; Charbonnier, C; Wallon, D; Quenez, O; Bellenguez, C; Grenier-Boley, B; Rousseau, S; Richard, A-C; Rovelet-Lecrux, A; Le Guennec, K; Bacq, D; Garnier, J-G; Olaso, R; Boland, A; Meyer, V; Deleuze, J-F; Amouyel, P; Munter, H M; Bourque, G; Lathrop, M; Frebourg, T; Redon, R; Letenneur, L; Dartigues, J-F; Génin, E; Lambert, J-C; Hannequin, D; Campion, D

    2016-06-01

    The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

  16. Novel P-TEN-induced putative kinase 1 (PINK1) variant in Indian Parkinson's disease patient.

    Science.gov (United States)

    Halder, Tamali; Raj, Janak; Sharma, Vivek; Das, Parimal

    2015-09-25

    Loss-of-function mutation in PINK1 is known for causing autosomal recessive early onset Parkinsonism accounting approximately 6.5% of PD cases. Recently, PINK1 has also been shown to cause Parkinson's disease (PD) in eastern India. Present study is aimed to see its contribution in north-Indian PD patients. A total of 106 PD patients and 60 ethnically matched healthy controls were included in the study. All the patients were screened for mutation in PINK1 by direct DNA sequence analysis of the PCR amplicons covering all exons and exon-intron boundaries. Identified novel variant was reconfirmed by DNA sequencing of 10 randomly selected TA clones containing the variant amplicon. In vitro functional assay of the mutant protein was performed by transfecting COS-7 cell line with wild type and mutant (created by site-directed-mutagenesis) cDNA construct of PINK1 fused to N' terminal GFP followed by western blot analysis. Two potentially pathogenic, one being novel (p.Q267X) and 6 other apparently non-pathogenic variants were identified. Western blot analysis reveals production of truncated PINK1 fusion protein of ∼55kDa in p.Q267X mutant instead of 82/93kDa of wild type PINK1 fusion protein (molecular weight of GFP is ∼27kDa). Our study concludes that PINK1 variants are prevalent for causing Parkinson's disease (PD) in India, as revealed by the occurrence of 1.8% (2/106) in PD patients from north Indian population. The novel homozygous variant of PINK1 (c.799C>T) reported here is the plausible cause for disease manifestation in this patient. Future study, however, would be helpful to understand the functional mechanism how this premature PINK1 protein (p.Q267X) responds to cellular stress leading to the PD pathophysiology. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Imaging pitfalls, normal anatomy, and anatomical variants that can simulate disease on cardiac imaging as demonstrated on multidetector computed tomography

    International Nuclear Information System (INIS)

    Terpenning, Silanath; White, Charles S

    2015-01-01

    Advances in computed tomography have led to continuous improvement in cardiac imaging. Dedicated postprocessing capabilities, faster scan times, and cardiac gating methods reveal details of normal cardiac anatomy and anatomic variants that can mimic pathologic conditions. This article will review normal cardiac anatomy and variants that can mimic disease. Radiologists should be familiar with normal cardiac anatomy and anatomic variants to avoid misinterpretation of normal findings for pathologic processes

  18. Detection and characterization of interleukin-6 gene variants in Canis familiaris: association studies with periodontal disease.

    Science.gov (United States)

    Morinha, Francisco; Albuquerque, Carlos; Requicha, João; Dias, Isabel; Leitão, José; Gut, Ivo; Guedes-Pinto, Henrique; Viegas, Carlos; Bastos, Estela

    2011-10-10

    Periodontal disease (PD) is the most common inflammatory disease of the oral cavity of domestic carnivores. In Human Medicine molecular genetics research showed that several genes play a role in the predisposition and progression of this complex disease, primarily through the regulation of inflammatory mediators, but the exactly mechanisms are poorly understood. This study aims to contribute to the characterization of the genetic basis of PD in the dog, a classically accepted model in Periodontology. We searched for genetic variations in the interleukin-6 (IL6) gene, in order to verify its association with PD in a case-control study including 25 dogs in the PD case group and 45 dogs in the control group. We indentified and characterized three new genetic variations in IL6 gene. No statistically significant differences were detected between the control and PD cases groups. Our results do not support an evidence for a major role contribution of these variants in the susceptibility to PD in the analyzed population. Nevertheless, the sequence variant I/5_g.105G>A leads to an amino acid change (arginine to glutamine) and was predicted to be possibly damaging to the IL6 protein. A larger cohort and functional studies would be of extreme importance in a near future to understand the possible role of IL6 variants in this disease. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

    Science.gov (United States)

    Lal, Dennis; Reinthaler, Eva M; Dejanovic, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M Arfan; van Duijn, Cornelia M; Uitterlinden, Andre G; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G; Cilio, Maria Roberta; Kunz, Wolfram S; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A

    2016-01-01

    The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

  20. Phlebographic variants of valvular insufficiency of deep veins in varicose disease of the lower limbs

    International Nuclear Information System (INIS)

    Firsov, E.F.; Gladkikh, V.G.; Lazarenko, V.A.; Shevelev, E.L.; Pashin, S.V.

    1995-01-01

    Analysis of clinical data and results of retrograde femoral and popliteal phlebographics in 108 patients with varicose disease of the lower limbs permitted the authors to propose a three-stage classification of valvular insufficiency of the deep veins and to demonstrate that the disease compensation stages are related to the presence and degree of retrograde blood flow. Analysis of retrograde phlebograms helped single out 8 variants of retrograde blood flow in the deep femoral veins and 12 variants in the deep veins of the shin with valvular insufficiency thereof, which is practically important for interpretation of x-ray findings and for the choice of the optimal method and volume of surgical correction of this vascular abnormality. 4 refs.; 5 figs

  1. Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

    Science.gov (United States)

    Bravo-Alonso, Irene; Navarrete, Rosa; Arribas-Carreira, Laura; Perona, Almudena; Abia, David; Couce, María Luz; García-Cazorla, Angels; Morais, Ana; Domingo, Rosario; Ramos, María Antonia; Swanson, Michael A; Van Hove, Johan L K; Ugarte, Magdalena; Pérez, Belén; Pérez-Cerdá, Celia; Rodríguez-Pombo, Pilar

    2017-06-01

    The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches. © 2017 Wiley Periodicals, Inc.

  2. Common variants in Mendelian kidney disease genes and their association with renal function.

    Science.gov (United States)

    Parsa, Afshin; Fuchsberger, Christian; Köttgen, Anna; O'Seaghdha, Conall M; Pattaro, Cristian; de Andrade, Mariza; Chasman, Daniel I; Teumer, Alexander; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Kim, Young J; Taliun, Daniel; Li, Man; Feitosa, Mary; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C; Glazer, Nicole; Isaacs, Aaron; Rao, Madhumathi; Smith, Albert V; O'Connell, Jeffrey R; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Hwang, Shih-Jen; Atkinson, Elizabeth J; Lohman, Kurt; Cornelis, Marilyn C; Johansson, Asa; Tönjes, Anke; Dehghan, Abbas; Couraki, Vincent; Holliday, Elizabeth G; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B; Launer, Lenore J; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D; Boerwinkle, Eric; Schmidt, Helena; Hofer, Edith; Hu, Frank; Demirkan, Ayse; Oostra, Ben A; Turner, Stephen T; Ding, Jingzhong; Andrews, Jeanette S; Freedman, Barry I; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H-Erich; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H; Wright, Alan F; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G; Rivadeneira, Fernando; Aulchenko, Yurii S; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K; Portas, Laura; Ford, Ian; Buckley, Brendan M; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J Wouter; Probst-Hensch, Nicole M; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; van Duijn, Cornelia M; Borecki, Ingrid; Kardia, Sharon L R; Liu, Yongmei; Curhan, Gary C; Rudan, Igor; Gyllensten, Ulf; Wilson, James F; Franke, Andre; Pramstaller, Peter P; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M; Bochud, Murielle; Heid, Iris M; Siscovick, David S; Fox, Caroline S; Kao, W Linda; Böger, Carsten A

    2013-12-01

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

  3. In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease

    NARCIS (Netherlands)

    van der Tol, Linda; Verhamme, Camiel; van Schaik, Ivo N.; van der Kooi, Anneke J.; Hollak, Carla E. M.; Biegstraaten, Marieke

    2016-01-01

    Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency due to pathogenic variants in the α-galactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite

  4. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus; Pipper, Christian Bressen; Tavendale, Roger

    2010-01-01

    Copenhagen Prospective Study on Asthma in Childhood (COPSAC) was one of the discovery cohorts of the association between eczema and variants in the filaggrin coding gene (FLG). Here, we study the FLG-associated risk of asthma symptoms in early life and describe the temporal relationship in the de......Copenhagen Prospective Study on Asthma in Childhood (COPSAC) was one of the discovery cohorts of the association between eczema and variants in the filaggrin coding gene (FLG). Here, we study the FLG-associated risk of asthma symptoms in early life and describe the temporal relationship...... diagnosed prospectively by the investigators. FLG variants R501X and Del4 were determined in 382 Caucasians. Filaggrin variants increased risk of developing recurrent wheeze, asthma and asthma exacerbations (hazard ratio 1.82 [1.06-3.12], p = 0.03), which was expressed within the first 1.5 yr of life...... fully in the first year of life (point prevalence ratio for age 0-5 was 1.75 [1.29-2.37]; p-value = 0.0003) contrasting the increased risk of specific sensitization by age 4 (odds ratio 3.52 [1.72-7.25], p = 0.0007) but not age 1.5. This study describes a FLG-associated pattern of atopic diseases...

  5. The D313Y variant in the GLA gene - no evidence of a pathogenic role in Fabry disease

    DEFF Research Database (Denmark)

    Hasholt, Lis; Ballegaard, Martin; Bundgaard, Henning

    2017-01-01

    Fabry disease is an X- linked inherited lysosomal storage disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A). The possible pathological significance of the D313Y variant in the GLA gene has not been verified and it may be a Fabry variant. Our......, and the presence in Fabry females did not significantly enhance the phenotype of a known causative mutation in the GLA gene (G271S). Our findings indicate that the D313Y variant is not causative to nor enhancing Fabry disease phenotype. The D313Y variant in the GLA gene was not disease causative in 2 Danish...... families. Investigating male family members were crucial in excluding the Fabry phenotype, and thus very important for proper genetic counceling of all family members, as well as overdiagnosing a devastating genetic disease....

  6. Incidence of sickle cell disease and other hemoglobin variants in 10,095 Lebanese neonates.

    Directory of Open Access Journals (Sweden)

    Evelyne Khoriaty

    Full Text Available Hemoglobinopathies are highly prevalent diseases and impose a public health burden. Early diagnosis and treatment can ameliorate the course of these diseases and improve survival. Despite purported high incidence of hemoglobinopathies in Lebanon, there are no nationwide screening programs. In this study, newborn screening utilizing high pressure liquid chromatography was executed in all public hospitals across Lebanon between 2010 and 2013. All newborns with an abnormal hemoglobin (Hb were offered genetic counseling and all those with disease were enrolled in comprehensive hemoglobinopathy clinics. Among newborns, 2.1% were found to have an abnormal Hb variant with sickle Hb being the most common while 0.1% were found to have sickle cell disease (SCD. The majority of those with SCD had non-Lebanese origins. The most common causes of hospitalizations in infants with SCD were acute splenic sequestration and pain crises. No bacteremia or other life threatening infections were noted. At a median follow up 14 months (follow up range 7 to 34 months, all children with disease are alive and compliant with treatment. Systematic screening for SCD and other Hb variants was shown to be feasible, cost effective, and of accurate predictive value. This program was also clinically effective because it led to the identification of babies with disease and to providing them with free early multidisciplinary care. Conclusively, a newborn screening program should be implemented across Lebanon to detect hemoglobinopathies and initiate early therapeutic and preventive strategies and genetic counseling.

  7. Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs.

    Directory of Open Access Journals (Sweden)

    Jonas Donner

    2018-04-01

    Full Text Available Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com, an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of

  8. New variant of Creutzfeldt-Jakob (vCJD) disease and other human prion diseases under epidemiological surveillance in Brazil

    OpenAIRE

    Gattás, Vera Lúcia; Lima Neto, Antonio Silva; Dimech, George Santiago; Mancini, Denise; Cantarino, Ligia Maria; Marins, José Ricardo Pio; Luna, Expedito José Albuquerque

    2007-01-01

    Abstract To increase the timeliness of detection of human cases of the new variant of Creutzfeldt-Jakob disease (vCJD) and to reduce the risk of transmission, the Brazilian Ministry of Health has established and standardized rules and control measures. These include the definition of criteria for suspect cases, reporting, monitoring, and control measures for illness prevention and transmission. Guidelines to be used by the team of health care staff were published and distributed to health wor...

  9. Functional study of DAND5 variant in patients with Congenital Heart Disease and laterality defects.

    Science.gov (United States)

    Cristo, Fernando; Inácio, José M; de Almeida, Salomé; Mendes, Patrícia; Martins, Duarte Saraiva; Maio, José; Anjos, Rui; Belo, José A

    2017-07-24

    Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Indeed, in the last decade, it has been reported that the etiology of isolated cases of CHDs or cases of laterality defects with associated CHDs is linked with variants of genes involved in the Nodal signaling pathway. With this in mind, we analyzed a cohort of 38 unrelated patients with Congenital Heart Defects that can arise from initial perturbations in the formation of the Left-Right axis and 40 unrelated ethnically matched healthy individuals as a control population. Genomic DNA was extracted from buccal epithelial cells, and variants screening was performed by PCR and direct sequencing. A Nodal-dependent luciferase assay was conducted in order to determine the functional effect of the variant found. In this work, we report two patients with a DAND5 heterozygous non-synonymous variant (c.455G > A) in the functional domain of the DAND5 protein (p.R152H), a master regulator of Nodal signaling. Patient 1 presents left isomerism, ventricular septal defect with overriding aorta and pulmonary atresia, while patient 2 presents ventricular septal defect with overriding aorta, right ventricular hypertrophy and pulmonary atresia (a case of extreme tetralogy of Fallot phenotype). The functional analysis assay showed a significant decrease in the activity of this variant protein when compared to its wild-type counterpart. Altogether, our results provide new insight into the molecular mechanism of the laterality defects and related CHDs, priming for the first time DAND5 as one of multiple candidate determinants for CHDs in humans.

  10. The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease

    Science.gov (United States)

    Gan, Earn H; MacArthur, Katie; Mitchell, Anna L; Pearce, Simon H S

    2012-01-01

    Background Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD. Method We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products. Results A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS). Conclusion We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect. PMID:23011869

  11. Variants of Interleukin-22 Gene Confer Predisposition to Autoimmune Thyroid Disease

    Directory of Open Access Journals (Sweden)

    Rong-hua Song

    2017-01-01

    Full Text Available As there are no previous studies on the interleukin-22 (IL-22 variants in autoimmune thyroid disease (AITD, the present study aimed to explore the association between polymorphisms of IL-22 and the predisposition to AITD. The study had 975 AITD patients, including 639 Graves’ disease (GD and 336 Hashimoto’s thyroiditis (HT individuals and 851 healthy cohorts. Ligase detection reaction (LDR and direct sequencing method were used for genotyping the IL-22 gene polymorphisms at rs2046068, rs2227478, rs2227485, rs11611206, and rs1179251. In comparison to female controls, genotype CC of rs1179251 was increased in the female AITD patients. Alleles C at rs2046068, C at rs2227478, and C at rs1179251 linked to the susceptibility of HT males. Genotype CC in rs1179251 was higher in male HT. Variants at rs2046068, rs2227478, and rs1179251 were associated with the AITD teenagers. Besides, genotype GG in rs11611206 was correlated with thyroid-associated ophthalmopathy (TAO. Moreover, allele G at rs11611206 was associated with decreased risk for TAO by 28.9%. Similarly, genotype CC of rs1179251 and genotype GG of rs11611206 were associated with Graves’ ophthalmopathy (GO. Allele G in rs11611206 increased people with HT towards the predisposition of hypothyroidism. In conclusion, genetic variants of IL-22 are associated with the occurrence of AITD.

  12. Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

    DEFF Research Database (Denmark)

    Ellinghaus, David; Zhang, Hu; Zeissig, Sebastian

    2013-01-01

    BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through...... detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico...... mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare...

  13. PANTHER-PSEP: predicting disease-causing genetic variants using position-specific evolutionary preservation.

    Science.gov (United States)

    Tang, Haiming; Thomas, Paul D

    2016-07-15

    PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease. Several previous variant pathogenicity prediction methods have been proposed that quantify evolutionary conservation among homologous proteins from different organisms. PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors. Here, we describe the PSEP tool, and assess its performance on standard benchmarks for distinguishing disease-associated from neutral variation in humans. On these benchmarks, PSEP outperforms not only previous tools that utilize evolutionary conservation, but also several highly used tools that include multiple other sources of information as well. For predicting pathogenic human variants, the trace back of course starts with a human 'reference' protein sequence, but the PSEP tool can also be applied to predicting deleterious or pathogenic variants in reference proteins from any of the ∼100 other species in the PANTHER database. PANTHER-PSEP is freely available on the web at http://pantherdb.org/tools/csnpScoreForm.jsp Users can also download the command-line based tool at ftp://ftp.pantherdb.org/cSNP_analysis/PSEP/ CONTACT: pdthomas@usc.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Geographical distribution of complement receptor type 1 variants and their associated disease risk.

    Directory of Open Access Journals (Sweden)

    Thaisa Lucas Sandri

    Full Text Available Pathogens exert selective pressure which may lead to substantial changes in host immune responses. The human complement receptor type 1 (CR1 is an innate immune recognition glycoprotein that regulates the activation of the complement pathway and removes opsonized immune complexes. CR1 genetic variants in exon 29 have been associated with expression levels, C1q or C3b binding and increased susceptibility to several infectious diseases. Five distinct CR1 nucleotide substitutions determine the Knops blood group phenotypes, namely Kna/b, McCa/b, Sl1/Sl2, Sl4/Sl5 and KCAM+/-.CR1 variants were genotyped by direct sequencing in a cohort of 441 healthy individuals from Brazil, Vietnam, India, Republic of Congo and Ghana.The distribution of the CR1 alleles, genotypes and haplotypes differed significantly among geographical settings (p≤0.001. CR1 variants rs17047660A/G (McCa/b and rs17047661A/G (Sl1/Sl2 were exclusively observed to be polymorphic in African populations compared to the groups from Asia and South-America, strongly suggesting that these two SNPs may be subjected to selection. This is further substantiated by a high linkage disequilibrium between the two variants in the Congolese and Ghanaian populations. A total of nine CR1 haplotypes were observed. The CR1*AGAATA haplotype was found more frequently among the Brazilian and Vietnamese study groups; the CR1*AGAATG haplotype was frequent in the Indian and Vietnamese populations, while the CR1*AGAGTG haplotype was frequent among Congolese and Ghanaian individuals.The African populations included in this study might have a selective advantage conferred to immune genes involved in pathogen recognition and signaling, possibly contributing to disease susceptibility or resistance.

  15. Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

    DEFF Research Database (Denmark)

    Gusev, Alexander; Lee, S Hong; Trynka, Gosia

    2014-01-01

    Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common...... diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach...... partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment...

  16. HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease

    Science.gov (United States)

    Ali-Rahmani, Fatima; Schengrund, Cara-Lynne; Connor, James R.

    2014-01-01

    Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer’s disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases. PMID:25071582

  17. HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease.

    Science.gov (United States)

    Ali-Rahmani, Fatima; Schengrund, Cara-Lynne; Connor, James R

    2014-01-01

    Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer's disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.

  18. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

    Directory of Open Access Journals (Sweden)

    Dennis Lal

    Full Text Available The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic.We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients.We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%. Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1 are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test, previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

  19. The Number of Candidate Variants in Exome Sequencing for Mendelian Disease under No Genetic Heterogeneity

    Directory of Open Access Journals (Sweden)

    Jo Nishino

    2013-01-01

    Full Text Available There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of “no genetic heterogeneity.” All variants were assumed to be under the “null model,” and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N=20, 50, filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no “genetic heterogeneity” is appropriate and could provide general guidelines for sample size determination.

  20. SNCA 3'UTR genetic variants in patients with Parkinson's disease and REM sleep behavior disorder.

    Science.gov (United States)

    Toffoli, M; Dreussi, E; Cecchin, E; Valente, M; Sanvilli, N; Montico, M; Gagno, S; Garziera, M; Polano, M; Savarese, M; Calandra-Buonaura, G; Placidi, F; Terzaghi, M; Toffoli, G; Gigli, G L

    2017-07-01

    REM sleep behavior disorder (RBD) is an early marker of Parkinson's disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3'UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD. We recruited 113 consecutive patients with a diagnosis of iRBD (56 patients) or PD (with or without RBD, 57 patients). Sequencing of SNCA-3'UTR was performed on genomic DNA extracted from peripheral blood samples. Bioinformatic analyses were carried out to predict the potential effect of the identified genetic variants on microRNA binding. We found three SNCA-3'UTR SNPs (rs356165, rs3857053, rs1045722) to be more frequent in PD patients than in iRBD patients (p = 0.014, 0.008, and 0.008, respectively). Four new or previously reported but not annotated specific genetic variants (KP876057, KP876056, NM_000345.3:c*860T>A, NM_000345.3:c*2320A>T) have been observed in the RBD population. The in silico approach highlighted that these variants could affect microRNA-mediated gene expression control. Our data show specific SNPs in the SNCA-3'UTR that may bear a risk for RBD to be associated with PD. Moreover, new genetic variants were identified in patients with iRBD.

  1. Functional paraoxonase 1 variants modify the risk of Parkinson's disease due to organophosphate exposure.

    Science.gov (United States)

    Lee, Pei-Chen; Rhodes, Shannon L; Sinsheimer, Janet S; Bronstein, Jeff; Ritz, Beate

    2013-06-01

    We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants. From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California. We genotyped three well-known functional PON1 SNPs: two exonic polymorphisms (PON1L55M and PON1Q192R) and the promoter region variant (PON1C-108T). Ambient exposures to diazinon, chlorpyrifos, and parathion at residential and workplace addresses were assessed using a validated geographic information system-based model incorporating records of agricultural pesticide applications in California. The odds ratio (OR) for Caucasians exposed to OPs at either residential or workplace addresses varied by PON1 genotype; for exposed carriers of the "faster" metabolizer genotypes, ML or LL, we estimated lower odds ratios (range, 1.20-1.39) than for exposed carriers of the "slower" metabolizer genotype MM (range, 1.78-2.45) relative to unexposed carriers of the faster genotypes. We observed similarly increased ORs for exposure across PON1Q192R genotypes, but no differences across PON1C-108T genotypes. The largest ORs were estimated for exposed carriers of both PON1192QQ and PON155MM (OR range, 2.84-3.57). Several functional PON1 variants may act together to modify PD risk for ambient OP exposures. While either PON1L55M or PON1Q192R may be sufficient to identify increased susceptibility, carriers of both slow metabolizer variants seem most susceptible to OP exposures. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

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    Robin G Walters

    Full Text Available The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25, we had sufficient statistical power to detect the large majority (80% of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4 (95% confidence interval [9.6×10(-5-3.1×10(-4]; accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10; odds ratio = 25.0 [9.9-60.6]; and results in a mean body mass index (BMI increase of 5.8 kg.m(-2 [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially

  3. Association between Age at Diagnosis of Graves' Disease and Variants in Genes Involved in Immune Response

    Science.gov (United States)

    Jurecka-Lubieniecka, Beata; Ploski, Rafal; Kula, Dorota; Krol, Aleksandra; Bednarczuk, Tomasz; Kolosza, Zofia; Tukiendorf, Andrzej; Szpak-Ulczok, Sylwia; Stanjek-Cichoracka, Anita; Polanska, Joanna; Jarzab, Barbara

    2013-01-01

    Background Graves' disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. The aim of the study was to examine the association between genetic variants in genes encoding proteins involved in immune response and the age at diagnosis of GD. Methods 735 GD patients and 1216 healthy controls from Poland were included into the study. Eight genetic variants in the HLA-DRB1, TNF, CTLA4, CD40, NFKb, PTPN22, IL4 and IL10 genes were genotyped. Patients were stratified by the age at diagnosis of GD and the association with genotype was analysed. Results Polymorphism in the HLA-DRB1, TNF and CTLA4 genes were associated with GD. The carriers of the HLA DRB1*03 allele were more frequent in patients with age at GD diagnosis ≤30 years than in patients with older age at GD diagnosis. Conclusions HLADRB1*03 allele is associated with young age at diagnosis of Graves' disease in polish population. PMID:23544060

  4. Coronary artery disease-associated genetic variants and biomarkers of inflammation

    DEFF Research Database (Denmark)

    Christiansen, Morten Krogh; Larsen, Sanne Bøjet; Nyegaard, Mette

    2017-01-01

    score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. RESULTS:The minor allele (G) (CAD risk allele) of rs2075650......INTRODUCTION:Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD...

  5. Analysis of IL12B gene variants in inflammatory bowel disease.

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    Jürgen Glas

    Full Text Available BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD. However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD and ulcerative colitis (UC. Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695. Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066 and UC (OR 1.18 [0.97-1.43], p = 0.092. CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5; OR = 2.84, 95% CI 1.66-4.84, while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92. In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694 in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05 but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE: The IL12B SNP rs6887695

  6. Analysis of IL12B Gene Variants in Inflammatory Bowel Disease

    Science.gov (United States)

    Wagner, Johanna; Olszak, Torsten; Fries, Christoph; Tillack, Cornelia; Friedrich, Matthias; Beigel, Florian; Stallhofer, Johannes; Steib, Christian; Wetzke, Martin; Göke, Burkhard; Ochsenkühn, Thomas; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

    2012-01-01

    Background IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. Methodology/Principal Findings We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01–1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99–1.31], p = 0.066) and UC (OR 1.18 [0.97–1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10−5; OR = 2.84, 95% CI 1.66–4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14–0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. Conclusions/Significance The IL12B SNP rs6887695 modulates

  7. Strategies for Enriching Variant Coverage in Candidate Disease Loci on a Multiethnic Genotyping Array.

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    Stephanie A Bien

    Full Text Available Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II, Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328, Hispanic/Latino (22,379, Asian/Pacific Islander (8,640, and American Indian (653 and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease.

  8. A rare variant of α 1 antitrypsin mutations detected in Vietnamese children with liver disease.

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    Hoàng, Thu Hà; Phạm, Thiên Ngọc; Nguyễn, Gia Khánh; Lê, Quang Huấn

    2013-07-01

    Alpha 1 antitrypsin (A1AT) is the major plasma serine protease inhibitor that is produced in liver cells. A1AT deficiency is recognized globally as a common genetic cause of liver disease in children, which results from mutations in the SERine Protease INhibitor A1 (SERPINA1) gene. The importance of A1AT deficiency in Viet Nam is unclear. The aim of this study was to determine the A1AT variants present in paediatric patients with liver diseases in order to clarify whether A1AT deficiency is present in Viet Nam. A1AT studies were carried out in 130 children with liver disease of indeterminate aetiology. A1AT levels were determined by immunoturbidimetry. Phenotype analysis of A1AT was performed by isoelectric focusing (IEF) in all patients. Genotype analyses to determine A1AT mutations were performed by direct sequencing. We identified a rare variant of A1AT named Zbristol. The Zbristol appeared to be deficient in the plasma to about the same degree as the PI S protein resulting in low concentration of A1AT in one of these two Vietnamese patients. No other deficient A1AT allele was detected, although 11 patients (8.5%) showed a reduced serum concentration of A1AT. These are the first two cases of a rare A1AT deficiency allele to be found in Viet Nam clearly inferring that A1AT deficiency is not just a disease of Caucasians. As such, the laboratory diagnosis of A1AT deficiency including A1AT concentration determination and phenotype and genotype testing should form part of the routine differential diagnosis of paediatric liver disease of indeterminate aetiology in Vietnamese patients.

  9. MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Rips, Jonathan; Meyer-Schuman, Rebecca; Breuer, Oded; Tsabari, Reuven; Shaag, Avraham; Revel-Vilk, Shoshana; Reif, Shimon; Elpeleg, Orly; Antonellis, Anthony; Harel, Tamar

    2018-04-12

    Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  10. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Bishop, Matthew T; Diack, Abigail B; Ritchie, Diane L; Ironside, James W; Will, Robert G; Manson, Jean C

    2013-04-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt-Jakob disease. Three cases of variant Creutzfeldt-Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt-Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt-Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt-Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt-Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt-Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt-Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen

  11. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt–Jakob disease

    Science.gov (United States)

    Bishop, Matthew T.; Diack, Abigail B.; Ritchie, Diane L.; Ironside, James W.; Will, Robert G.

    2013-01-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt–Jakob disease. Three cases of variant Creutzfeldt–Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt–Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt–Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt–Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt–Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt–Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt–Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and

  12. Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases.

    Science.gov (United States)

    Yan, Jin; Feng, Jinong; Craddock, Nick; Jones, Ian R; Cook, Edwin H; Goldman, David; Heston, Leonard L; Chen, Jiesheng; Burkhart, Patricia; Li, Wenyan; Shibayama, Akane; Sommer, Steve S

    Intriguing parallels have been noted previously between the biology of Vitamin D and the epidemiology of schizophrenia. We have scanned the Vitamin D receptor (VDR) gene by DOVAM-S (Detection of Virtually All Mutations-SSCP), a robotically enhanced multiplexed scanning method. In total, 100 patients with schizophrenia (86 Caucasians and 14 African-Americans) were scanned. In addition, pilot experiments were performed in patients with bipolar disorder (BPD) (24), autism (24), attention deficit hyperactivity disorder (ADHD) (24), and alcoholism (20). A total of 762 kb of the VDR genomic sequence was scanned. R208N and V339I were each found in one African-American patient, while absent in 35 African-American controls without schizophrenia (2/14 versus 0/35, P=0.08). Within the power of the study (> or =1.6-fold relative risk), the common M1T variant is not associated with schizophrenia. In the 92 scanned patients with other psychiatric diseases, R173S was found in a single patient with bipolar disorder. In conclusion, we describe three novel structural variants of the Vitamin D receptor. Further study is required to clarify their role, if any, in psychiatric disease.

  13. Genetic mapping and exome sequencing identify variants associated with five novel diseases.

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    Erik G Puffenberger

    Full Text Available The Clinic for Special Children (CSC has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain children. Among the Plain people, we have used single nucleotide polymorphism (SNP microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb that contain many genes (mean = 79. For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

  14. The First Report of a Patient with Probable Variant Creutzfeldt-Jakob Disease in Turkey

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    Demet Özbabalık Adapınar

    2011-12-01

    Full Text Available Variant Creutzfeldt-Jakob disease (vCJD was first reported in the UK in 1996. Here, we report the first Turkish case of vCJD. A 47-year-old man, who has never lived outside of Turkey and had had no transfusion, was admitted to the University Hospital with speech disorder, cognitive decline and ataxia following depression, irritability, and personality change. The immunoassay of the 14-3-3 protein in the cerebrospinal fluid was negative. Brain magnetic resonance imaging revealed high-signal lesions involving the bilateral caudate and lentiform nucleus on T2- and diffusion-weighted imaging. The patient developed akinetic mutism 10 months after disease onset. The clinical presentation and neuroimaging findings were compatible with the vCJD cases reported since 1996 and met the World Health Organization’s case definition for probable vCJD.

  15. Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

    Science.gov (United States)

    Maheshwari, Atul; Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D; Maddox, Ryan A; Mead, Simon; Goodman, Clay; Kass, Joseph S; Schonberger, Lawrence B; Hussein, Haitham M

    2015-05-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.

  16. Heterozygous genotype at codon 129 correlates with prolonged disease course in Heidenhain variant sporadic CJD: case report.

    Science.gov (United States)

    Townley, Ryan A; Dawson, Elliot T; Drubach, Daniel A

    2018-02-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.

  17. Similarities of Variant Creutzfeldt-Jakob Disease Strain in Mother and Son in Spain to UK Reference Case.

    Science.gov (United States)

    Diack, Abigail B; Boyle, Aileen; Ritchie, Diane; Plinston, Chris; Kisielewski, Dorothy; de Pedro-Cuesta, Jesús; Rábano, Alberto; Will, Robert G; Manson, Jean C

    2017-09-01

    We investigated transmission characteristics of variant Creutzfeldt-Jakob disease in a mother and son from Spain. Despite differences in patient age and disease manifestations, we found the same strain properties in these patients as in UK vCJD cases. A single strain of agent appears to be responsible for all vCJD cases to date.

  18. A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia.

    Science.gov (United States)

    Coulthart, Michael B; Geschwind, Michael D; Qureshi, Shireen; Phielipp, Nicolas; Demarsh, Alex; Abrams, Joseph Y; Belay, Ermias; Gambetti, Pierluigi; Jansen, Gerard H; Lang, Anthony E; Schonberger, Lawrence B

    2016-10-01

    As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease-the human form of a prion disease of cattle, bovine spongiform encephalopathy-have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980-96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient's life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient's residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual's dates of birth and symptom onset ('lifetime'), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and

  19. Epstein-Barr virus strains and variations: Geographic or disease-specific variants?

    Science.gov (United States)

    Neves, Marco; Marinho-Dias, Joana; Ribeiro, Joana; Sousa, Hugo

    2017-03-01

    The Epstein-Barr Virus (EBV) is associated with the development of several diseases, including infectious mononucleosis (IM), Burkitt's Lymphoma (BL), Nasopharyngeal Carcinoma, and other neoplasias. The publication of EBV genome 1984 led to several studies regarding the identification of different viral strains. Currently, EBV is divided into EBV type 1 (B95-8 strain) and EBV type 2 (AG876 strain), also known as type A and type B, which have been distinguished based upon genetic differences in the Epstein-Barr nuclear antigens (EBNAs) sequence. Several other EBV strains have been described in the past 10 years considering variations on EBV genome, and many have attempted to clarify if these variations are ethnic or geographically correlated, or if they are disease related. Indeed, there is an increasing interest to describe possible specific disease associations, with emphasis on different malignancies. These studies aim to clarify if these variations are ethnic or geographically correlated, or if they are disease related, thus being important to characterize the epidemiologic genetic distribution of EBV strains on our population. Here, we review the current knowledge on the different EBV strains and variants and its association with different diseases. J. Med. Virol. 89:373-387, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis.

    Science.gov (United States)

    Zabalza, Michel; Subirana, Isaac; Lluis-Ganella, Carla; Sayols-Baixeras, Sergi; de Groot, Eric; Arnold, Roman; Cenarro, Ana; Ramos, Rafel; Marrugat, Jaume; Elosua, Roberto

    2015-10-01

    Recent studies have identified several genetic variants associated with coronary artery disease. Some of these genetic variants are not associated with classical cardiovascular risk factors and the mechanism of such associations is unclear. The aim of the study was to determine whether these genetic variants are related to subclinical atherosclerosis measured by carotid intima media thickness, carotid stiffness, and ankle brachial index. A cross-sectional study nested in the follow-up of the REGICOR cohort was undertaken. The study included 2667 individuals. Subclinical atherosclerosis measurements were performed with standardized methods. Nine genetic variants were genotyped to assess associations with subclinical atherosclerosis, individually and in a weighted genetic risk score. A systematic review and meta-analysis of previous studies that analyzed these associations was undertaken. Neither the selected genetic variants nor the genetic risk score were significantly associated with subclinical atherosclerosis. In the meta-analysis, the rs1746048 (CXCL12; n = 10581) risk allele was directly associated with carotid intima-media thickness (β = 0.008; 95% confidence interval, 0.001-0.015), whereas the rs6725887 (WDR12; n = 7801) risk allele was inversely associated with this thickness (β = -0.013; 95% confidence interval, -0.024 to -0.003). The analyzed genetic variants seem to mediate their association with coronary artery disease through different mechanisms. Our results generate the hypothesis that the CXCL12 variant appears to influence coronary artery disease risk through arterial remodeling and thickening, whereas the WDR12 risk variant could be related to higher plaque vulnerability. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  1. New variant of Creutzfeldt-Jakob (vCJD disease and other human prion diseases under epidemiological surveillance in Brazil

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    Vera Lúcia Gattás

    Full Text Available Abstract To increase the timeliness of detection of human cases of the new variant of Creutzfeldt-Jakob disease (vCJD and to reduce the risk of transmission, the Brazilian Ministry of Health has established and standardized rules and control measures. These include the definition of criteria for suspect cases, reporting, monitoring, and control measures for illness prevention and transmission. Guidelines to be used by the team of health care staff were published and distributed to health workers. A detailed proposal for a simplified system of surveillance for prion diseases was developed and mandatory reporting introduced. Additional effort is necessary to increase vCJD case detection, thus making it necessary to establish a partnership with health care services for best identification of suspected cases and dissemination of information to all involved in the service dealing with vCJD investigation.

  2. Comprehensive analysis of three TYK2 gene variants in the susceptibility to Chagas disease infection and cardiomyopathy

    Science.gov (United States)

    Carmona, F. David; Dolade, Nuria; Vargas, Sofia; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2018-01-01

    Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population. A total of 1,323 individuals from a Colombian endemic region for Chagas disease were enrolled in the study. They were classified as seronegative (n = 445), seropositive asymptomatic (n = 336), and chronic Chagas Cardiomyopathy subjects (n = 542). DNA samples were genotyped using TaqMan probes. Our results showed no statistically significant differences between the allelic frequencies of the three analyzed variants when seropositive and seronegative individuals were compared, therefore these variants were not associated with susceptibility to Chagas disease. Moreover, when Chagas cardiomyopathy patients were compared to asymptomatic patients, no significant associations were found. Previous reports highlighted the association of this gene in immune-related disorders under an autoimmunity context, but not predisposing patients to infectious diseases, which is consistent with our findings. Therefore, according to our results, TYK2 gene variants do not seem to play an important role in Chagas disease susceptibility and/or chronic Chagas cardiomyopathy. PMID:29304122

  3. Association study of functional genetic variants of innate immunity related genes in celiac disease

    Directory of Open Access Journals (Sweden)

    Martín J

    2005-08-01

    Full Text Available Abstract Background Recent evidence suggest that the innate immune system is implicated in the early events of celiac disease (CD pathogenesis. In this work for the first time we have assessed the relevance of different proinflammatory mediators typically related to innate immunity in CD predisposition. Methods We performed a familial study in which 105 celiac families characterized by the presence of an affected child with CD were genotyped for functional polymorphisms located at regulatory regions of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes. Familial data was analysed with a transmission disequilibrium test (TDT that revealed no statistically significant differences in the transmission pattern of the different genetic markers considered. Results The TDT analysis for IL-1α, IL-1β, IL-1RN, IL-18, and MCP-1 genes genetic variants did not reveal biased transmission to the affected offspring. Only a borderline association of RANTES promoter genetic variants with CD predisposition was observed. Conclusion Our results suggest that the analysed polymorphisms of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes do not seem to play a major role in CD genetic predisposition in our population.

  4. Role and diagnostic value of gene variants in assessing the risk of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Yan, Z P; Tong, X; Liu, S T; Ma, Y; Peng, S F; Yang, X; Fan, H

    2016-05-13

    Meta-analyses have revealed many positive associations between gene variants and susceptibility to chronic obstructive pulmonary disease (COPD). However, some of those positive results may be false positives. Therefore, we investigated the genetic polymorphisms associated with COPD risk and determined their diagnostic value. We extracted the odds ratio (OR) and 95% confidence interval for each polymorphism from published meta-analyses concerning gene variants and COPD susceptibility in October 2014, subsequently we calculated false-positive report probabilities (FPRPs) for statistically significant associations (P value value of the true positive polymorphisms of COPD using the Meta-DiSc software. Twenty-five gene polymorphisms were significantly associated with COPD risk. The FPRP test results were as follows: 1) when the prior probability was 0.001 and the OR was 1.5, ADAM33 rs612709, CHRNA3/5 rs1051730, CHRNA3/5 rs8034191, CHRNA3/5 rs16969968, and TGFB1 rs1800470 were truly associated with COPD risk (FPRP value for COPD diagnosis.

  5. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Johanna Jakobsdottir

    2016-10-01

    Full Text Available We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations. In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI = 7.5 (3.5-15.9, p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

  6. Behavioral variant frontotemporal dementia: advanced disease stages and death. A step to palliative care.

    Science.gov (United States)

    Diehl-Schmid, J; Richard-Devantoy, S; Grimmer, T; Förstl, H; Jox, R

    2017-08-01

    The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Association of gene variants in TLR4 and IL-6 genes with Perthes disease

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    Srzentić Sanja

    2014-01-01

    Full Text Available Introduction. Perthes disease is idiopathic avascular osteonecrosis of the hip in children, with unknown etiology. Inflammation is present during development of Perthes disease and it is known that this process influences bone remodeling. Objective. Since genetic studies related to inflammation have not been performed in Perthes disease so far, the aim of this study was to analyze the association of frequencies of genetic variants of immune response genes, toll-like receptor 4 (TLR4 and interleukin-6 (IL-6, with this disease. Methods. The study cohort consisted of 37 patients with Perthes disease and 50 healthy controls. Polymorphisms of well described inflammatory mediators: TLR4 (Asp299Gly, Thr399Ile and IL-6 (G-174C, G- 597A were determined by polymerase chain reaction restriction fragment length polymorphism method. Results. IL-6 G-174C and G-597A polymorphisms were in complete linkage disequilibrium. A statistically significant increase of heterozygote subjects for IL-6 G-174C/G-597A was found in controls in comparison to Perthes patient group (p=0.047, OR=2.49, 95% CI=1.00-6.21. Also, the patient group for IL-6 G-174C/G- 597A polymorphisms was not in Hardy-Weinberg equilibrium. No statistically significant differences were found between patient and control groups for TLR4 analyzed polymorphisms. A stratified analysis by the age at disease onset also did not reveal any significant difference for all analyzed polymorphisms. Conclusion. Our study revealed that heterozygote subjects for the IL-6 G-174C/G-597A polymorphisms were significantly overrepresented in the control group than in the Perthes patient group. Consequently, we concluded that children who are heterozygous for these polymorphisms have a lower chance of developing Perthes disease than carriers of both homozygote genotypes. [Projekat Ministarstva nauke Republike Srbije, br. III41004

  8. The Heidenhain variant of Creutzfeldt-Jakob disease and concomitant tau pathology: A case report.

    Science.gov (United States)

    Ehler, Edvard; Pipka, Michael; Meleková, Alena; Mandysová, Petra; Johanidesová, Silvie; Matěj, Radoslav; Rusina, Robert

    The Heidenhain form of Creutzfeldt-Jakob disease (CJD) is a rare CJD variant with predominantly visual symptoms in the early stages. Clinical manifestations of metamorphopsia, hemianopia and Balint's syndrome correlate with the involvement of the posterior cortical regions. A 71-year old healthy and very active man was admitted because of impaired visual acuity, hemianopia, and gait disturbance progressing over one week. MRI found typical cortical hyperintensities in the occipital regions while rhythm slowing and sharp waves were seen in the occipital regions on EEG. Protein 14-3-3 was detected in the cerebrospinal fluid. Postmortem neuropathology revealed typical histopathological changes consistent with CJD. Moreover, we found deposits of phosphorylated tau protein in the limbic regions that met the criteria for primary age-related tauopathy (PART); representing an additional and interesting finding in our case. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

    DEFF Research Database (Denmark)

    Nioi, P.; Sigurdsson, A. S.; Thorleifsson, G.

    2016-01-01

    codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P = 1.0×10-16), and a lower risk...... of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0×10-6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P = 1...

  10. Variant in GALNT3 Gene Linked with Reduced Coronary Artery Disease Risk in Chinese Population.

    Science.gov (United States)

    Guo, Liwei; Li, Duan; Li, Mengting; Li, Lin; Huang, Yanmei

    2017-07-01

    Our previous study found expression of GALNT3 gene was reduced in coronary artery disease (CAD) patients, and it contributed to endothelial injury by regulating apoptosis and matrix metalloproteinase (MMP) expression. GALNT3 gene may be a potential target for future therapeutic intervention of CAD. However, none reports linking the GALNT3 gene to susceptibility of CAD. This study investigated the variant associations of GALNT3 gene and CAD. Thirteen single nucleotide polymorphism (SNP) in and around the GALNT3 gene were tagged and analyzed in CAD patients (n = 1515) and control individuals (n = 5019), and the SNPs with CAD were tested with multiple logistic regression analysis in an additive genetic model (with one degree of freedom) after adjusting for age and sex. Expression of GALNT3 gene was detected by real-time PCR and Western blot. Luciferase reporter assays were used to detect the allele-specific effect of rs4621175 on transcriptional activity. Two GALNT3 markers, rs13427924 and rs4621175, were significantly associated with CAD (odds ratio [OR] = 0.87, p = 1.01 × 10 -3 and OR = 0.75, p = 2.51 × 10 -4 , respectively), and the risk A allele of rs4621175 was associated with lower GALNT3 expression in both mRNA and protein level; also, A allele showed decreased reporter activity. In addition, we found the level of GALNT3 negatively correlated with MMP-2 gene expression. This study identified GALNT3 as a novel gene that rendered patients susceptible to CAD, and the A allele of a disease-associated variant rs4621175 linked reduced CAD risk through decreased GALNT3 expression. These results confirmed the role of GALNT3 gene in CAD and provided new insights into the genetic regulation of the GALNT3 gene with respect to the pathogenesis of CAD.

  11. Toxin Gene Analysis of a Variant Strain of Clostridium difficile That Causes Human Clinical Disease

    Science.gov (United States)

    Sambol, Susan P.; Merrigan, Michelle M.; Lyerly, David; Gerding, Dale N.; Johnson, Stuart

    2000-01-01

    A toxin variant strain of Clostridium difficile was isolated from two patients with C. difficile-associated disease (CDAD), one of whom died from extensive pseudomembranous colitis. This strain, identified by restriction endonuclease analysis (REA) as type CF2, was not detected by an immunoassay for C. difficile toxin A. Culture supernatants of CF2 failed to elicit significant enterotoxic activity in the rabbit ileal loop assay but did produce atypical cytopathic effects in cell culture assay. Southern hybridization, PCR amplification, and DNA sequence analyses were performed on the toxin A (tcdA) and toxin B (tcdB) genes of type CF2 isolate 5340. Type CF2 5340 tcdA exhibited a 1,821-bp truncation, due to three deletions in the 3′ end of the gene, and a point mutation in the 5′ end of the gene, resulting in a premature stop codon at tcdA position 139. Type CF2 5340 tcdB exhibited multiple nucleotide base substitutions in the 5′ end of the gene compared to tcdB of the standard toxigenic strain VPI 10463. Type CF2 5340 toxin gene nucleotide sequences and deduced amino acid sequences showed a strong resemblance to those of the previously described variant C. difficile strain 1470, a strain reported to have reduced pathogenicity and no association with clinical illness in humans. REA of strain 1470 identified this strain as a distinct type (CF1) within the same REA group as the closely related type CF2. A review of our clinical-isolate collection identified five additional patients infected with type CF2, three of whom had documented CDAD. PCR amplification of the 3′ end of tcdA demonstrated identical 1.8-kb deletions in all seven type CF2 isolates. REA type CF2 is a toxin variant strain of C. difficile that retains the ability to cause disease in humans but is not detected in clinical immunoassays for toxin A. PMID:10992443

  12. Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Marina V. Shulskaya

    2018-05-01

    Full Text Available Background: Parkinson’s disease (PD is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated.Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas.Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS, Combined Annotation Dependent Depletion (CADD and Rare Exome Variant Ensemble Learner (REVEL software. Functional evaluation was performed using the Pathway Studio database.Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7 were the most significant.Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.

  13. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

    Science.gov (United States)

    Sims, Rebecca; van der Lee, Sven J; Naj, Adam C; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W; Boland, Anne; Raybould, Rachel; Bis, Joshua C; Martin, Eden R; Grenier-Boley, Benjamin; Heilmann-Heimbach, Stefanie; Chouraki, Vincent; Kuzma, Amanda B; Sleegers, Kristel; Vronskaya, Maria; Ruiz, Agustin; Graham, Robert R; Olaso, Robert; Hoffmann, Per; Grove, Megan L; Vardarajan, Badri N; Hiltunen, Mikko; Nöthen, Markus M; White, Charles C; Hamilton-Nelson, Kara L; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W; Dulary, Cécile; Herms, Stefan; Smith, Albert V; Funk, Cory C; Derbois, Céline; Forstner, Andreas J; Ahmad, Shahzad; Li, Hongdong; Bacq, Delphine; Harold, Denise; Satizabal, Claudia L; Valladares, Otto; Squassina, Alessio; Thomas, Rhodri; Brody, Jennifer A; Qu, Liming; Sánchez-Juan, Pascual; Morgan, Taniesha; Wolters, Frank J; Zhao, Yi; Garcia, Florentino Sanchez; Denning, Nicola; Fornage, Myriam; Malamon, John; Naranjo, Maria Candida Deniz; Majounie, Elisa; Mosley, Thomas H; Dombroski, Beth; Wallon, David; Lupton, Michelle K; Dupuis, Josée; Whitehead, Patrice; Fratiglioni, Laura; Medway, Christopher; Jian, Xueqiu; Mukherjee, Shubhabrata; Keller, Lina; Brown, Kristelle; Lin, Honghuang; Cantwell, Laura B; Panza, Francesco; McGuinness, Bernadette; Moreno-Grau, Sonia; Burgess, Jeremy D; Solfrizzi, Vincenzo; Proitsi, Petra; Adams, Hieab H; Allen, Mariet; Seripa, Davide; Pastor, Pau; Cupples, L Adrienne; Price, Nathan D; Hannequin, Didier; Frank-García, Ana; Levy, Daniel; Chakrabarty, Paramita; Caffarra, Paolo; Giegling, Ina; Beiser, Alexa S; Giedraitis, Vilmantas; Hampel, Harald; Garcia, Melissa E; Wang, Xue; Lannfelt, Lars; Mecocci, Patrizia; Eiriksdottir, Gudny; Crane, Paul K; Pasquier, Florence; Boccardi, Virginia; Henández, Isabel; Barber, Robert C; Scherer, Martin; Tarraga, Lluis; Adams, Perrie M; Leber, Markus; Chen, Yuning; Albert, Marilyn S; Riedel-Heller, Steffi; Emilsson, Valur; Beekly, Duane; Braae, Anne; Schmidt, Reinhold; Blacker, Deborah; Masullo, Carlo; Schmidt, Helena; Doody, Rachelle S; Spalletta, Gianfranco; Longstreth, W T; Fairchild, Thomas J; Bossù, Paola; Lopez, Oscar L; Frosch, Matthew P; Sacchinelli, Eleonora; Ghetti, Bernardino; Yang, Qiong; Huebinger, Ryan M; Jessen, Frank; Li, Shuo; Kamboh, M Ilyas; Morris, John; Sotolongo-Grau, Oscar; Katz, Mindy J; Corcoran, Chris; Dunstan, Melanie; Braddel, Amy; Thomas, Charlene; Meggy, Alun; Marshall, Rachel; Gerrish, Amy; Chapman, Jade; Aguilar, Miquel; Taylor, Sarah; Hill, Matt; Fairén, Mònica Díez; Hodges, Angela; Vellas, Bruno; Soininen, Hilkka; Kloszewska, Iwona; Daniilidou, Makrina; Uphill, James; Patel, Yogen; Hughes, Joseph T; Lord, Jenny; Turton, James; Hartmann, Annette M; Cecchetti, Roberta; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina; Caltagirone, Carlo; Orfei, Maria Donata; Ciaramella, Antonio; Pichler, Sabrina; Mayhaus, Manuel; Gu, Wei; Lleó, Alberto; Fortea, Juan; Blesa, Rafael; Barber, Imelda S; Brookes, Keeley; Cupidi, Chiara; Maletta, Raffaele Giovanni; Carrell, David; Sorbi, Sandro; Moebus, Susanne; Urbano, Maria; Pilotto, Alberto; Kornhuber, Johannes; Bosco, Paolo; Todd, Stephen; Craig, David; Johnston, Janet; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Fox, Nick C; Hardy, John; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Asthana, Sanjay; Atwood, Craig S; Baldwin, Clinton T; Barnes, Lisa L; Barral, Sandra; Beach, Thomas G; Becker, James T; Bigio, Eileen H; Bird, Thomas D; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Burke, James R; Burns, Jeffrey M; Buxbaum, Joseph D; Cairns, Nigel J; Cao, Chuanhai; Carlson, Chris S; Carlsson, Cynthia M; Carney, Regina M; Carrasquillo, Minerva M; Carroll, Steven L; Diaz, Carolina Ceballos; Chui, Helena C; Clark, David G; Cribbs, David H; Crocco, Elizabeth A; DeCarli, Charles; Dick, Malcolm; Duara, Ranjan; Evans, Denis A; Faber, Kelley M; Fallon, Kenneth B; Fardo, David W; Farlow, Martin R; Ferris, Steven; Foroud, Tatiana M; Galasko, Douglas R; Gearing, Marla; Geschwind, Daniel H; Gilbert, John R; Graff-Radford, Neill R; Green, Robert C; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Honig, Lawrence S; Huentelman, Matthew J; Hulette, Christine M; Hyman, Bradley T; Jarvik, Gail P; Abner, Erin; Jin, Lee-Way; Jun, Gyungah; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Kowall, Neil W; Kramer, Joel H; LaFerla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Ge; Lieberman, Andrew P; Lunetta, Kathryn L; Lyketsos, Constantine G; Marson, Daniel C; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Morris, John C; Murrell, Jill R; Myers, Amanda J; O'Bryant, Sid; Olichney, John M; Pankratz, Vernon S; Parisi, Joseph E; Paulson, Henry L; Perry, William; Peskind, Elaine; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reisberg, Barry; Reitz, Christiane; Ringman, John M; Roberson, Erik D; Rogaeva, Ekaterina; Rosen, Howard J; Rosenberg, Roger N; Sager, Mark A; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Swerdlow, Russell H; Tanzi, Rudolph E; Thornton-Wells, Tricia A; Trojanowski, John Q; Troncoso, Juan C; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Wilhelmsen, Kirk C; Williamson, Jennifer; Wingo, Thomas S; Woltjer, Randall L; Wright, Clinton B; Yu, Chang-En; Yu, Lei; Garzia, Fabienne; Golamaully, Feroze; Septier, Gislain; Engelborghs, Sebastien; Vandenberghe, Rik; De Deyn, Peter P; Fernadez, Carmen Muñoz; Benito, Yoland Aladro; Thonberg, Hakan; Forsell, Charlotte; Lilius, Lena; Kinhult-Stählbom, Anne; Kilander, Lena; Brundin, RoseMarie; Concari, Letizia; Helisalmi, Seppo; Koivisto, Anne Maria; Haapasalo, Annakaisa; Dermecourt, Vincent; Fievet, Nathalie; Hanon, Olivier; Dufouil, Carole; Brice, Alexis; Ritchie, Karen; Dubois, Bruno; Himali, Jayanadra J; Keene, C Dirk; Tschanz, JoAnn; Fitzpatrick, Annette L; Kukull, Walter A; Norton, Maria; Aspelund, Thor; Larson, Eric B; Munger, Ron; Rotter, Jerome I; Lipton, Richard B; Bullido, María J; Hofman, Albert; Montine, Thomas J; Coto, Eliecer; Boerwinkle, Eric; Petersen, Ronald C; Alvarez, Victoria; Rivadeneira, Fernando; Reiman, Eric M; Gallo, Maura; O'Donnell, Christopher J; Reisch, Joan S; Bruni, Amalia Cecilia; Royall, Donald R; Dichgans, Martin; Sano, Mary; Galimberti, Daniela; St George-Hyslop, Peter; Scarpini, Elio; Tsuang, Debby W; Mancuso, Michelangelo; Bonuccelli, Ubaldo; Winslow, Ashley R; Daniele, Antonio; Wu, Chuang-Kuo; Peters, Oliver; Nacmias, Benedetta; Riemenschneider, Matthias; Heun, Reinhard; Brayne, Carol; Rubinsztein, David C; Bras, Jose; Guerreiro, Rita; Al-Chalabi, Ammar; Shaw, Christopher E; Collinge, John; Mann, David; Tsolaki, Magda; Clarimón, Jordi; Sussams, Rebecca; Lovestone, Simon; O'Donovan, Michael C; Owen, Michael J; Behrens, Timothy W; Mead, Simon; Goate, Alison M; Uitterlinden, Andre G; Holmes, Clive; Cruchaga, Carlos; Ingelsson, Martin; Bennett, David A; Powell, John; Golde, Todd E; Graff, Caroline; De Jager, Philip L; Morgan, Kevin; Ertekin-Taner, Nilufer; Combarros, Onofre; Psaty, Bruce M; Passmore, Peter; Younkin, Steven G; Berr, Claudine; Gudnason, Vilmundur; Rujescu, Dan; Dickson, Dennis W; Dartigues, Jean-François; DeStefano, Anita L; Ortega-Cubero, Sara; Hakonarson, Hakon; Campion, Dominique; Boada, Merce; Kauwe, John Keoni; Farrer, Lindsay A; Van Broeckhoven, Christine; Ikram, M Arfan; Jones, Lesley; Haines, Jonathan L; Tzourio, Christophe; Launer, Lenore J; Escott-Price, Valentina; Mayeux, Richard; Deleuze, Jean-François; Amin, Najaf; Holmans, Peter A; Pericak-Vance, Margaret A; Amouyel, Philippe; van Duijn, Cornelia M; Ramirez, Alfredo; Wang, Li-San; Lambert, Jean-Charles; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D

    2017-09-01

    We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

  14. Cathepsin D SNP associated with increased risk of variant Creutzfeldt-Jakob disease

    Directory of Open Access Journals (Sweden)

    Sanchez-Juan Pascual

    2008-04-01

    Full Text Available Abstract Background Variant Creutzfeldt-Jakob disease (vCJD originally resulted from the consumption of foodstuffs contaminated by bovine spongiform encephalopathy (BSE material, with 163 confirmed cases in the UK to date. Many thousands are likely to have been exposed to dietary infection and so it is important (for surveillance, epidemic modelling, public health and understanding pathogenesis to identify genetic factors that may affect individual susceptibility to infection. This study looked at a polymorphism in the cathepsin D gene (refSNP ID: rs17571 previously examined in Alzheimer's disease (AD. Methods Blood samples taken from 110 vCJD patients were tested for the C-T base change, and genotype data were compared with published frequencies for a control population using multiple logistic regression. Results There was a significant excess of the cathepsin D polymorphism TT genotype in the vCJD cohort compared to controls. The TT genotype was found to have a 9.75 fold increase in risk of vCJD compared to the CT genotype and a 10.92 fold increase compared to the CC genotype. Conclusion This mutation event has been observed to alter the protease activity of the cathepsin D protein and has been linked to an increase in amyloid beta plaque formation in AD. vCJD neuropathology is characterised by the presence of amyloid plaques, formed from the prion protein, and therefore alterations in the amyloid processing activity of cathepsin D may affect the neuropathogenesis of this disease.

  15. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

    Science.gov (United States)

    Ehret, Georg B; Munroe, Patricia B; Rice, Kenneth M; Bochud, Murielle; Johnson, Andrew D; Chasman, Daniel I; Smith, Albert V; Tobin, Martin D; Verwoert, Germaine C; Hwang, Shih-Jen; Pihur, Vasyl; Vollenweider, Peter; O'Reilly, Paul F; Amin, Najaf; Bragg-Gresham, Jennifer L; Teumer, Alexander; Glazer, Nicole L; Launer, Lenore; Zhao, Jing Hua; Aulchenko, Yurii; Heath, Simon; Sõber, Siim; Parsa, Afshin; Luan, Jian'an; Arora, Pankaj; Dehghan, Abbas; Zhang, Feng; Lucas, Gavin; Hicks, Andrew A; Jackson, Anne U; Peden, John F; Tanaka, Toshiko; Wild, Sarah H; Rudan, Igor; Igl, Wilmar; Milaneschi, Yuri; Parker, Alex N; Fava, Cristiano; Chambers, John C; Fox, Ervin R; Kumari, Meena; Go, Min Jin; van der Harst, Pim; Kao, Wen Hong Linda; Sjögren, Marketa; Vinay, D G; Alexander, Myriam; Tabara, Yasuharu; Shaw-Hawkins, Sue; Whincup, Peter H; Liu, Yongmei; Shi, Gang; Kuusisto, Johanna; Tayo, Bamidele; Seielstad, Mark; Sim, Xueling; Nguyen, Khanh-Dung Hoang; Lehtimäki, Terho; Matullo, Giuseppe; Wu, Ying; Gaunt, Tom R; Onland-Moret, N Charlotte; Cooper, Matthew N; Platou, Carl G P; Org, Elin; Hardy, Rebecca; Dahgam, Santosh; Palmen, Jutta; Vitart, Veronique; Braund, Peter S; Kuznetsova, Tatiana; Uiterwaal, Cuno S P M; Adeyemo, Adebowale; Palmas, Walter; Campbell, Harry; Ludwig, Barbara; Tomaszewski, Maciej; Tzoulaki, Ioanna; Palmer, Nicholette D; Aspelund, Thor; Garcia, Melissa; Chang, Yen-Pei C; O'Connell, Jeffrey R; Steinle, Nanette I; Grobbee, Diederick E; Arking, Dan E; Kardia, Sharon L; Morrison, Alanna C; Hernandez, Dena; Najjar, Samer; McArdle, Wendy L; Hadley, David; Brown, Morris J; Connell, John M; Hingorani, Aroon D; Day, Ian N M; Lawlor, Debbie A; Beilby, John P; Lawrence, Robert W; Clarke, Robert; Hopewell, Jemma C; Ongen, Halit; Dreisbach, Albert W; Li, Yali; Young, J Hunter; Bis, Joshua C; Kähönen, Mika; Viikari, Jorma; Adair, Linda S; Lee, Nanette R; Chen, Ming-Huei; Olden, Matthias; Pattaro, Cristian; Bolton, Judith A Hoffman; Köttgen, Anna; Bergmann, Sven; Mooser, Vincent; Chaturvedi, Nish; Frayling, Timothy M; Islam, Muhammad; Jafar, Tazeen H; Erdmann, Jeanette; Kulkarni, Smita R; Bornstein, Stefan R; Grässler, Jürgen; Groop, Leif; Voight, Benjamin F; Kettunen, Johannes; Howard, Philip; Taylor, Andrew; Guarrera, Simonetta; Ricceri, Fulvio; Emilsson, Valur; Plump, Andrew; Barroso, Inês; Khaw, Kay-Tee; Weder, Alan B; Hunt, Steven C; Sun, Yan V; Bergman, Richard N; Collins, Francis S; Bonnycastle, Lori L; Scott, Laura J; Stringham, Heather M; Peltonen, Leena; Perola, Markus; Vartiainen, Erkki; Brand, Stefan-Martin; Staessen, Jan A; Wang, Thomas J; Burton, Paul R; Soler Artigas, Maria; Dong, Yanbin; Snieder, Harold; Wang, Xiaoling; Zhu, Haidong; Lohman, Kurt K; Rudock, Megan E; Heckbert, Susan R; Smith, Nicholas L; Wiggins, Kerri L; Doumatey, Ayo; Shriner, Daniel; Veldre, Gudrun; Viigimaa, Margus; Kinra, Sanjay; Prabhakaran, Dorairaj; Tripathy, Vikal; Langefeld, Carl D; Rosengren, Annika; Thelle, Dag S; Corsi, Anna Maria; Singleton, Andrew; Forrester, Terrence; Hilton, Gina; McKenzie, Colin A; Salako, Tunde; Iwai, Naoharu; Kita, Yoshikuni; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ueshima, Hirotsugu; Umemura, Satoshi; Eyheramendy, Susana; Meitinger, Thomas; Wichmann, H-Erich; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Scott, James; Sehmi, Joban S; Zhang, Weihua; Hedblad, Bo; Nilsson, Peter; Smith, George Davey; Wong, Andrew; Narisu, Narisu; Stančáková, Alena; Raffel, Leslie J; Yao, Jie; Kathiresan, Sekar; O'Donnell, Christopher J; Schwartz, Stephen M; Ikram, M Arfan; Longstreth, W T; Mosley, Thomas H; Seshadri, Sudha; Shrine, Nick R G; Wain, Louise V; Morken, Mario A; Swift, Amy J; Laitinen, Jaana; Prokopenko, Inga; Zitting, Paavo; Cooper, Jackie A; Humphries, Steve E; Danesh, John; Rasheed, Asif; Goel, Anuj; Hamsten, Anders; Watkins, Hugh; Bakker, Stephan J L; van Gilst, Wiek H; Janipalli, Charles S; Mani, K Radha; Yajnik, Chittaranjan S; Hofman, Albert; Mattace-Raso, Francesco U S; Oostra, Ben A; Demirkan, Ayse; Isaacs, Aaron; Rivadeneira, Fernando; Lakatta, Edward G; Orru, Marco; Scuteri, Angelo; Ala-Korpela, Mika; Kangas, Antti J; Lyytikäinen, Leo-Pekka; Soininen, Pasi; Tukiainen, Taru; Würtz, Peter; Ong, Rick Twee-Hee; Dörr, Marcus; Kroemer, Heyo K; Völker, Uwe; Völzke, Henry; Galan, Pilar; Hercberg, Serge; Lathrop, Mark; Zelenika, Diana; Deloukas, Panos; Mangino, Massimo; Spector, Tim D; Zhai, Guangju; Meschia, James F; Nalls, Michael A; Sharma, Pankaj; Terzic, Janos; Kumar, M V Kranthi; Denniff, Matthew; Zukowska-Szczechowska, Ewa; Wagenknecht, Lynne E; Fowkes, F Gerald R; Charchar, Fadi J; Schwarz, Peter E H; Hayward, Caroline; Guo, Xiuqing; Rotimi, Charles; Bots, Michiel L; Brand, Eva; Samani, Nilesh J; Polasek, Ozren; Talmud, Philippa J; Nyberg, Fredrik; Kuh, Diana; Laan, Maris; Hveem, Kristian; Palmer, Lyle J; van der Schouw, Yvonne T; Casas, Juan P; Mohlke, Karen L; Vineis, Paolo; Raitakari, Olli; Ganesh, Santhi K; Wong, Tien Y; Tai, E Shyong; Cooper, Richard S; Laakso, Markku; Rao, Dabeeru C; Harris, Tamara B; Morris, Richard W; Dominiczak, Anna F; Kivimaki, Mika; Marmot, Michael G; Miki, Tetsuro; Saleheen, Danish; Chandak, Giriraj R; Coresh, Josef; Navis, Gerjan; Salomaa, Veikko; Han, Bok-Ghee; Zhu, Xiaofeng; Kooner, Jaspal S; Melander, Olle; Ridker, Paul M; Bandinelli, Stefania; Gyllensten, Ulf B; Wright, Alan F; Wilson, James F; Ferrucci, Luigi; Farrall, Martin; Tuomilehto, Jaakko; Pramstaller, Peter P; Elosua, Roberto; Soranzo, Nicole; Sijbrands, Eric J G; Altshuler, David; Loos, Ruth J F; Shuldiner, Alan R; Gieger, Christian; Meneton, Pierre; Uitterlinden, Andre G; Wareham, Nicholas J; Gudnason, Vilmundur; Rotter, Jerome I; Rettig, Rainer; Uda, Manuela; Strachan, David P; Witteman, Jacqueline C M; Hartikainen, Anna-Liisa; Beckmann, Jacques S; Boerwinkle, Eric; Vasan, Ramachandran S; Boehnke, Michael; Larson, Martin G; Järvelin, Marjo-Riitta; Psaty, Bruce M; Abecasis, Gonçalo R; Chakravarti, Aravinda; Elliott, Paul; van Duijn, Cornelia M; Newton-Cheh, Christopher; Levy, Daniel; Caulfield, Mark J; Johnson, Toby

    2011-09-11

    Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

  16. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease.

    Science.gov (United States)

    Morimoto, Takaaki; Mineharu, Yohei; Ono, Koh; Nakatochi, Masahiro; Ichihara, Sahoko; Kabata, Risako; Takagi, Yasushi; Cao, Yang; Zhao, Lanying; Kobayashi, Hatasu; Harada, Kouji H; Takenaka, Katsunobu; Funaki, Takeshi; Yokota, Mitsuhiro; Matsubara, Tatsuaki; Yamamoto, Ken; Izawa, Hideo; Kimura, Takeshi; Miyamoto, Susumu; Koizumi, Akio

    2017-01-01

    The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested. We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37-6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16-21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87-16.77; p = 0.076). The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.

  17. Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.

    Science.gov (United States)

    Barrett, Matthew J; Koeppel, Alexander F; Flanigan, Joseph L; Turner, Stephen D; Worrall, Bradford B

    2016-01-01

    Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE  70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.

  18. Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction.

    Science.gov (United States)

    Larsson, Susanna C; Burgess, Stephen; Michaëlsson, Karl

    2017-07-25

    Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction. To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization. The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis. Genetic risk score based on genetic variants related to elevated serum calcium levels. Co-primary outcomes were the odds of CAD and myocardial infarction. Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically

  19. Association of Multiple Genetic Variants with the Extension and Severity of Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Simone Cristina Pinto Matheus Fischer

    2018-02-01

    Full Text Available Abstract Background: Metabolic syndrome (MS is a condition that, when associated with ischemic heart disease and cardiovascular events, can be influenced by genetic variants and determine more severe coronary atherosclerosis. Objectives: To examine the contribution of genetic polymorphisms to the extension and severity of coronary disease in subjects with MS and recent acute coronary syndrome (ACS. Methods: Patients (n = 116, 68% males aged 56 (9 years, with criteria for MS, were prospectively enrolled to the study during the hospitalization period after an ACS. Clinical and laboratory parameters, high-sensitivity C-reactive protein, thiobarbituric acid reactive substances, adiponectin, endothelial function, and the Gensini score were assessed. Polymorphisms of paraoxonase-1 (PON-1, methylenotetrahydrofolate reductase (MTHFR, endothelial nitric oxide synthase (ENOS, angiotensin-converting enzyme (ACE, angiotensin II type 1 receptor (AT1R, apolipoprotein C3 (APOC3, lipoprotein lipase (LPL were analysed by polymerase chain reaction (PCR technique, followed by the identification of restriction fragment length polymorphisms (RFLP, and a genetic score was calculated. Parametric and non-parametric tests were used, as appropriate. Significance was set at p < 0.05. Results: Polymorphisms of PON-1, MTHFR and ENOS were not in the Hardy-Weinberg equilibrium. The DD genotype of LPL was associated with higher severity and greater extension of coronary lesions. Genetic score tended to be higher in patients with Gensini score < P50 (13.7 ± 1.5 vs. 13.0 ± 1.6, p = 0.066, with an inverse correlation between genetic and Gensini scores (R = -0.194, p = 0.078. Conclusions: The LPL polymorphism contributed to the severity of coronary disease in patients with MS and recent ACS. Combined polymorphisms were associated with the extension of coronary disease, and the lower the genetic score the more severe the disease.

  20. Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.

    Science.gov (United States)

    Ito, Kaoru; Bick, Alexander G; Flannick, Jason; Friedman, David J; Genovese, Giulio; Parfenov, Michael G; Depalma, Steven R; Gupta, Namrata; Gabriel, Stacey B; Taylor, Herman A; Fox, Ervin R; Newton-Cheh, Christopher; Kathiresan, Sekar; Hirschhorn, Joel N; Altshuler, David M; Pollak, Martin R; Wilson, James G; Seidman, J G; Seidman, Christine

    2014-02-28

    Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population. We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans. We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4×10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4×10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37×10(-3); JHS and WHI combined, P=8.5×10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease. APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

  1. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

    Science.gov (United States)

    Schott, Jonathan M; Crutch, Sebastian J; Carrasquillo, Minerva M; Uphill, James; Shakespeare, Tim J; Ryan, Natalie S; Yong, Keir X; Lehmann, Manja; Ertekin-Taner, Nilufer; Graff-Radford, Neill R; Boeve, Bradley F; Murray, Melissa E; Khan, Qurat Ul Ain; Petersen, Ronald C; Dickson, Dennis W; Knopman, David S; Rabinovici, Gil D; Miller, Bruce L; González, Aida Suárez; Gil-Néciga, Eulogio; Snowden, Julie S; Harris, Jenny; Pickering-Brown, Stuart M; Louwersheimer, Eva; van der Flier, Wiesje M; Scheltens, Philip; Pijnenburg, Yolande A; Galasko, Douglas; Sarazin, Marie; Dubois, Bruno; Magnin, Eloi; Galimberti, Daniela; Scarpini, Elio; Cappa, Stefano F; Hodges, John R; Halliday, Glenda M; Bartley, Lauren; Carrillo, Maria C; Bras, Jose T; Hardy, John; Rossor, Martin N; Collinge, John; Fox, Nick C; Mead, Simon

    2016-08-01

    The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  2. The 15q24/25 Susceptibility Variant for Lung Cancer and Chronic Obstructive Pulmonary Disease Is Associated with Emphysema

    NARCIS (Netherlands)

    Lambrechts, Diether; Buysschaert, Ian; Zanen, Pieter; Coolen, Johan; Lays, Natacha; Cuppens, Harry; Groen, Harry J. M.; Dewever, Walter; van Klaveren, Rob J.; Verschakelen, Johny; Wijmenga, Cisca; Postma, Dirkje S.; Decramer, Marc; Janssens, Wim

    2010-01-01

    Rationale: Genome-wide association studies have identified genetic variants in the nicotinic acetylcholine receptor (nAChR) on chromosome 15q24/25 as a risk for nicotine dependence, lung cancer, and chronic obstructive pulmonary disease (COPD). Assessment of bronchial obstruction by spirometry,

  3. Relationship between common lipoprotein lipase gene sequence variants, hyperinsulinemia, and risk of ischemic heart disease: A population-based study

    DEFF Research Database (Denmark)

    Jeppesen, Jørgen; Hansen, Tine Willum; Torp-Pedersen, Christian

    2010-01-01

    Hyperinsulinemia and lipoprotein lipase (LPL) are important determinants of fasting and postprandial plasma triglyceride levels. High insulin and high triglyceride levels are associated with an increased risk of ischemic heart disease (IHD). This study aimed to find out whether common LPL gene se...... sequence variants could change the relationship between insulin and IHD....

  4. Clinical Utility of Short Social Cognitive Tests in Early Differentiation of Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease

    DEFF Research Database (Denmark)

    Buhl, Christian; Stokholm, Jette; Gade, Anders

    2013-01-01

    Traditional cognitive tests used in clinical practice may not be sensitive enough for the early differentiation of behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD). A growing body of literature has shown that deficits in various aspects of social cognition can be f...

  5. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance

    NARCIS (Netherlands)

    van der Tol, L.; Smid, B. E.; Poorthuis, B. J. H. M.; Biegstraaten, M.; Deprez, R. H. Lekanne; Linthorst, G. E.; Hollak, C. E. M.

    2014-01-01

    Screening for Fabry disease (FD) reveals a high prevalence of individuals with α-galactosidase A (GLA) genetic variants of unknown significance (GVUS). These individuals often do not express characteristic features of FD. A systematic review on FD screening studies was performed to interpret the

  6. The Glucocerobrosidase E326K Variant Predisposes to Parkinson’s Disease, But Does Not Cause Gaucher’s Disease

    Science.gov (United States)

    Angeli, Aikaterini V.; Shoai, Maryam; Deas, Emma; Houlden, Henry; Mehta, Atul; Hughes, Derralynn; Cox, Timothy M.; Deegan, Patrick; Schapira, Anthony H.; Lees, Andrew J.; Limousin, Patricia; Jarman, Paul R.; Bhatia, Kailash P.; Wood, Nicholas W.; Hardy, John; Foltynie, Tom

    2014-01-01

    Background Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher’s disease (GD), are the strongest known risk factor for Parkinson’s disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. Methods One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. Results We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. Conclusions Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. PMID:23225227

  7. IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series.

    Science.gov (United States)

    Carruthers, Mollie N; Park, Sujin; Slack, Graham W; Dalal, Bakul I; Skinnider, Brian F; Schaeffer, David F; Dutz, Jan P; Law, Joanna K; Donnellan, Fergal; Marquez, Vladimir; Seidman, Michael; Wong, Patrick C; Mattman, Andre; Chen, Luke Y C

    2017-04-01

    To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE. Comparative case series of 31 patients with IgG4-RD and 13 patients with L-HES. Peripheral blood eosinophilia was present in eight of 31 patients with IgG4-RD compared to 13 of 13 patients with L-HES (median eosinophils 0.4 vs 7.0 giga/L, P=.001) and 12 of 20 patients with IgG4-RD had increased serum IgE compared to eight of 13 patients with L-HES, P=.930. Twenty-seven of 30 patients with IgG4-RD had elevated serum IgG4 compared to five of 12 patients with L-HES (median IgG4 9.6 g/L vs 0.80 g/L, P=.002). Flow cytometry demonstrated an aberrant T-cell phenotype in 7 of 23 patients with IgG4-RD and 13 of 13 patients with L-HES (PIgG4-RD vs 10 of 13 patients with L-HES (P=.143). Patients in both groups received corticosteroids as first-line therapy. For refractory disease in IgG4-RD, rituximab was the most common steroid-sparing agent, whereas in L-HES, it was pegylated interferon-α-2a. The overlapping features of these two diseases with divergent treatment options demonstrate the importance of familiarity with both entities to optimize diagnosis and treatment. © 2016 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

  8. A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

    Science.gov (United States)

    Hafkemeijer, Anne; Möller, Christiane; Dopper, Elise G P; Jiskoot, Lize C; van den Berg-Huysmans, Annette A; van Swieten, John C; van der Flier, Wiesje M; Vrenken, Hugo; Pijnenburg, Yolande A L; Barkhof, Frederik; Scheltens, Philip; van der Grond, Jeroen; Rombouts, Serge A R B

    2017-01-01

    Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

  9. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Concha-Marambio, Luis; Pritzkow, Sandra; Moda, Fabio; Tagliavini, Fabrizio; Ironside, James W; Schulz, Paul E; Soto, Claudio

    2016-12-21

    Human prion diseases are infectious and invariably fatal neurodegenerative diseases. They include sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, and variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrP Sc ) in the blood of patients affected by prion disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrP Sc could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrP Sc concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology. Copyright © 2016, American Association for the Advancement of Science.

  10. Short TE quantitative proton magnetic resonance spectroscopy in variant Creutzfeldt-Jakob disease

    International Nuclear Information System (INIS)

    Cordery, R.J.; Godbolt, A.; Rossor, M.N.; MacManus, D.; Waldman, A.D.

    2006-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegerative disorder. Clinical diagnosis is difficult in the early stages as the disease often presents with non-specific psychiatric and neurological symptoms. To investigate the diagnostic potential of quantitative short TE in vivo MRS, and the nature and anatomical distribution of biochemical abnormalities in vCJD, localised single-voxel spectra (TE/TR 30 ms/2,000 ms) were acquired from three brain regions: thalami, caudate nuclei and frontal white matter. Metabolite concentrations and ratios from three patients with definite or probable vCJD were compared with eight normal age-matched controls. Abnormal signal on T2-weighted MRI was apparent in the pulvinar region in all vCJD patients; this region also showed greatly increased myo-inositol [MI] (mean 2.5-fold, P=0.01) and decreased N-acetyl-aspartate (NAA; mean 2-fold, P=0.01). Two patients also showed increased [MI] (z=17, 11; one with decreased NAA, z=-12) in normal-appearing caudate nuclei. The magnitude of metabolite abnormalities in the thalami in moderately advanced vCJD suggests a potential role in earlier diagnosis. Short TE protocols allow the measurement of MI, which adds discriminant power to the MRS examination. (orig.)

  11. Differences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease.

    Science.gov (United States)

    Huh, Young Eun; Park, Jongkyu; Suh, Mee Kyung; Lee, Sang Eun; Kim, Jumin; Jeong, Yuri; Kim, Hee-Tae; Cho, Jin Whan

    2015-08-01

    In Parkinson variant of multiple system atrophy (MSA-P), patterns of early speech impairment and their distinguishing features from Parkinson's disease (PD) require further exploration. Here, we compared speech data among patients with early-stage MSA-P, PD, and healthy subjects using quantitative acoustic and perceptual analyses. Variables were analyzed for men and women in view of gender-specific features of speech. Acoustic analysis revealed that male patients with MSA-P exhibited more profound speech abnormalities than those with PD, regarding increased voice pitch, prolonged pause time, and reduced speech rate. This might be due to widespread pathology of MSA-P in nigrostriatal or extra-striatal structures related to speech production. Although several perceptual measures were mildly impaired in MSA-P and PD patients, none of these parameters showed a significant difference between patient groups. Detailed speech analysis using acoustic measures may help distinguish between MSA-P and PD early in the disease process. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. ELISA for detection of variant rabbit haemorrhagic disease virus RHDV2 antigen in liver extracts.

    Science.gov (United States)

    Dalton, K P; Podadera, A; Granda, V; Nicieza, I; Del Llano, D; González, R; de Los Toyos, J R; García Ocaña, M; Vázquez, F; Martín Alonso, J M; Prieto, J M; Parra, F; Casais, R

    2018-01-01

    The emergence and rapid spread of variant of the rabbit hemorrhagic disease virus (RHDV2) require new diagnostic tools to ensure that efficient control measures are adopted. In the present study, a specific sandwich enzyme-linked immunosorbent assay (ELISA) for detection of RHDV2 antigens in rabbit liver homogenates, based on the use of an RHDV2-specific monoclonal antibody (Mab) 2D9 for antigen capture and an anti-RHDV2 goat polyclonal antibody (Pab), was developed. This ELISA was able to successfully detect RHDV2 and RHDV2 recombinant virions with high sensitivity (100%) and specificity (97.22%). No cross-reactions were detected with RHDV G1 viruses while low cross-reactivity was detected with one of the RHDVa samples analyzed. The ELISA afforded good repeatability and had high analytical sensitivity as it was able to detect a dilution 1:163,640 (6.10ng/mL) of purified RHDV-N11 VLPs, which contained approximately 3.4×10 8 molecules/mL particles. The reliable discrimination between closely related viruses is crucial to understand the epidemiology and the interaction of co-existing pathogens. In the work described here we design and validate an ELISA for laboratory based, specific, sensitive and reliable detection of RHDVb/RHDV2. This ELISA is a valuable, specific virological tool for monitoring virus circulation, which will permit a better control of this disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms

    Directory of Open Access Journals (Sweden)

    Stephen eSalton

    2013-08-01

    Full Text Available The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs, where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs, with neuropsychiatric, endocrine and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A of the human brain-derived neurotrophic factor (BDNF gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

  14. Identification of MHCII variants associated with chlamydial disease in the koala (Phascolarctos cinereus

    Directory of Open Access Journals (Sweden)

    Quintin Lau

    2014-06-01

    Full Text Available Chlamydiosis, the most common infectious disease in koalas, can cause chronic urogenital tract fibrosis and infertility. High titres of serum immunoglobulin G against 10 kDa and 60 kDa chlamydial heat-shock proteins (c-hsp10 and c-hsp60 are associated with fibrous occlusion of the koala uterus and uterine tube. Murine and human studies have identified associations between specific major histocompatibility complex class II (MHCII alleles or genotypes, and higher c-hsp 60 antibody levels or chlamydia-associated disease and infertility. In this study, we characterised partial MHCII DAB and DBB genes in female koalas (n = 94 from a single geographic population, and investigated associations among antibody responses to c-hsp60 quantified by ELISA, susceptibility to chlamydial infection, or age. The identification of three candidate MHCII variants provides additional support for the functional role of MHCII in the koala, and will inform more focused future studies. This is the first study to investigate an association between MHC genes with chlamydial pathogenesis in a non-model, free-ranging species.

  15. Population-specific association between ABCG2 variants and tophaceous disease in people with gout.

    Science.gov (United States)

    He, Wendy; Phipps-Green, Amanda; Stamp, Lisa K; Merriman, Tony R; Dalbeth, Nicola

    2017-03-07

    Tophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the role of SLC2A9 and ABCG2 variants in tophaceous disease in people with gout. Participants (n = 1778) with gout fulfilling the 1977 American Rheumatism Association (ARA) classification criteria, who were recruited from primary and secondary care, attended a detailed study visit. The presence of palpable tophi was recorded. SLC2A9 rs11942223, ABCG2 rs2231142 and ABCG2 rs10011796 were genotyped. Data were analysed according to tophus status. Compared to participants without tophi, those with tophi were older, had longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry. SLC2A9 rs11942223 was not associated with tophi. However, the risk alleles for both ABCG2 single nucleotide polymorphisms (SNPs) were present more frequently in those with tophi (OR (95% CI) 1.24 (1.02-1.51) for rs2231142 and 1.33 (1.01-1.74) for rs10011796, p gout.

  16. A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

    Science.gov (United States)

    Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

    2016-06-22

    A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance.

  17. Constant Transmission Properties of Variant Creutzfeldt-Jakob Disease in 5 Countries

    Science.gov (United States)

    Diack, Abigail B.; Ritchie, Diane; Bishop, Matthew; Pinion, Victoria; Brandel, Jean-Philippe; Haik, Stephane; Tagliavini, Fabrizio; Van Duijn, Cornelia; Belay, Ermias D.; Gambetti, Pierluigi; Schonberger, Lawrence B.; Piccardo, Pedro; Will, Robert G.

    2012-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases. PMID:23017202

  18. Short TE quantitative proton magnetic resonance spectroscopy in variant Creutzfeldt-Jakob disease

    Energy Technology Data Exchange (ETDEWEB)

    Cordery, R.J.; Godbolt, A.; Rossor, M.N. [University College London, Dementia Research Group, Institute of Neurology, London (United Kingdom); Imperial College of Science, Technology and Medicine, Division of Neuroscience and Psychological Medicine, Faculty of Medicine, London (United Kingdom); MacManus, D. [University College London, NMR Research Unit, Department of Clinical Neurology,Institute of Neurology, London (United Kingdom); Waldman, A.D. [University College London, Dementia Research Group, Institute of Neurology, London (United Kingdom); Imperial College of Science, Technology and Medicine, Division of Neuroscience and Psychological Medicine, Faculty of Medicine, London (United Kingdom); Charing Cross Hospital, Department of Imaging, London (United Kingdom); National Hospital for Neurology and Neurosurgery, Dementia Research Group, London (United Kingdom)

    2006-08-15

    Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegerative disorder. Clinical diagnosis is difficult in the early stages as the disease often presents with non-specific psychiatric and neurological symptoms. To investigate the diagnostic potential of quantitative short TE in vivo MRS, and the nature and anatomical distribution of biochemical abnormalities in vCJD, localised single-voxel spectra (TE/TR 30 ms/2,000 ms) were acquired from three brain regions: thalami, caudate nuclei and frontal white matter. Metabolite concentrations and ratios from three patients with definite or probable vCJD were compared with eight normal age-matched controls. Abnormal signal on T2-weighted MRI was apparent in the pulvinar region in all vCJD patients; this region also showed greatly increased myo-inositol [MI] (mean 2.5-fold, P=0.01) and decreased N-acetyl-aspartate (NAA; mean 2-fold, P=0.01). Two patients also showed increased [MI] (z=17, 11; one with decreased NAA, z=-12) in normal-appearing caudate nuclei. The magnitude of metabolite abnormalities in the thalami in moderately advanced vCJD suggests a potential role in earlier diagnosis. Short TE protocols allow the measurement of MI, which adds discriminant power to the MRS examination. (orig.)

  19. Laminar Distribution of the Pathological Changes in Sporadic and Variant Creutzfeldt-Jakob Disease

    Directory of Open Access Journals (Sweden)

    R. A. Armstrong

    2011-01-01

    Full Text Available The laminar distributions of the pathological changes in the cerebral cortex were compared in the prion diseases sporadic Creutzfeldt-Jakob disease (sCJD and variant CJD (vCJD. First, in some cortical regions, the vacuolation (“spongiform change” was more generally distributed across the cortex in sCJD. Second, there was greater neuronal loss in the upper cortex in vCJD and in the lower cortex in sCJD. Third, the “diffuse” and “florid” prion protein (PrPsc deposits were more frequently distributed in the upper cortex in vCJD and the “synaptic” deposits in the lower cortex in sCJD. Fourth, there was a significant gliosis mainly affecting the lower cortex of both disorders. The data suggest that the pattern of cortical degeneration is different in sCJD and vCJD which may reflect differences in aetiology and the subsequent spread of prion pathology within the brain.

  20. GM2-gangliosidosis variant 0 (Sandhoff-like disease) in a family of Japanese domestic cats.

    Science.gov (United States)

    Yamato, O; Matsunaga, S; Takata, K; Uetsuka, K; Satoh, H; Shoda, T; Baba, Y; Yasoshima, A; Kato, K; Takahashi, K; Yamasaki, M; Nakayama, H; Doi, K; Maede, Y; Ogawa, H

    2004-12-04

    A five-month-old, female Japanese domestic shorthair cat with proportionate dwarfism developed neurological disorders, including ataxia, decreased postural responses and generalised body and head tremors, at between two and five months of age. Leucocytosis due to lymphocytosis with abnormal cytoplasmic vacuolations was observed. The concentration of G(M2)-ganglioside in its cerebrospinal fluid was markedly higher than in normal cats, and the activities of beta-hexosaminidases A and B in its leucocytes were markedly reduced. On the basis of these biochemical data, the cat was diagnosed antemortem with G(M2)-gangliosidosis variant 0 (Sandhoff-like disease). The neurological signs became more severe and the cat died at 10 months of age. Histopathologically, neurons throughout the central nervous system were distended, and an ultrastructural study revealed membranous cytoplasmic bodies in these distended neurons. The compound which accumulated in the brain was identified as G(M2)-ganglioside, confirming G(M2)-gangliosidosis. A family study revealed that there were probable heterozygous carriers in which the activities of leucocyte beta-hexosaminidases A and B were less than half the normal value. The Sandhoff-like disease observed in this family of Japanese domestic cats is the first occurrence reported in Japan.

  1. Identification of MHCII variants associated with chlamydial disease in the koala (Phascolarctos cinereus).

    Science.gov (United States)

    Lau, Quintin; Griffith, Joanna E; Higgins, Damien P

    2014-01-01

    Chlamydiosis, the most common infectious disease in koalas, can cause chronic urogenital tract fibrosis and infertility. High titres of serum immunoglobulin G against 10 kDa and 60 kDa chlamydial heat-shock proteins (c-hsp10 and c-hsp60) are associated with fibrous occlusion of the koala uterus and uterine tube. Murine and human studies have identified associations between specific major histocompatibility complex class II (MHCII) alleles or genotypes, and higher c-hsp 60 antibody levels or chlamydia-associated disease and infertility. In this study, we characterised partial MHCII DAB and DBB genes in female koalas (n = 94) from a single geographic population, and investigated associations among antibody responses to c-hsp60 quantified by ELISA, susceptibility to chlamydial infection, or age. The identification of three candidate MHCII variants provides additional support for the functional role of MHCII in the koala, and will inform more focused future studies. This is the first study to investigate an association between MHC genes with chlamydial pathogenesis in a non-model, free-ranging species.

  2. Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β.

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-02-11

    We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.

  3. Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid-β

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  4. Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease

    NARCIS (Netherlands)

    Kauwe, John S. K.; Cruchaga, Carlos; Karch, Celeste M.; Sadler, Brooke; Lee, Mo; Mayo, Kevin; Latu, Wayne; Su'a, Manti; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Goate, Alison M.; Saradha, A.; Abdi, Hervé; Abeliovich, Asa; Abellan van Kan, Gabor; Abner, Erin; Acharya, Deepa; Adams, Nicholas; Adler, Daniel; Agrusti, Antonella; Agyemang, Alex; Ahdidan, Jamila; Ahn, Jae Eun; Aisen, Paul; Aksu, Yaman; Al-Akhras, Mousa; Alarcon, Marcelo; Alberca, Roman; Alexander, Gene; Alexander, Daniel; Almeida, Fabio; Amlien, Inge; Anand, Shyam; Andrew, Marilee; Angersbach, Steve; Anjum, Ayesha; Aoyama, Eiji; Arfanakis, Konstantinos; Armor, Tom; Arnold, Steven; Asatryan, Albert; Ashe-McNalley, Cody; Ashiga, Hirokazu; Assareh, Arezoo; Le Page, Aurelie; Avants, Brian; Avinash, Gopal; Awasthi, Sukrati; Ayan-Oshodi, Mosun; Babic, Tomislav; Baek, Young; Bagci, Ulas; Bai, Shuyang; Baird, Geoffrey; Baker, John; Banks, Sarah; Bard, Jonathan; Barnes, Josephine; Barret, Olivier; Bartlett, Jonathan; Bartzokis, George; Barua, Neil; Bauer, Corinna; Becker, James; Becker, J. Alex; Beckett, Laurel; Bednar, Martin; Beg, Mirza Faisal; Bek, Stephan; Belmokhtar, Nabil; Bernard, Charlotte; Bertram, Lars; Bhaskar, Uday; Biffi, Alessandro; Bigler, Erin; Bilgic, Basar; Bishop, Courtney; Bittner, Daniel; Black, Ronald; Blennow, Kaj; Bogorodzki, Piotr; Bokde, Arun; Bonner-Jackson, Aaron; Boppana, Madhu; Bourgeat, Pierrick; Bowes, Mike; Bowman, Gene; Braskie, Meredith; Braunewell, Karl; Breitner, Joihn; Brewer, James; Brickman, Adam; Britschgi, Markus; Broadbent, Steve; Brogren, Jacob; Brooks, David; Browndyke, Jeffrey; Brunton, Simon; Buchert, Ralph; Buchsbaum, Monte; Buckley, Chris; Buerger, Katharina; Burger, Cyrill; Burnham, Samantha; Burns, Jeffrey; Burton, David; Butman, John; Cabeza, Rafael; Cairns, Nigel; Callhoff, Johanna; Calvini, Piero; Cantillon, Marc; Capella, Heraldo; Cardona-Sanclemente, Luis Eduardo; Carle, Adam; Carmasin, Jeremy; Carranza-Ath, Fredy; Casabianca, Jodi; Casanova, Ramon; Cash, David; Cedarbaum, Jesse; Cella, Massimo; Celsis, Pierre; Chaney, Megan; Chanu, Pascal; Chao, Linda; Charil, Arnaud; Chemali, Zeina; Chen, Kewei; Chen, Minhua; Chen, Rong; Chen, Baojiang; Chen, Jake; Chen, Gennan; Chen, Wei; Cheng, Wei-Chen; Chertkow, Howard; Cheung, Charlton; Cheung, Vinci; Chiang, Gloria; Chiba, Koji; Chin, Simon; Chisholm, Jane; Cho, Youngsang; Choe, John; Choubey, Suresh; Christensen, Anette Luther; Clark, Chris; Clark, David; Clarkson, Matt; Clayton, David; Clunie, David; Coimbra, Alexandre; Compton, David; Coppola, Giovanni; Cover, Keith S.; Crane, Paul; Crans, Gerald; Croop, Robert; Crowther, Daniel; Crum, William; Cui, Yue; Curry, Charles; Curtis, Steven; Cutter, Gary; Daiello, Lori; Dake, Michael; Dale, Anders; Daliri, Mohammad Reza; Damato, Vito Domenico; Darby, Eveleen; Darkner, Sune; Davatzikos, Christos; Dave, Jay; David, Renaud; Davidson, Julie; de Bruijne, Marleen; de Meyer, Geert; de Nunzio, Giorgio; Decarli, Charles; Dechairo, Bryan; DeDuck, Kristina; Dehghan, Hossein; Dejkam, Arsalan; Delfino, Manuel; Dellavedova, Luca; Delpassand, Ebrahim; Delrieu, Julien; Deniz, Oscar; Denney, Douglas; DeOrchis, Vincent; Dépy Carron, Delphine; deToledo-Morrell, Leyla; Devanand, Davangere; Devanarayan, Viswanath; Diaz-Arrastia, Ramon; Dickerson, Bradford; Ding, Xiaobo; Dinov, Ivo; Dobson, Howard; Dodge, Hiroko; Donohue, Michael; Dore, Vincent; Dorflinger, Ernest; Dowling, Maritza; Duan, Xujun; Dubal, Dena; Duchesne, Simon; Duff, Kevin; Dukart, Jürgen; Durazzo, Timothy; Dykstra, Kevin; Earl, Nancy; Edula, Goutham; Ekin, Ahmet; Elcoroaristizabal, Xabier; Emahazion, Tesfai; Engelman, Corinne; Epstein, Noam; Erten-Lyons, Deniz; Eskildsen, Simon; Falcone, Guido; Fan, Yong; Fan, Lingzhong; Farb, Norman; Farnum, Michael; Farrer, Lindsay; Farzan, Ali; Faux, Noel; Feldman, Howard; Feldman, Susan; Fennema-Notestine, Christine; Fernandes, Michel; Fernandez, Elsa; Ferrarini, Luca; Ferreira, Manuel Joao; Ferrer, Eugene; Figurski, Michal; Filipovych, Roman; Fillit, Howard; Finch, Stephen; Finlay, Daniel; Fiot, Jean-Baptiste; Flenniken, Derek; Fletcher, P. Thomas; Fletcher, Evan; Flynn Longmire, Crystal; Focke, Niels; Forman, Mark; Forsythe, Alan; Fox, Steven; Fox-Bosetti, Sabrina; Francis, Alexander L.; Franco-Villalobos, Conrado; Franko, Edit; Freeman, Stefanie; Friedrich, Christoph M.; Friesenhahn, Michel; Frings, Lars; Frisoni, Giovanni; Fritzsche, Klaus; Fujimoto, Yoko; Fujiwara, Ken; Fullerton, Terence; Furney, Simon; Gallins, Paul; Gamst, Anthony; Gan, Ke; Garcia, Maria Teresa; Garg, Gaurav; Gaser, Christian; Gastineau, Edward; Gauthier, Serge; Gavett, Brandon; Gavidia, Giovana; Gazdzinski, Stefan; Ge, Qi; Gemme, Gianluca; Geraci, Joseph; German, Dwight; Ghassabi, Zeinab; Gieschke, Ronald; Gil, Juan E.; Gill, Ryan; Gitelman, Darren; Gleason, Carey; Godbey, Michael; Goghari, Vina; Gold, Michael; Goldberg, Terry; Gomeni, Roberto; Gong, Shangwenyan; Gonzales, Celedon; Goodro, Robert; Gordon, Brian; Gorriz, Juan Manuel; Grachev, Igor; Grandey, Emily; Grasela, Thaddeus; Gratt, Jeremy; Gray, Katherine; Greenberg, Barry; Gregg, Keith; Gregory, Erik; Greicius, Michael; Greve, Douglas; Grill, Joshua; Gross, Alden; Gross, Alan; Guignot, Isabelle; Guo, Qimiao; Guo, Hongbin; Guo, Lianghao; Guo, Jeffrey; Habeck, Christian; Hai, Yizhen; Haight, Thaddeus; Hammarstrom, Per; Hampel, Harald; Han, Jian; Han, Tony; Hanif, Muhammad; Hanna, Yousef; Hardy, Peter; Harvey, Danielle; Hasan, Md Kamrul; Hayashi, Toshihiro; Hazart, Aurelien; He, Huiguang; He, Yong; Head, Denise; Heckemann, Rolf; Heidebrink, Judith; Henderson, David; Henrard, Sébastien; Herholz, Karl; Hernandez, Monica; Herskovits, A. Zara; Hess, Christopher; Hildenbrand, Maike; Hobart, Jeremy; Hoffman, John; Holder, Daniel; Honigberg, Lee; Hoppin, Jack; Horsfield, Mark; Hou, Yangyang; Hsu, Ailing; Hsu, Wei-Wen; Hu, Zhiwei; Hu, Xiaolan; Hu, Zhenghui; Hu, William; Huang, Chien-Chih; Huang, Chingwen; Huang, Shuai; Huang, Yifan; Huang, Juebin; Huang, Chun-Jung; Huang, Shu-Pang; Huang, Fude; Hubbard, Rebecca; Huentelman, Matthew; Hui, Shen; Huppertz, Hans-Jürgen; Hurko, Orest; Hurt, Stephen; Huyck, Susan; Hwang, Scott; Hyun, JungMoon; Ifeachor, Emmanuel; Iglesias, Martina; Ikari, Yasuhiko; Ikonomidou, Vasiliki; Immermann, Fred; Inoue, Lurdes; Insel, Philip; Irizarry, Michael; Irungu, Benson mwangi; Ishibashi, Taro; Ishii, Kenji; Ismail, Sara; Ismail, Shahina; Ito, Kaori; Iturria-Medina, Yasser; Iwatsubo, Takeshi; Iyer, Madhumitha; Jacobson, Mark; Jafari, Aria; Jafari-Khouzani, Kourosh; Jaffe, Carl; Jagust, William; Jara, Hernan; Jasperse, Bas; Jedynak, Bruno; Jefferson, Angela; Jennings, J. Richard; Jessen, Walter; Jia, Fucang; Jiang, Tianzi; Jing, Huang; Johnson, David K.; Jones, Richard; Juengling, Freimut; Juh, Rahyeong; Julin, Per; Uday Bhaskar, K.; Kadish, Bill; Kahle-Wrobleski, Kristin; Kallam, Hanimi Reddy; Kamboh, M. Ilyas; Kaneko, Tomoki; Kaneta, Tomohiro; Karageorgiou, Elissaios; Karantzoulis, Stella; Karlawish, Jason; Katz, Elyse; Kaushik, Sandeep S.; Kauwe, John; Kawakami, Hirofumi; Kazimipoor, Borhan; Kelleher, Thomas; Kennedy, Richard; Kerr, Douglas; Kerrouche, Nacer; Khalil, Iya; Khalil, Andre; Killeen, Neil; Killiany, Ron; Kim, Ana; Kim, Yeonhee; Kim, Heeyoung; Kim, Jong Hun; Kim, Hyoungkyu; Kim, Seongkyun; Kim, Hyewon; Kimberg, Daniel; Kimura, Tokunori; King, Richard; Kirby, Justin; Kirsch, Wolff; Klimas, Michael; Kline, Richard; Kling, Mitchel; Klopfenstein, Erin; Kobayashi, Dione; Koikkalainen, Juha; Kokomoor, Anders; Kolasny, Anthony; Koppel, Jeremy; Korolev, Igor; Kotran, Nickolas; Kouassi, Alex; Kowalczyk, Adam; Kozma, Lynn; Kratzer, Martina; Kuceyeski, Amy; Kuhn, Félix Pierre; Kulkarni, Mauktik; Kumar, Sreedhar; Kuo, Hsun Ting; Kuo, Julie; Kurosawa, Ken; Kwon, Oh Hun; Laforet, Genevieve; Lai, Song; Lakatos, Anita; Lam, On Ki; Lampron, Antoine; Landau, Susan; Landen, Jaren; Lane, Richard; Langbaum, Jessica; Langford, Dianne; Lanius, Vivian; Lavault, Romain; Laxamana, Joel; Le, Trung; Leahy, Richard; Lee, Noah; Lee, Dongsoo; Lee, Vita; Lee, Joseph H.; Lee, Jong-Min; Lefkimmiatis, Stamatis; Lemaitre, Herve; Lenz, Robert; Lester, Gayle; Levey, Allan; Li, Wenjun; Li, Shanshan; Li, Xiaodong; Li, Gang; Li, Ming; Li, Chin-Shang; Li, Lexin; Li, Jinhe; Li, Quanzheng; Li, Yi; Li, Rui; Li, Shi-jiang; Liang, Peipeng; Liang, Lichen; Liang, Kuchang; Liao, Yuan-Lin; Lin, Ling-chih; Lin, Mingkuan; Lin, Ai-Ling; Lin, Lan; Liu, Tianming; Liu, Meijie; Liu, Tao; Liu, Li; Liu, Xiuwen; Liu, Sophia; Liu, Dazhong; Liu, Songling; Liu, Yuan; Liu, Pu; Lo, Raymond; Lobanov, Victor; Loewenstein, David; Logovinsky, Veronika; Long, Xiaojing; Long, Ziyi; Looi, Jeffrey; Lu, Po-Haong; Lukic, Ana; Lull, Juan J.; Luo, Xiongjian; Lynch, John; Ma, Lei; Mackin, Scott; Magda, Sebastian; Maglio, Silvio; Mak, Henry Ka-Fung; Malave, Vicente; Maldjian, Joseph; Mandal, Pravat; Mangin, Jean-Francois; Manjon, Jose; Manohar, Deepak; Mansouri, Chemseddine; Mantri, Ninad; Manzour, Amir; Marambaud, Philippe; Marchewka, Artur; Marek, Kenneth; Markind, Samuel; Marshall, Gad; Martinez Torteya, Antonio; Mather, Mara; Mathis, Chester; Matoug, Sofia; Matsuo, Yoshiyuki; Matthews, Dawn; McArdle, John; McEvoy, Linda; McGeown, William; McIntyre, John; McQuail, Joseph; Meadowcroft, Mark; Meda, Shashwath; Mehta, Nirav; Mendonca, Brian; Menendez, Manuel; Meredith, Jere; Merrill, David; Mesulam, Marek-Marsel; Metti, Andrea; Meyer, Carsten; Mez, Jesse; Mickael, Guedj; Miftahof, Roustem; Mikhno, Arthur; Miller, David; Millikin, Colleen; Min, Ye; Mirza, Mubeena; Mitsis, Effie; Mohan, Ananth; Montana, Giovanni; Moore, Dana; Moradi Birgani, Parmida; Moratal, David; Morimoto, Bruce; Mortamet, Bénédicte; Moscato, Pablo; Motyl, Rafal; Mueller, Kathyrne; Mueller, Susanne; Mueller, Notger; Mukherjee, Shubhabrata; Mulder, Emma; Murayama, Shigeo; Murphy, Michael; Murray, Brian; Musiek, Erik; Myers, Amanda; Najafi, Shahla; Nazarparvar, Babak; Nazeri, Arash; Nettiksimmons, Jasmine; Neu, Scott; Neves, Simone; Ng, Yen-Bee; Nguyen, Nghi; Nguyen Xuan, Tuong; Nicodemus, Kristin; Niecko, Timothy; Nielsen, Casper; Notomi, Keiji; Nuneez Benjumea, Francisco; O'Bryant, Sid; O'Neil, Alison; Obisesan, Thomas; Oh, Dong Hoon; Oh, Joonmi; Okonkwo, Ozioma; Olde Rikkert, Marcel; Olmos, Salvador; Ortner, Marion; Ostrowitzki, Susanne; Oswald, Annahita; Ott, Brian; Ourselin, Sebastien; Ouyang, Gaoxiang; Paiva, Renata; Pan, Zhifang; Pande, Yogesh; Pardo, Jose; Pardoe, Heath; Park, Hyunjin; Park, Moon Ho; Park, Sang hyun; Park, Kee Hyung; Park, Sujin; Parsey, Ramin; Parveen, Riswana; Paskavitz, James; Patel, Yogen; Patil, Manasi; Pawlak, Mikolaj; Payoux, Pierre; Pearson, Jim; Peavy, Guerry; Pell, Gaby; Peng, Yahong; Pennec, Xavier; Pepin, Jean louis; Perea, Rodrigo; Perneczky, Robert; Petitti, Diana; Petrella, Jeffrey; Peyrat, Jean-Marc; Pezoa, Jorge; Pham, Chi-Tuan; Phillips, Nicole; Pierson, Ronald; Piovezan, Mauro; Podhorski, Adam; Pollari, Mika; Pontecorvo, Michael; Poppenk, Jordan; Posner, Holly; Potkin, Steven; Potter, Elizabeth; Poulin, Stephane; Prasad, Gautam; Prenger, Kurt; Prince, Jerry; Priya, Anandh; Puchakayala, Shashidhar Reddy; Qiu, Anqi; Qiu, Ruolun; Qiu, Wendy; Qualls, Constance Dean; Rabie, Huwaida; Rajeesh, Rajeesh; Rallabandi, V. P. Subramanyam; Ramage, Amy; Randolph, Christopher; Rao, Anil; Rao, Divya; Raubertas, Richard; Ray, Debashis; Razak, Hana; Redolfi, Alberto; Reed, Bruce; Reid, Andrew; Reilhac, Anthonin; Reinsberger, Claus; Restrepo, Lucas; Retico, Alessandra; Rezaeitabar, Yousef; Richards, John; Richter, Mirco; Riddle, William; Ries, Michele; Rincón, Mariano; Rischall, Matt; Robieson, Weining; Rocha-Rego, Vanessa; Rogalski, Emily; Rogers, Elizabeth; Rojas, Ignacio; Rojas Balderrama, Javier; Romero, Klaus; Rorden, Chris; Rosand, Jonathan; Rosen, Allyson; Rosen, Ori; Rosenberg, Paul; Ross, David; Ross, Joel; Roubini, Eli; Rousseau, François; Rowe, Christopher; Rubin, Daniel; Rubright, Jonathan; Ruiz, Agustin; Rusinek, Henry; Ryan, Laurie; Saad, Ahmed; Sabbagh, Marway; Sabuncu, Mert; Sachs, Michael; Sacuiu, Simona; Sadeghi, Ali; Said, Yasmine; Saint-Aubert, Laure; Sakata, Muneyuki; Salat, David; Salmon, David; Salomi, Sharmila; Salter, Hugh; Samwald, Matthias; Sanchez, Luciano; Sanders, Elizabeth; Sanjo, Nobuo; Sarnel, Haldun; Sato, Shinji; Sato, Hajime; Saumier, Daniel; Savio, Alexandre; Sawada, Ikuhisa; Saykin, Andrew; Schaffer, J. David; Scharre, Douglas; Schegerin, Marc; Schlosser, Gretchen; Schmand, Ben; Schmansky, Nick; Schmidt, Mark; Schneider, Lon; Schramm, Hauke; Schuerch, Markus; Schwartz, Craig; Schwartz, Eben; Schwarz, Adam; Seethamraju, Ravi; Seixas, Flavio; Selnes, Per; Senjem, Matthew; Senlin, Wang; Seo, Sang Won; Sethuraman, Gopalan; Sevigny, Jeffrey; Sfikas, Giorgos; Sghedoni, Roberto; Shah, Said Khalid; Shahbaba, Babak; Shams, Soheil; Shattuck, David; Shaw, Leslie; Sheela, Jaba; Shen, Weijia; Shen, Qian; Shera, David; Sherman, John; Sherva, Richard; Shi, Feng; Shukla, Vinay; Shuler, Catherine; Shulman, Joshua; Siegel, Rene; Siemers, Eric; Silveira, Margarida; Silver, Michael; Silverman, Daniel; Sim, Ida; Simmons, Andy; Simoes, Rita; Simon, Melvin; Simpson, Ivor; Singh, Simer Preet; Singh, Nikhil; Siuciak, Judy; Sjögren, Niclas; Skup, Martha; Small, Gary; Smith, Michael; Smith, Charles; Smith, Benjamin; Smyth, Timothy; Snow, Sarah; Soares, Holly; Soldea, Octavian; Solomon, Alan; Solomon, Paul; Som, Subhojit; Song, Changhong; Song, Mingli; Sorensen, Greg; Soudah, Eduardo; Spampinato, Maria Vittoria; Spenger, Christian; Sperling, Reisa; Spiegel, René; Spies, Lothar; Squarcia, Sandro; Squire, Larry; Staff, Roger; Stern, Yaakov; Straw, Jack; Strittmatter, Stephen; Stühler, Elisabeth; Styren, Scot; Subramanian, Vijayalakshmi; Sugishita, Morihiro; Sukkar, Rafid; Sun, Ying; Sun, Yu; Sun, Jia; Sundell, Karen; Suri, Muhammad; Suzuki, Akiyuki; Svetnik, Vladimir; Swan, Melanie; Takahasi, Tetsuhiko; Takeuchi, Tomoko; Tanaka, Shoji; Tancredi, Daniel; Tang, Songyuan; Tao, Dacheng; Tao, Wenwen; Tariot, Pierre; Taylor-Reinwald, Lisa; Teng, Edmond; Terlizzi, Rita; Thiele, Frank; Thomas, Ronald; Thomas, Benjamin; Thompson, Paul; Thompson, Wesley; Thornton-Wells, Tricia; Thurfjell, Lennart; Titeux, Laurence; Tokuda, Takahiko; Toledo, Juan B.; Tolli, Tuomas; Toma, Ahmed; Tomita, Naoki; Toro, Roberto; Tosun, Duygu; Tousian, Mona; Toussaint, Paule; Toyoshiba, Hiroyoshi; Tractenberg, Rochelle E.; Trittschuh, Emily; Trojanowski, John; Truran, Diana; Tsechpenakis, Gavriil; Tucker-Drob, Elliot; Tufail, Ahsan; Tung, Joyce; Ueda, Yoji; Ullrich, Lauren; Umadevi Venkataraju, Kannan; Umar, Nisser; Uzunbas, Gokhan; van de Nes, Joseph; van der Brug, Marcel; van Horn, John; van Leemput, Koen; van Train, Kenneth; van Zeeland, Ashley; Vasanawala, Minal; Vemuri, Prashanthi; Verwaerde, Philippe; Videbaek, Charlotte; Vidoni, Eric; Vigneron, Vincent; Villanueva-Meyer, Javier; Visser, Pieter Jelle; Vitolo, Ottavio; Vounou, Maria; Wade, Sara; Walhovd, Kristine B.; Wan, Hong; Wang, Lubin; Wang, Xu; Wang, Ze; Wang, Angela; Wang, Tiger; Wang, Yongmei Michelle; Wang, Yaping; Wang, Wei; Wang, Huali; Wang, Yue; Wang, Li-San; Wang, Huanli; Wang, Alex; Wang, Yalin; Wang, Lei; Ward, Michael; Warfield, Simon; Waring, Stephen; Watanabe, Toshiyuki; Webb, David; Wei, Lili; Weiner, Michael; Wen, Shu-Hui; Wenjing, Li; Wenzel, Fabian; Westlye, Lars T.; Whitcher, Brandon; Whitlow, Christopher; Whitwell, Jennifer; Wilhelmsen, Kirk; Williams, David; Wilmot, Beth; Wingo, Thomas; Winkler, Andreas; Wiste, Heather; Wolfson, Tanya; Wolke, Ira; Wolz, Robin; Woo, Jongwook; Woo, Ellen; Woods, Lynn; Worth, Andrew; Worth, Eric; Wouters, Hans; Wu, Teresa; Wu, Ellen; Wu, Yi-Gen; Wu, Liang; Wu, Xiaoling; Wyman, Bradley; Wyss-Coray, Tony; Xiao, Liu; Xiao, Guanghua; Xie, Sharon; Xu, Jun; Xu, Ye; Xu, Yi-Zheng; Xu, Guofan; Yamane, Tomohiko; Yamashita, Fumio; Yan, Yunyi; Yan, Pingkun; Yang, Jinzhong; Yang, Qing X.; Yang, Zijiang; Yang, Guang; Yang, Wenlu; Yang, Eric; Yang, Zhitong; Ye, Jieping; Ye, Jong; Ye, Liang; Ye, Byoung Seok; Yee, Laura; Yesavage, Jerome; Ying, Song; Yoo, Bongin; Young, Jonathan; Yu, Dongchuan; Yu, Shiwei; Yuan, Kai; Yuan, Guihong; Yushkevich, Paul; Zaborszky, Laszlo; Zagorodnov, Vitali; Zagorski, Michael; Zawadzki, Rezi; Zeitzer, Jamie; Zhang, Huixiong; Zhang, Tianhao; Zhang, Ping; Zhang, Xin; Zhang, Bin; Zhang, Jing; Zhang, Linda; Zhang, Lijun; Zhang, Kurt; Zhao, Jim; Zhao, Peng; Zhao, Qinying; Zhen, Xiantong; Zheng, Yuanjie; Zhijun, Yao; Zhou, Sheng; Zhou, Bin; Zhu, Wanlin; Zhu, Hongtu; Zhu, Wen; Zito, Giancarlo; Zou, Heng

    2011-01-01

    Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom

  5. BRCA2 Variants and cardiovascular disease in a multi-ethnic study

    Directory of Open Access Journals (Sweden)

    Zbuk Kevin

    2012-07-01

    Full Text Available Abstract Background Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD. Methods Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP, the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8% reported a CVD event, defined as myocardial infarction (MI, angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART, and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS. Results Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01 p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0

  6. Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene.

    Science.gov (United States)

    Backer, Julie De; Braverman, Alan C

    2018-05-01

    Predominant cardiovascular manifestations in the spectrum of Heritable Thoracic Aortic Disease include by default aortic root aneurysms- and dissections, which may be associated with aortic valve disease. Mitral- and tricuspid valve prolapse are other commonly recognized features. Myocardial disease, characterized by heart failure and/or malignant arrhythmias has been reported in humans and in animal models harboring pathogenic variants in the Fibrillin1 gene. Description of clinical history of three cases from one family in Ghent (Belgium) and one family in St. Louis (US). We report on three cases from two families presenting end-stage heart failure (in two) and lethal arrhythmias associated with moderate left ventricular dilatation (in one). All three cases harbor a pathogenic variant in the SMAD3 gene, known to cause aneurysm osteoarthritis syndrome, Loeys-Dietz syndrome type 3 or isolated Heritable Thoracic Aortic Disease. These unusual presentations warrant awareness for myocardial disease in patients harboring pathogenic variants in genes causing Heritable Thoracic Aortic Disease and indicate the need for prospective studies in larger cohorts. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  7. Fronto-striatal atrophy in behavioural variant frontotemporal dementia & Alzheimer’s disease

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    Maxime eBertoux

    2015-07-01

    Full Text Available Behavioural variant frontotemporal dementia (bvFTD has only recently been associated with significant striatal atrophy, whereas the striatum appears to be relatively preserved in Alzheimer’s disease (AD. Considering the critical role the striatum has in cognition and behaviour, striatal degeneration, together with frontal atrophy, could be responsible of some characteristic symptoms in bvFTD and emerges therefore as promising novel diagnostic biomarker to distinguish bvFTD and AD. Previous studies have, however, only taken either cortical or striatal atrophy into account when comparing the two diseases. In this study, we establish for the first time a profile of fronto-striatal atrophy in 23 bvFTD and 29 AD patients at presentation, based on the structural connectivity of striatal and cortical regions. Patients are compared to 50 healthy controls by using a novel probabilistic connectivity atlas, which defines striatal regions by their cortical white matter connectivity, allowing us to explore the degeneration of the frontal and striatal regions that are functionally linked. Comparisons with controls revealed that bvFTD showed substantial fronto-striatal atrophy affecting the ventral as well as anterior and posterior dorso-lateral prefrontal cortices and the related striatal subregions. By contrast, AD showed few fronto-striatal atrophy, despite having significant posterior dorso-lateral prefrontal degeneration. Direct comparison between bvFTD and AD revealed significantly more atrophy in the ventral striatal-ventromedial prefrontal cortex regions in bvFTD. Consequently, deficits in ventral fronto-striatal regions emerge as promising novel and efficient diagnosis biomarker for bvFTD. Future investigations into the contributions of these fronto-striatal loops on bvFTD symptomology are needed to develop simple diagnostic and disease tracking algorithms.

  8. Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease.

    Science.gov (United States)

    Deshpande, Vikram; Huck, Amelia; Ooi, Esther; Stone, John H; Faquin, William C; Nielsen, G Petur

    2012-08-01

    Hashimoto thyroiditis (HT) and the fibrosing variant of Hashimoto thyroiditis (FVHT) are immune-mediated tumefactive lesions of the thyroid. Immunoglobulin G4-related disease (IgG4-RD) is now a widely recognised multi-organ system disease characterised by elevated serum and tissue concentrations of IgG4. In this study, the authors address several unresolved questions pertaining to the relationship between HT and FVHT, and the association of each of these diseases with IgG4-RD. The authors evaluated 28 consecutive cases of HT and nine cases of FVHT. The clinical, demographic and serological data were recorded. The slides were stained immunohistochemically using antibodies to IgG4 and IgG and the quantitative analysis was recorded. Data on thyroid function tests were available on seven cases of FVHT and 14 cases of HT. Based on the availability of data, hypothyroidism was noted in 62% (9/14) of HT and 86% of FVHT (6/7). FVHT demonstrated an exaggerated lobular pattern with lobules separated by cellular storiform-type fibrosis, resembling fibrosis seen in other forms of IgG-RD. The median IgG4 counts per high power field (×40) in HT and FVHT were 2.3 and 22, respectively. The median IgG4:IgG ratios in HT and FVHT were 0.11 and 0.58, respectively. The authors propose that FVHT belongs to the spectrum of IgG4-RD. Although a proportion of cases of HT show elevated numbers of IgG4 positive plasma cells, these cases lack the histological features typically associated with IgG4-RD, and thus the relationship between HT and IgG4-RD remains unproven.

  9. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.

    Directory of Open Access Journals (Sweden)

    Carlos Cruchaga

    Full Text Available Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD. Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7% carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09 × 10⁻⁵; OR = 2.21; 95%CI = 1.49-3.28 or an unselected population of 12,481 samples (p = 6.82 × 10⁻⁵; OR = 2.19; 95%CI = 1.347-3.26. Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.

  10. Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression.

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    Peter Messiaen

    Full Text Available BACKGROUND: As Lens epithelium-derived growth factor (LEDGF/p75 is an important co-factor involved in HIV-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs. Few data are available on the genetic variability of LEDGF/p75 and the influence on HIV disease in vivo. This study evaluated the relation between LEDGF/p75 genetic variation, mRNA expression and HIV-1 disease progression in order to guide future clinical use of LEDGINs. METHODS: Samples were derived from a therapy-naïve cohort at Ghent University Hospital and a Spanish long-term-non-progressor cohort. High-resolution melting curve analysis and Sanger sequencing were used to identify all single nucleotide polymorphisms (SNPs in the coding region, flanking intronic regions and full 3'UTR of LEDGF/p75. In addition, two intronic tagSNPs were screened based on previous indication of influencing HIV disease. LEDGF/p75 mRNA was quantified in patient peripheral blood mononuclear cells (PBMC using RT-qPCR. RESULTS: 325 samples were investigated from patients of Caucasian (n = 291 and African (n = 34 origin, including Elite (n = 49 and Viremic controllers (n = 62. 21 SNPs were identified, comprising five in the coding region and 16 in the non-coding regions and 3'UTR. The variants in the coding region were infrequent and had no major impact on protein structure according to SIFT and PolyPhen score. One intronic SNP (rs2737828 was significantly under-represented in Caucasian patients (P<0.0001 compared to healthy controls (HapMap. Two SNPs showed a non-significant trend towards association with slower disease progression but not with LEDGF/p75 expression. The observed variation in LEDGF/p75 expression was not correlated with disease progression. CONCLUSIONS: LEDGF/p75 is a highly conserved protein. Two non-coding polymorphisms were identified indicating a correlation with disease outcome, but further

  11. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

    DEFF Research Database (Denmark)

    Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun

    2011-01-01

    steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (~26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n¿=¿880 to 3,070). By carrying out a fixed-effects meta......-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ~2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome......Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic...

  12. Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study.

    Science.gov (United States)

    Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong

    2016-05-01

    Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.

  13. Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    Science.gov (United States)

    Scott, Robert A.; Freitag, Daniel F.; Li, Li; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; V.Varga, Tibor; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M.; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J.; Gillson, Christopher; Olama, Ali Amin Al; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C.; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L. Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A.; Earl, Helena M.; Ehret, Georg B.; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas; Ford, Ian; Forouhi, Nita G.; Gianfagna, Francesco; Gonzalez, Carlos; Grioni, Sara; Hiller, Louise; Jansson, Jan-Håkan; Jørgensen, Marit E.; Jukema, J. Wouter; Kaaks, Rudolf; Kee, Frank; Kerrison, Nicola D.; Key, Timothy J.; Kontto, Jukka; Kote-Jarai, Zsofia; Kraja, Aldi T.; Kuulasmaa, Kari; Kuusisto, Johanna; Linneberg, Allan; Liu, Chunyu; Marenne, Gaëlle; Mohlke, Karen L.; Morris, Andrew P.; Muir, Kenneth; Müller-Nurasyid, Martina; Munroe, Patricia B.; Navarro, Carmen; Nielsen, Sune F.; Nilsson, Peter M.; Nordestgaard, Børge G.; Packard, Chris J.; Palli, Domenico; Panico, Salvatore; Peloso, Gina M.; Perola, Markus; Peters, Annette; Poole, Christopher J.; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salomaa, Veikko; Sánchez, María-José; Sattar, Naveed; Sharp, Stephen J.; Sims, Rebecca; Slimani, Nadia; Smith, Jennifer A.; Thompson, Deborah J.; Trompet, Stella; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Virtamo, Jarmo; Walker, Mark; Walter, Klaudia; Abraham, Jean E.; Amundadottir, Laufey T.; Aponte, Jennifer L.; Butterworth, Adam S.; Dupuis, Josée; Easton, Douglas F.; Eeles, Rosalind A.; Erdmann, Jeanette; Franks, Paul W.; Frayling, Timothy M.; Hansen, Torben; Howson, Joanna M. M.; Jørgensen, Torben; Kooner, Jaspal; Laakso, Markku; Langenberg, Claudia; McCarthy, Mark I.; Pankow, James S.; Pedersen, Oluf; Riboli, Elio; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schunkert, Heribert; Vollenweider, Peter; O'Rahilly, Stephen; Deloukas, Panos; Danesh, John; Goodarzi, Mark O.; Kathiresan, Sekar; Meigs, James B.; Ehm, Margaret G.; Wareham, Nicholas J.; Waterworth, Dawn M.

    2016-01-01

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. PMID:27252175

  14. Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease.

    Science.gov (United States)

    Kelsen, Judith R; Dawany, Noor; Moran, Christopher J; Petersen, Britt-Sabina; Sarmady, Mahdi; Sasson, Ariella; Pauly-Hubbard, Helen; Martinez, Alejandro; Maurer, Kelly; Soong, Joanne; Rappaport, Eric; Franke, Andre; Keller, Andreas; Winter, Harland S; Mamula, Petar; Piccoli, David; Artis, David; Sonnenberg, Gregory F; Daly, Mark; Sullivan, Kathleen E; Baldassano, Robert N; Devoto, Marcella

    2015-11-01

    Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn's disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups. Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the

  15. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

    DEFF Research Database (Denmark)

    Lal, Dennis; Reinthaler, Eva M; Dejanovic, Borislav

    2016-01-01

    OBJECTIVE: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are...

  16. Common variants associated with plasma triglycerides and risk for coronary artery disease.

    Science.gov (United States)

    Do, Ron; Willer, Cristen J; Schmidt, Ellen M; Sengupta, Sebanti; Gao, Chi; Peloso, Gina M; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L; Mora, Samia; Beckmann, Jacques S; Bragg-Gresham, Jennifer L; Chang, Hsing-Yi; Demirkan, Ayşe; Den Hertog, Heleen M; Donnelly, Louise A; Ehret, Georg B; Esko, Tõnu; Feitosa, Mary F; Ferreira, Teresa; Fischer, Krista; Fontanillas, Pierre; Fraser, Ross M; Freitag, Daniel F; Gurdasani, Deepti; Heikkilä, Kauko; Hyppönen, Elina; Isaacs, Aaron; Jackson, Anne U; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kettunen, Johannes; Kleber, Marcus E; Li, Xiaohui; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Magnusson, Patrik K E; Mangino, Massimo; Mihailov, Evelin; Montasser, May E; Müller-Nurasyid, Martina; Nolte, Ilja M; O'Connell, Jeffrey R; Palmer, Cameron D; Perola, Markus; Petersen, Ann-Kristin; Sanna, Serena; Saxena, Richa; Service, Susan K; Shah, Sonia; Shungin, Dmitry; Sidore, Carlo; Song, Ci; Strawbridge, Rona J; Surakka, Ida; Tanaka, Toshiko; Teslovich, Tanya M; Thorleifsson, Gudmar; Van den Herik, Evita G; Voight, Benjamin F; Volcik, Kelly A; Waite, Lindsay L; Wong, Andrew; Wu, Ying; Zhang, Weihua; Absher, Devin; Asiki, Gershim; Barroso, Inês; Been, Latonya F; Bolton, Jennifer L; Bonnycastle, Lori L; Brambilla, Paolo; Burnett, Mary S; Cesana, Giancarlo; Dimitriou, Maria; Doney, Alex S F; Döring, Angela; Elliott, Paul; Epstein, Stephen E; Eyjolfsson, Gudmundur Ingi; Gigante, Bruna; Goodarzi, Mark O; Grallert, Harald; Gravito, Martha L; Groves, Christopher J; Hallmans, Göran; Hartikainen, Anna-Liisa; Hayward, Caroline; Hernandez, Dena; Hicks, Andrew A; Holm, Hilma; Hung, Yi-Jen; Illig, Thomas; Jones, Michelle R; Kaleebu, Pontiano; Kastelein, John J P; Khaw, Kay-Tee; Kim, Eric; Klopp, Norman; Komulainen, Pirjo; Kumari, Meena; Langenberg, Claudia; Lehtimäki, Terho; Lin, Shih-Yi; Lindström, Jaana; Loos, Ruth J F; Mach, François; McArdle, Wendy L; Meisinger, Christa; Mitchell, Braxton D; Müller, Gabrielle; Nagaraja, Ramaiah; Narisu, Narisu; Nieminen, Tuomo V M; Nsubuga, Rebecca N; Olafsson, Isleifur; Ong, Ken K; Palotie, Aarno; Papamarkou, Theodore; Pomilla, Cristina; Pouta, Anneli; Rader, Daniel J; Reilly, Muredach P; Ridker, Paul M; Rivadeneira, Fernando; Rudan, Igor; Ruokonen, Aimo; Samani, Nilesh; Scharnagl, Hubert; Seeley, Janet; Silander, Kaisa; Stančáková, Alena; Stirrups, Kathleen; Swift, Amy J; Tiret, Laurence; Uitterlinden, Andre G; van Pelt, L Joost; Vedantam, Sailaja; Wainwright, Nicholas; Wijmenga, Cisca; Wild, Sarah H; Willemsen, Gonneke; Wilsgaard, Tom; Wilson, James F; Young, Elizabeth H; Zhao, Jing Hua; Adair, Linda S; Arveiler, Dominique; Assimes, Themistocles L; Bandinelli, Stefania; Bennett, Franklyn; Bochud, Murielle; Boehm, Bernhard O; Boomsma, Dorret I; Borecki, Ingrid B; Bornstein, Stefan R; Bovet, Pascal; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C; Chen, Yii-Der Ida; Collins, Francis S; Cooper, Richard S; Danesh, John; Dedoussis, George; de Faire, Ulf; Feranil, Alan B; Ferrières, Jean; Ferrucci, Luigi; Freimer, Nelson B; Gieger, Christian; Groop, Leif C; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B; Hingorani, Aroon; Hirschhorn, Joel N; Hofman, Albert; Hovingh, G Kees; Hsiung, Chao Agnes; Humphries, Steve E; Hunt, Steven C; Hveem, Kristian; Iribarren, Carlos; Järvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kaprio, Jaakko; Kesäniemi, Antero; Kivimaki, Mika; Kooner, Jaspal S; Koudstaal, Peter J; Krauss, Ronald M; Kuh, Diana; Kuusisto, Johanna; Kyvik, Kirsten O; Laakso, Markku; Lakka, Timo A; Lind, Lars; Lindgren, Cecilia M; Martin, Nicholas G; März, Winfried; McCarthy, Mark I; McKenzie, Colin A; Meneton, Pierre; Metspalu, Andres; Moilanen, Leena; Morris, Andrew D; Munroe, Patricia B; Njølstad, Inger; Pedersen, Nancy L; Power, Chris; Pramstaller, Peter P; Price, Jackie F; Psaty, Bruce M; Quertermous, Thomas; Rauramaa, Rainer; Saleheen, Danish; Salomaa, Veikko; Sanghera, Dharambir K; Saramies, Jouko; Schwarz, Peter E H; Sheu, Wayne H-H; Shuldiner, Alan R; Siegbahn, Agneta; Spector, Tim D; Stefansson, Kari; Strachan, David P; Tayo, Bamidele O; Tremoli, Elena; Tuomilehto, Jaakko; Uusitupa, Matti; van Duijn, Cornelia M; Vollenweider, Peter; Wallentin, Lars; Wareham, Nicholas J; Whitfield, John B; Wolffenbuttel, Bruce H R; Altshuler, David; Ordovas, Jose M; Boerwinkle, Eric; Palmer, Colin N A; Thorsteinsdottir, Unnur; Chasman, Daniel I; Rotter, Jerome I; Franks, Paul W; Ripatti, Samuli; Cupples, L Adrienne; Sandhu, Manjinder S; Rich, Stephen S; Boehnke, Michael; Deloukas, Panos; Mohlke, Karen L; Ingelsson, Erik; Abecasis, Goncalo R; Daly, Mark J; Neale, Benjamin M; Kathiresan, Sekar

    2013-11-01

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

  17. Cranial computed tomography in a patient with a variant form of maple syrup urine disease

    International Nuclear Information System (INIS)

    Suzuki, S.; Naito, H.; Abe, T.; Nihei, K.

    1983-01-01

    A male infant, who was suspected to be a case of variant form of maple syrup urine disease has been given dietary treatment since the age of 9 months. Prior to the treatment, computed tomography showed abnormally high lucidity in the cerebral white matter area with the marked narrowness in size of the frontal horn of lateral ventricles. As the treatment proceeded, clinical symptoms alleviated, and CT findings have gradually changed with the result of improved density of the white matter. 2 months after starting the treatment, however, the patient suddenly developed a hyperaminoacidemic crisis that lasted 4-5 days. Despite this hyperaminoacidemia, CT scan taken during the crisis have revealed unexpectedly normal lucidity of the white matter as well as the normal width of the frontal horn. From these findings it was concluded that markedly lucent area in CT findings prior to the treatment was not due to an acute change in serum aminoacid concentration, but rather to chronic brain edema which had insidiously and gradually developed. (orig.)

  18. Factors determining the potential for onward transmission of variant Creutzfeldt–Jakob disease via surgical instruments

    Science.gov (United States)

    Garske, Tini; Ward, Hester J.T; Clarke, Paul; Will, Robert G; Ghani, Azra C

    2006-01-01

    While the number of variant Creutzfeldt–Jakob disease (vCJD) cases continues to decline, concern has been raised that transmission could occur directly from one person to another through routes including the transfer of blood and shared use of surgical instruments. Here we firstly present data on the surgical procedures undertaken on vCJD patients prior to onset of clinical symptoms, which supports the hypothesis that cases via this route are possible. We then apply a mathematical framework to assess the potential for self-sustaining epidemics via surgical procedures. Data from hospital episode statistics on the rates of high- and medium-risk procedures in the UK were used to estimate model parameters, and sensitivity to other unknown parameters about surgically transmitted vCJD was assessed. Our results demonstrate that a key uncertainty determining the scale of an epidemic and whether it is self-sustaining is the number of times a single instrument is re-used, alongside the infectivity of contaminated instruments and the effectiveness of cleaning. A survey into the frequency of re-use of surgical instruments would help reduce these uncertainties. PMID:17015298

  19. Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Anne eHafkemeijer

    2015-09-01

    Full Text Available Alzheimer’s disease (AD and behavioral variant frontotemporal dementia (bvFTD are the most common types of early-onset dementia. Here, we apply resting state functional magnetic resonance imaging (fMRI to study functional brain connectivity differences between AD and bvFTD.We used resting state fMRI data of 31 AD patients, 25 bvFTD patients, and 29 controls. We studied functional connectivity throughout the entire brain, applying two different analysis techniques, studying network-to-region and region-to-region connectivity. A general linear model approach was used to study group differences, while controlling for physiological noise, age, gender, study center, and regional gray matter volume. Given gray matter differences, we observed decreased network-to-region connectivity in bvFTD between a lateral visual cortical network and lateral occipital and cuneal cortex, and b auditory system network and angular gyrus. In AD, we found decreased network-to-region connectivity between the dorsal visual stream network and lateral occipital and parietal opercular cortex. Region-to-region connectivity was decreased in bvFTD between superior temporal gyrus and cuneal, supracalcarine, intracalcarine cortex, and lingual gyrus. We showed that the pathophysiology of functional brain connectivity is different between AD and bvFTD. However, the group differences in functional connectivity are less abundant than has been shown in previous studies.

  20. Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease.

    Science.gov (United States)

    Clark, Lorraine N; Chan, Robin; Cheng, Rong; Liu, Xinmin; Park, Naeun; Parmalee, Nancy; Kisselev, Sergey; Cortes, Etty; Torres, Paola A; Pastores, Gregory M; Vonsattel, Jean P; Alcalay, Roy; Marder, Karen; Honig, Lawrence L; Fahn, Stanley; Mayeux, Richard; Shelanski, Michael; Di Paolo, Gilbert; Lee, Joseph H

    2015-01-01

    Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. In a 'gene-wise' analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03-4.14 x10(-5)). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (plipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.

  1. Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease.

    Directory of Open Access Journals (Sweden)

    Lorraine N Clark

    Full Text Available Variants in GBA are associated with Lewy Body (LB pathology. We investigated whether variants in other lysosomal storage disorder (LSD genes also contribute to disease pathogenesis.We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD changes (n = 59, AD without significant LB pathology (n = 71, Alzheimer disease and lewy body variant (ADLBV (n = 68, and control brains without LB or AD neuropathology (n = 33. Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64 that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67 which included LBD (n = 34, ADLBV (n = 3, AD (n = 4, PD (n = 9 and control brains (n = 17, comparing GBA mutation carriers to non-carriers.In a 'gene-wise' analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03-4.14 x10(-5. Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001. A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01.Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.

  2. Evidence for more than one Parkinson's disease-associated variant within the HLA region.

    Directory of Open Access Journals (Sweden)

    Erin M Hill-Burns

    Full Text Available Parkinson's disease (PD was recently found to be associated with HLA in a genome-wide association study (GWAS. Follow-up GWAS's replicated the PD-HLA association but their top hits differ. Do the different hits tag the same locus or is there more than one PD-associated variant within HLA? We show that the top GWAS hits are not correlated with each other (0.00≤r(2≤0.15. Using our GWAS (2000 cases, 1986 controls we conducted step-wise conditional analysis on 107 SNPs with P<10(-3 for PD-association; 103 dropped-out, four remained significant. Each SNP, when conditioned on the other three, yielded P(SNP1 = 5×10(-4, P(SNP2 = 5×10(-4, P(SNP3 = 4×10(-3 and P(SNP4 = 0.025. The four SNPs were not correlated (0.01≤r(2≤0.20. Haplotype analysis (excluding rare SNP2 revealed increasing PD risk with increasing risk alleles from OR = 1.27, P = 5×10(-3 for one risk allele to OR = 1.65, P = 4×10(-8 for three. Using additional 843 cases and 856 controls we replicated the independent effects of SNP1 (P(conditioned-on-SNP4 = 0.04 and SNP4 (P(conditioned-on-SNP1 = 0.04; SNP2 and SNP3 could not be replicated. In pooled GWAS and replication, SNP1 had OR(conditioned-on-SNP4 = 1.23, P(conditioned-on-SNP4 = 6×10(-7; SNP4 had OR(conditioned-on-SNP1 = 1.18, P(conditioned-on-SNP1 = 3×10(-3; and the haplotype with both risk alleles had OR = 1.48, P = 2×10(-12. Genotypic OR increased with the number of risk alleles an individual possessed up to OR = 1.94, P = 2×10(-11 for individuals who were homozygous for the risk allele at both SNP1 and SNP4. SNP1 is a variant in HLA-DRA and is associated with HLA-DRA, DRB5 and DQA2 gene expression. SNP4 is correlated (r(2 = 0.95 with variants that are associated with HLA-DQA2 expression, and with the top HLA SNP from the IPDGC GWAS (r(2 = 0.60. Our findings suggest more than one PD-HLA association; either different alleles of the same gene

  3. Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease.

    Science.gov (United States)

    Sribudiani, Y; Chauhan, R K; Alves, M M; Petrova, L; Brosens, E; Harrison, C; Wabbersen, T; de Graaf, B M; Rügenbrink, T; Burzynski, G; Brouwer, R W W; IJcken, W F J van; Maas, S M; de Klein, A; Osinga, J; Eggen, B J L; Burns, A J; Brooks, A S; Shepherd, I T; Hofstra, R M W

    2018-03-27

    Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multi-generational family with history of HSCR in a linkage region previously associated with the disease (4q31.3-q32.3) and exome wide. We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3-q32.3. However, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons. Within the linkage region, we identified 1 putative splice variant in the LPS responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on mRNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found variants in the indian hedgehog gene (IHH) and its mediator

  4. Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene.

    Science.gov (United States)

    Thonberg, Håkan; Chiang, Huei-Hsin; Lilius, Lena; Forsell, Charlotte; Lindström, Anna-Karin; Johansson, Charlotte; Björkström, Jenny; Thordardottir, Steinunn; Sleegers, Kristel; Van Broeckhoven, Christine; Rönnbäck, Annica; Graff, Caroline

    2017-06-09

    Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them.

  5. NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

    Directory of Open Access Journals (Sweden)

    Toshiyuki Sato

    2017-07-01

    Full Text Available Background/Aims: Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826 remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD.Methods: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing.Results: None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks and late (≥8 weeks leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined.Conclusions: Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

  6. The human prion diseases. A review with special emphasis on new variant CJD and comments on surveillance.

    LENUS (Irish Health Repository)

    Keohane, C

    2012-02-03

    The transmissible spongiform encephalopathies or prion diseases represent a new group of diseases with unique clinical and neuropathological features, the transmission of which is both genetic and infectious. The responsible agent is unconventional and appears to be largely composed of a glycoprotein, the prion protein PrP. This is normally present on different cells. In prion diseases, it becomes converted to the pathogenic form PrPres which is resistant to proteinase and accumulates within the brain and this process is accompanied by the development of spongiform change, gliosis and neuronal loss. The human prion diseases include Kuru a progressive cerebellar degeneration with late dementia affecting Fore tribes in New-Guinea, now almost extinct, regarded as being related to cannibalism. Creutzfeldt-Jakob disease is the more frequent human prion disease. Its incidence is approximately one case per million per year. Four variants are now recognized: sporadic, familial, iatrogenic and the new variant. The latter represents a distinct clinico-pathological entity. It is now widely accepted that it is due to the same agent responsible for Bovine Spongiform Encephalopathy in cattle. Gerstmann-Straussler-Scheinker disease is a very rare inherited disorder due to a number of different mutations in the PRP gene, characterized by abundant deposits of plaque PrPres in the cerebral grey matter. Fatal familial insomnia is another inherited disorder due to a mutation at codon 178 of the PRP gene associated with methionine on codon 129 of the mutant allele. The main neuropathological change is neuronal loss in the thalamus with little or no spongiosis and usually no PrPres deposition. Following the emergence of new variant CJD in 1996, surveillance of all forms of prion diseases has been now been actively introduced in many European nations in order to determine the true incidence and geographic distribution of these rare disorders in humans.

  7. Association between allelic variants of the human glucocorticoid receptor gene and autoimmune diseases: A systematic review and meta-analysis.

    Science.gov (United States)

    Herrera, Cristian; Marcos, Miguel; Carbonell, Cristina; Mirón-Canelo, José Antonio; Espinosa, Gerard; Cervera, Ricard; Chamorro, Antonio-Javier

    2018-05-01

    The human glucocorticoid receptor gene (NR3C1) is considered to play a role in the differences and sensitivities of the glucocorticoid response in individuals with autoimmune diseases. The objective of this study was to examine by means of a systematic review previous findings regarding allelic variants of NR3C1 in relation to the risk of developing systemic autoimmune diseases. Studies that analysed the genotype distribution of NR3C1 allelic variants among patients with systemic autoimmune diseases were retrieved. A meta-analysis was conducted with a random effects model. Odds ratios (ORs) and their confidence intervals (CIs) were calculated. In addition, sub-analysis by ethnicity, sensitivity analysis and tests for heterogeneity of the results were performed. Eleven studies met the inclusion criteria for meta-analysis. We found no evidence that the analysed NR3C1 polymorphisms, rs6198, rs56149945, and rs6189/rs6190, modulate the risk of developing a systemic autoimmune disease. Nonetheless, a protective role for the minor allele of rs41423247 was found among Caucasians (OR=0.78; 95% CI: 0.65, 0.92; P=0.004). A subgroup analysis according to underlying diseases revealed no significant association either for Behçet's disease or rheumatoid arthritis, while correlations between NR3C1 polymorphisms and disease activity or response to glucocorticoids could not be evaluated due to insufficient data. There is no clear evidence that the analysed NR3C1 allelic variants confer a risk for developing systemic autoimmune diseases although the minor G allele of rs41423247 may be protective among Caucasians. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings.

    Science.gov (United States)

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2016-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

  9. False recognition in behavioural variant frontotemporal dementia and Alzheimer’s disease – disinhibition or amnesia?

    Directory of Open Access Journals (Sweden)

    Emma C Flanagan

    2016-07-01

    Full Text Available Episodic memory recall processes in Alzheimer’s disease (AD and behavioural variant frontotemporal dementia (bvFTD can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT in 39 bvFTD, 77 AD and 61 control participants from two centres (India, Australia, as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits - false-positives. Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients.

  10. An automated microfluidic DNA microarray platform for genetic variant detection in inherited arrhythmic diseases.

    Science.gov (United States)

    Huang, Shu-Hong; Chang, Yu-Shin; Juang, Jyh-Ming Jimmy; Chang, Kai-Wei; Tsai, Mong-Hsun; Lu, Tzu-Pin; Lai, Liang-Chuan; Chuang, Eric Y; Huang, Nien-Tsu

    2018-03-12

    In this study, we developed an automated microfluidic DNA microarray (AMDM) platform for point mutation detection of genetic variants in inherited arrhythmic diseases. The platform allows for automated and programmable reagent sequencing under precise conditions of hybridization flow and temperature control. It is composed of a commercial microfluidic control system, a microfluidic microarray device, and a temperature control unit. The automated and rapid hybridization process can be performed in the AMDM platform using Cy3 labeled oligonucleotide exons of SCN5A genetic DNA, which produces proteins associated with sodium channels abundant in the heart (cardiac) muscle cells. We then introduce a graphene oxide (GO)-assisted DNA microarray hybridization protocol to enable point mutation detection. In this protocol, a GO solution is added after the staining step to quench dyes bound to single-stranded DNA or non-perfectly matched DNA, which can improve point mutation specificity. As proof-of-concept we extracted the wild-type and mutant of exon 12 and exon 17 of SCN5A genetic DNA from patients with long QT syndrome or Brugada syndrome by touchdown PCR and performed a successful point mutation discrimination in the AMDM platform. Overall, the AMDM platform can greatly reduce laborious and time-consuming hybridization steps and prevent potential contamination. Furthermore, by introducing the reciprocating flow into the microchannel during the hybridization process, the total assay time can be reduced to 3 hours, which is 6 times faster than the conventional DNA microarray. Given the automatic assay operation, shorter assay time, and high point mutation discrimination, we believe that the AMDM platform has potential for low-cost, rapid and sensitive genetic testing in a simple and user-friendly manner, which may benefit gene screening in medical practice.

  11. Tryptophan hydroxylase type 2 variants modulate severity and outcome of addictive behaviors in Parkinson's disease.

    Science.gov (United States)

    Cilia, Roberto; Benfante, Roberta; Asselta, Rosanna; Marabini, Laura; Cereda, Emanuele; Siri, Chiara; Pezzoli, Gianni; Goldwurm, Stefano; Fornasari, Diego

    2016-08-01

    Impulse control disorders and compulsive medication intake may occur in a minority of patients with Parkinson's disease (PD). We hypothesize that genetic polymorphisms associated with addiction in the general population may increase the risk for addictive behaviors also in PD. Sixteen polymorphisms in candidate genes belonging to five neurotransmitter systems (dopaminergic, catecholaminergic, serotonergic, glutamatergic, opioidergic) and the BDNF were screened in 154 PD patients with addictive behaviors and 288 PD control subjects. Multivariate analysis investigated clinical and genetic predictors of outcome (remission vs. persistence/relapse) after 1 year and at the last follow-up (5.1 ± 2.5 years). Addictive behaviors were associated with tryptophan hydroxylase type 2 (TPH2) and dopamine transporter gene variants. A subsequent analysis within the group of cases showed a robust association between TPH2 genotype and the severity of addictive behaviors, which survived Bonferroni correction for multiple testing. At multivariate analysis, TPH2 genotype resulted the strongest predictor of no remission at the last follow-up (OR[95%CI], 7.4[3.27-16.78] and 13.2[3.89-44.98] in heterozygous and homozygous carriers, respectively, p medication dose reduction was not a predictor. TPH2 haplotype analysis confirmed the association with more severe symptoms and lower remission rates in the short- and the long-term (p addictive behaviors in PD, modulating the severity of symptoms and the rate of remission at follow-up. If confirmed in larger independent cohorts, TPH2 genotype may become a useful biomarker for the identification of at-risk individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Strategic value-directed learning and memory in Alzheimer's disease and behavioural-variant frontotemporal dementia.

    Science.gov (United States)

    Wong, Stephanie; Irish, Muireann; Savage, Greg; Hodges, John R; Piguet, Olivier; Hornberger, Michael

    2018-02-12

    In healthy adults, the ability to prioritize learning of highly valued information is supported by executive functions and enhances subsequent memory retrieval for this information. In Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD), marked deficits are evident in learning and memory, presenting in the context of executive dysfunction. It is unclear whether these patients show a typical memory bias for higher valued stimuli. We administered a value-directed word-list learning task to AD (n = 10) and bvFTD (n = 21) patients and age-matched healthy controls (n = 22). Each word was assigned a low, medium or high point value, and participants were instructed to maximize the number of points earned across three learning trials. Participants' memory for the words was assessed on a delayed recall trial, followed by a recognition test for the words and corresponding point values. Relative to controls, both patient groups showed poorer overall learning, delayed recall and recognition. Despite these impairments, patients with AD preferentially recalled high-value words on learning trials and showed significant value-directed enhancement of recognition memory for the words and points. Conversely, bvFTD patients did not prioritize recall of high-value words during learning trials, and this reduced selectivity was related to inhibitory dysfunction. Nonetheless, bvFTD patients showed value-directed enhancement of recognition memory for the point values, suggesting a mismatch between memory of high-value information and the ability to apply this in a motivationally salient context. Our findings demonstrate that value-directed enhancement of memory may persist to some degree in patients with dementia, despite pronounced deficits in learning and memory. © 2018 The British Psychological Society.

  13. Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

    Directory of Open Access Journals (Sweden)

    Chi-Chun Ho

    2017-04-01

    Full Text Available Charcot-Marie-Tooth disease (CMT is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by long turnaround time, population-specific prevalence of causative variants and inability to assess multiple co-existing variants. In this study, a CMT gene panel comprising 27 genes was used to uncover the pathogenic mutations in two index patients. The first patient is a 15-year-old boy, born of consanguineous parents, who has had frequent trips and falls since infancy, and was later found to have inverted champagne bottle appearance of bilateral legs and foot drop. His elder sister is similarly affected. The second patient is a 37-year-old woman referred for pre-pregnancy genetic diagnosis. During early adulthood, she developed progressive lower limb weakness, difficulties in tip-toe walking and thinning of calf muscles. Both patients are clinically compatible with CMT, have undergone multiple genetic testings and have not previously received a definitive genetic diagnosis. Patients 1 and 2 were found to have pathogenic homozygous HSPB1:NM_001540:c.250G>A (p.G84R variant and heterozygous GDAP1:NM_018972:c.358C>T (p.R120W variant, respectively. Advantages and limitations of the current approach are discussed.

  14. Evaluation of regulatory genetic variants in POU5F1 and risk of congenital heart disease in Han Chinese.

    Science.gov (United States)

    Lin, Yuan; Ding, Chenyue; Zhang, Kai; Ni, Bixian; Da, Min; Hu, Liang; Hu, Yuanli; Xu, Jing; Wang, Xiaowei; Chen, Yijiang; Mo, Xuming; Cui, Yugui; Shen, Hongbing; Sha, Jiahao; Liu, Jiayin; Hu, Zhibin

    2015-10-28

    OCT4 is a transcription factor of the POU family, which plays a key role in embryonic development and stem cell pluripotency. Previous studies have shown that Oct4 is required for cardiomyocyte differentiation in mice and its depletion could result in cardiac morphogenesis in embryo. However, whether the genetic variations in OCT4 coding gene, POU5F1, confer the predisposition to congenital heart disease (CHD) is unclear. This study sought to investigate the associations between low-frequency (defined here as having minor allele frequency (MAF) between 0.1%-5%) and rare (MAF below 0.1%) variants with potential function in POU5F1 and risk of CHD. We conducted association analysis in a two-stage case-control study with a total of 2,720 CHD cases and 3,331 controls in Chinese. The low-frequency variant rs3130933 was observed to be associated with a significantly increased risk of CHD [additive model: adjusted odds ratio (OR) = 2.15, adjusted P = 3.37 × 10(-6)]. Furthermore, luciferase activity assay showed that the variant A allele led to significantly lower expression levels as compared to the G allele. These findings indicate for the first time that low-frequency functional variant in POU5F1 may contribute to the risk of congenital heart malformations.

  15. The rs3857059 variant of the SNCA gene is associated with Parkinson’s disease in Mexican Mestizos

    Directory of Open Access Journals (Sweden)

    S. García

    2016-06-01

    Full Text Available ABSTRACT Among the candidate genes for Parkinson’s disease (PD, SNCA has replicated association in different populations. Besides other known mutations in the SNCA gene, the rs3857059 variant has also been linked to various neurodegenerative disorders. Therefore, the aim of the present study was to search for association of this variant and sporadic PD in Mexican Mestizo patients. A case-control study was performed including 241 individuals, 106 patients, and 135 healthy controls. Genotyping was performed using real-time PCR. The rs3857059 variant demonstrated an association with PD in Mexican Mestizos (OR = 2.40, CI, 1.1 to 5.1, p = 0.02 under the recessive model. In addition, a gender effect was found for the GG genotype in females (OR = 1.31, CI, 1.01 to 1.7, p = 0.037. This is the first study to confirm an association of the rs3857059 variant with PD and also to show a gender effect. Our data contribute to the elucidation of the link between rs3857059 and susceptibility to PD observed in the Mexican Mestizo population.

  16. Evaluation of regulatory genetic variants in POU5F1 and risk of congenital heart disease in Han Chinese

    Science.gov (United States)

    Lin, Yuan; Ding, Chenyue; Zhang, Kai; Ni, Bixian; da, Min; Hu, Liang; Hu, Yuanli; Xu, Jing; Wang, Xiaowei; Chen, Yijiang; Mo, Xuming; Cui, Yugui; Shen, Hongbing; Sha, Jiahao; Liu, Jiayin; Hu, Zhibin

    2015-10-01

    OCT4 is a transcription factor of the POU family, which plays a key role in embryonic development and stem cell pluripotency. Previous studies have shown that Oct4 is required for cardiomyocyte differentiation in mice and its depletion could result in cardiac morphogenesis in embryo. However, whether the genetic variations in OCT4 coding gene, POU5F1, confer the predisposition to congenital heart disease (CHD) is unclear. This study sought to investigate the associations between low-frequency (defined here as having minor allele frequency (MAF) between 0.1%-5%) and rare (MAF below 0.1%) variants with potential function in POU5F1 and risk of CHD. We conducted association analysis in a two-stage case-control study with a total of 2,720 CHD cases and 3,331 controls in Chinese. The low-frequency variant rs3130933 was observed to be associated with a significantly increased risk of CHD [additive model: adjusted odds ratio (OR) = 2.15, adjusted P = 3.37 × 10-6]. Furthermore, luciferase activity assay showed that the variant A allele led to significantly lower expression levels as compared to the G allele. These findings indicate for the first time that low-frequency functional variant in POU5F1 may contribute to the risk of congenital heart malformations.

  17. Genetic burden of MS risk variants distinguish patients from healthy individuals but are not associated with disease activity

    DEFF Research Database (Denmark)

    Søndergaard, Helle Bach; Petersen, Eva Rosa; Magyari, Melinda

    2017-01-01

    Weighted genetic risk score (wGRS) was analysed for association with disease activity in more than 500 MS patients before and during interferon-beta treatment. The wGRS was higher in MS patients than in healthy controls when analysing eight HLA - and 109 non-HLA MS risk gene variants....... No significant associations were observed between number of relapses prior to or during treatment with interferon-beta, both with and without HLA risk alleles included in the wGRS. In conclusion, among Danes the wGRS was higher in MS patients than controls but was not associated with the overall disease activity...

  18. Genetic Variants in SNCA and the Risk of Sporadic Parkinson’s Disease and Clinical Outcomes: A Review

    Directory of Open Access Journals (Sweden)

    Clarissa Loureiro das Chagas Campêlo

    2017-01-01

    Full Text Available There is increasing evidence of the contribution of genetic susceptibility to the etiology of Parkinson’s disease (PD. Genetic variations in the SNCA gene are well established by linkage and genome-wide association studies. Positive associations of single nucleotide polymorphisms (SNPs in SNCA and increased risk for PD were found. However, the role of SNCA variants in individual traits or phenotypes of PD is unknown. Here, we reviewed the current literature and identified 57 studies, performed in fourteen different countries, that investigated SNCA variants and susceptibility to PD. We discussed the findings based on environmental factors, history of PD, clinical outcomes, and ethnicity. In conclusion, SNPs within the SNCA gene can modify the susceptibility to PD, leading to increased or decreased risk. The risk associations of some SNPs varied among samples. Of notice, no studies in South American or African populations were found. There is little information about the effects of these variants on particular clinical aspects of PD, such as motor and nonmotor symptoms. Similarly, evidence of possible interactions between SNCA SNPs and environmental factors or disease progression is scarce. There is a need to expand the clinical applicability of these data as well as to investigate the role of SNCA SNPs in populations with different ethnic backgrounds.

  19. A Case of New Familiar Genetic Variant of Autosomal Dominant Polycystic Kidney Disease-2: A Case Study.

    Science.gov (United States)

    Litvinchuk, Tetiana; Tao, Yunxia; Singh, Ruchi; Vasylyeva, Tetyana L

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation due to mutations in genes coding for polycystin-1 [PKD1 (85-90% of cases), on ch 16p13.3] and polycystin-2 [PKD2 (10-15% of cases), on ch 4q13-23] and PKD3 gene (gene unmapped). It is also associated with TSC2/PKD1 contiguous gene syndrome. ADPKD is usually inherited, but new mutations without a family history occur in approximately 10% of the cases. A 17-year-old boy was followed up for bilateral cystic kidney disease, hypertension, and obesity since he was 13 years old. The diagnosis was an accidental finding during abdominal CT at age 13 to rule out appendicitis. A renal ultrasonogram also demonstrated a multiple bilateral cysts. Because of parental history of bilateral renal cysts, PKD1 and PKD2, genetic testing was ordered. Results showed, PKD2 variant 1:3 bp deletion of TGT; nucleotide position: 1602-1604; codon position: 512-513; mRNA reading frame maintained. The same mutation was later identified in his father. A smaller number of patients have a defect in the PKD2 locus on chromosome 4 (resulting in PKD2 disease). There are no known published cases on this familiar genetic variant of ADPKD-2 cystic kidney disease. In this case, the disease is present unusually early in life.

  20. Association of usf1s2 variant in the upstream stimulatory factor 1 gene with premature coronary artery disease in southern population of Iran

    Directory of Open Access Journals (Sweden)

    Najmeh Jouyan

    2015-03-01

    Conclusion: It appears that the usf1s2 variant in upstream transcription factor 1 gene is an independent predictor of premature coronary artery disease in our population and applies its effects without affecting blood sugar and lipid levels.

  1. Distribution of Disease-Associated Copy Number Variants across Distinct Disorders of Cognitive Development

    Science.gov (United States)

    Pescosolido, Matthew F.; Gamsiz, Ece D.; Nagpal, Shailender; Morrow, Eric M.

    2013-01-01

    Objective: The purpose of the present study was to discover the extent to which distinct "DSM" disorders share large, highly recurrent copy number variants (CNVs) as susceptibility factors. We also sought to identify gene mechanisms common to groups of diagnoses and/or specific to a given diagnosis based on associations with CNVs. Method:…

  2. Molecular characterization of both alleles in an unusual Tay-Sachs disease BI variant

    Energy Technology Data Exchange (ETDEWEB)

    Coulter-Mackie, M.B. (Univ. of Western Ontario, London (Canada) Child Health Research Institute, Children' s Hospital of Western Ontario, London (Canada) Child Parent Resource Institute, London, Ontario (Canada))

    1994-06-01

    In a recent report, the authors described an exon 6 mutation in a Tay-Sachs B1 variant patient, first reported by Gordon et al. (1988), who displayed a typical B1 variant biochemical phenotype - i.e., (a) significant levels of hexosaminidase A (Hex A) activity in an assay with a neutral synthetic substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide, and (b) <2% of control Hex A in a test on the sulfated substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide-6-sulfate. The patient was found to carry a double mutation (G[sub 574][yields]C [val[sub 192][yields]leu] and G[sub 598][yields]A [val[sub 200][yields]met]) inherited from her mother. Only the 574 mutation produced a deleterious effect on Hex A activity in transfected COS0-1 cells, producing a B1 variant biochemical phenotype. The paternal allele apparently caused decreased abundance of mRNA, since no candidate paternal mutations were found in cloned reverse transcription-PCR (RT-PCR) products in the reported study. The biochemical phenotype of the original patient and the properties of the cDNA carrying the G[sub 574] [yields] C mutation in transient expression studies were compatible with a B1 variant mutation. The possibility remained that there might be some contribution from the paternal allele to the patient's phenotype. However, the paternal allele produces relatively low yields of a largely mis-spliced mRNA whose product would not be functional. Therefore, the G[sub 574] [yields] C (val[yields]leu) mutation in the maternal allele is clearly confirmed as a B1 variant mutation with all the ramifications for the substrate binding site and/or catalytic center that this implies.

  3. rs1004819 is the main disease-associated IL23R variant in German Crohn's disease patients: combined analysis of IL23R, CARD15, and OCTN1/2 variants.

    Directory of Open Access Journals (Sweden)

    Jürgen Glas

    Full Text Available BACKGROUND: The IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants. METHODS: Genomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD, 456 patients with ulcerative colitis (UC, and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T and SLC22A5/OCTN2 (-207 G-->C. RESULTS: All IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92x10(-11; OR 1.56; 95 % CI (1.37-1.78]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46-12.34]. The coding SNP rs11209026 (p.Arg381Gln was protective for CD [P = 8.04x10(-8; OR 0.43; CI (0.31-0.59]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5. CONCLUSION: IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.

  4. Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

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    Liang He

    2016-10-01

    Full Text Available Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1 endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2 time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM, cancer, cardiovascular diseases (CVDs and neurodegenerative diseases (NDs, and (3 both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08, out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2 and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory

  5. PREVALENCE OF CELIAC DISEASE PREDISPOSING GENOTYPES, INCLUDING HLA-DQ2.2 VARIANT, IN BRAZILIAN CHILDREN.

    Science.gov (United States)

    Selleski, Nicole; Almeida, Lucas Malta; Almeida, Fernanda Coutinho de; Pratesi, Claudia Beatriz; Nóbrega, Yanna Karla de Medeiros; Gandolfi, Lenora

    2018-01-01

    Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Almost all celiac patients carry immune recognition genes coding for HLA-DQ2.5 and DQ8 heterodimers. Over the last few years, great importance has been given to HLA-DQ2.2 as probable predisposing variant, although controversies still exist regarding its relevance. The aim of our study was to determine the possible existence of an association between HLA-DQ2.2 and celiac disease in Brazilian children by analyzing the prevalence of the predisposing variants for celiac disease in a representative group of children of a population in which this determination is still missing. HLA-DQ typing was performed in samples from a group of celiac (n=100) and non-celiac children (n=110). All samples were tested for the presence of the following variants: DQA1*05-DQB1*02 (DQ2.5), DQA1*03-DQB1*03:02 (DQ8) and DQA1*02:01-DQB1*02:02 (DQ2.2). Fisher`s exact test was used for statistical analysis. In the group of 100 celiac children, 78 (78%) were positive for DQ2, 13 (13 %) were DQ2/DQ8 and 6 (6%) were DQ8 positives. The HLA-DQ pattern in the 110 non-celiac children was as follows: positive for DQ2 in 33 (29.9%) samples, in 2 (1.8 %) was positive for DQ2/DQ8 and in 15 (13.6%) was positive for DQ8. We found significant differences between the distribution of some but not all of the analyzed alleles when comparing celiac and non-celiac children. The genotyping of celiac disease HLA-DQ predisposing alleles showed similarities with HLA-DQ patterns found in both European and non-European populations, which may be a reflection of the miscegenation, which gave origin to the current Brazilian population. No significant association was found between DQ2.2 variant and celiac disease in the studied population.

  6. PREVALENCE OF CELIAC DISEASE PREDISPOSING GENOTYPES, INCLUDING HLA-DQ2.2 VARIANT, IN BRAZILIAN CHILDREN

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    Nicole SELLESKI

    Full Text Available ABSTRACT BACKGROUND: Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Almost all celiac patients carry immune recognition genes coding for HLA-DQ2.5 and DQ8 heterodimers. Over the last few years, great importance has been given to HLA-DQ2.2 as probable predisposing variant, although controversies still exist regarding its relevance. OBJECTIVE: The aim of our study was to determine the possible existence of an association between HLA-DQ2.2 and celiac disease in Brazilian children by analyzing the prevalence of the predisposing variants for celiac disease in a representative group of children of a population in which this determination is still missing. METHODS: HLA-DQ typing was performed in samples from a group of celiac (n=100 and non-celiac children (n=110. All samples were tested for the presence of the following variants: DQA1*05-DQB1*02 (DQ2.5, DQA1*03-DQB1*03:02 (DQ8 and DQA1*02:01-DQB1*02:02 (DQ2.2. Fisher`s exact test was used for statistical analysis. RESULTS: In the group of 100 celiac children, 78 (78% were positive for DQ2, 13 (13 % were DQ2/DQ8 and 6 (6% were DQ8 positives. The HLA-DQ pattern in the 110 non-celiac children was as follows: positive for DQ2 in 33 (29.9% samples, in 2 (1.8 % was positive for DQ2/DQ8 and in 15 (13.6% was positive for DQ8. We found significant differences between the distribution of some but not all of the analyzed alleles when comparing celiac and non-celiac children. CONCLUSION: The genotyping of celiac disease HLA-DQ predisposing alleles showed similarities with HLA-DQ patterns found in both European and non-European populations, which may be a reflection of the miscegenation, which gave origin to the current Brazilian population. No significant association was found between DQ2.2 variant and celiac disease in the studied population.

  7. Forkhead box C2 promoter variant c.-512C>T is associated with increased susceptibility to chronic venous diseases.

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    Sumi Surendran

    Full Text Available Chronic venous disease (CVD is one of the most prevalent yet underrated disorders worldwide. High heritability estimates of CVD indicate prominent genetic components in its etiology and pathology. Mutations in human forkhead box C2 (FoxC2 gene are strongly associated with valve failure in saphenous and deep veins of lower extremities. We explored the association of genetic variants of FoxC2 as well as FoxC2 mRNA and protein expression levels with CVD of lower limbs. We systematically sequenced the single coding exon, 5' and 3' flanking regions of FoxC2 gene in 754 study subjects which includes 382 patients with CVD and 372 healthy subjects. Four novel and three reported polymorphisms were identified in our cohort. Three variants in 5' flanking region and one in 3' flanking region of FoxC2 gene were significantly associated with CVD risk. FoxC2 mRNA in vein tissues from 22 patients was 4±1.42 fold increased compared to saphenous veins from 20 normal subjects (pT (rs34221221: C>T variant which is located in the FoxC2 putative promoter region was further analyzed. Functional analysis of c.-512C>T revealed increased mRNA and protein expression in patients with homozygous TT genotype compared to heterozygous CT and wild CC genotypes. Luciferase assay indicated higher transcriptional activity of mutant compared to wild genotype of this variant. These findings suggested that c.-512C>T variant of FoxC2 was strongly associated with susceptibility to CVD and also that this variant resulted in FoxC2 overexpression. To obtain a mechanistic insight into the role of upregulated FoxC2 in varicosities, we overexpressed FoxC2 in venous endothelial cells and observed elevated expression of arterial markers Dll4 and Hey2 and downregulation of venous marker COUP-TFII. Our study indicates altered FoxC2-Notch signaling in saphenous vein wall remodeling in patients with varicose veins.

  8. Characterization of nodal/TGF-lefty signaling pathway gene variants for possible roles in congenital heart diseases.

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    Xia Deng

    Full Text Available BACKGROUND: Nodal/TGF-Lefty signaling pathway has important effects at early stages of differentiation of human embryonic stem cells in directing them to differentiate into different embryonic lineages. LEFTY, one of transforming growth factors in the Nodal/TGF-Lefty signaling pathway, plays an important role in the development of heart. The aim of this work was to find evidence on whether Lefty variations are associated with congenital heart diseases (CHD. METHODS: We sequenced the Lefty gene for 230 Chinese Han CHD patients and evaluated SNPs rs2295418, rs360057 and g.G169A, which are located within the translated regions of the genes. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0. The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE, and multiple-sequence alignments of LEFTY proteins were carried out using the Vector NTI software. RESULTS: Two heterozygous variants in Lefty1 gene, g.G169A and g.A1035C, and one heterozygous variant in Lefty2 gene, g.C925A, were identified. Statistical analyses showed that the rs2295418 (g.C925A variant in Lefty2 gene was obviously associated with the risk of CHD (P value = 0.0160.05. CONCLUSIONS: The SNP rs2295418 in the Lefty2 gene is associated with CHD in Chinese Han populations.

  9. Investigation of the role of interleukin-1 receptor antagonist VNTR variant on the Behçet’s disease

    Science.gov (United States)

    Dursun, Gül; Demir, Helin Deniz; Karakuş, Nevin; Demir, Osman; Yiğit, Serbülent

    2018-01-01

    Objective Behçet’s disease (BD), a chronic multisystem inflammatory disorder, is mainly characterized by relapsing periods of a wide range of clinical symptoms. Several cytokine genes may play important roles in the pathogenesis of BD. Therefore, interleukin-1 receptor antagonist (IL-1Ra) gene 86bp variable number tandem repeat (VNTR) variant was investigated in patients with BD in a Turkish population. Methods One hundred nine patients (60 females, 49 males; the mean age±standard deviation [SD] was 36.56±9.571 years) with BD and one hundred healthy individuals (54 females, 46 males; the mean age±SD was 36.64±2.294 years) were examined in the study. For genotyping, polymerase chain reaction-restriction fragment length polymorphism analysis was employed. Data were analyzed using Statistical Package for Social Sciences (SPSS) 22.0 (IBM Corp.; Armonk, NY, USA) (p0.05). The frequency of the a1/a1, a1/a2 genotypes and a1, a2 alleles were the most common both in patients and healthy controls (p=0.37, p=0.26, and p=0.53, respectively). Also, no statistically significant difference was found between the IL-1Ra VNTR variant genotypes and clinical characteristics (p>0.05). Conclusion The results of this study do not support an association between the IL-1Ra VNTR variant and the risk of BD in a Turkish population. However, further studies of this variant with larger sample sizes and different ethnicities are required for confirmation. PMID:29657871

  10. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?

    Science.gov (United States)

    Christensen, Alex Hørby; Benn, Marianne; Tybjaerg-Hansen, Anne; Haunso, Stig; Svendsen, Jesper Hastrup

    2010-01-01

    Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic. We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146-2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations. Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2, functional characterization and large-scale sequencing to clarify normal variation in the gene.

  11. Genetic variants in TGFβ-1 and PAI-1 as possible risk factors for cardiovascular disease after radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Hilbers, Florentine S.M.; Boekel, Naomi B.; Broek, Alexandra J. van den; Hien, Richard van; Cornelissen, Sten; Aleman, Berthe M.P.; Veer, Laura J. van’t; Leeuwen, Flora E. van; Schmidt, Marjanka K.

    2012-01-01

    Background and purpose: It has been established that radiotherapy can increase cardiovascular disease (CVD) risk. Genetic variants, which play a role in the tissue, damage response and angiogenesis regulating TGFβ pathway might give us insight into the mechanisms underlying radiation-induced CVD. We examined the effects of two polymorphisms, TGFβ1 29C > T and PAI-1 5G > 4G, on CVD incidence. Materials and methods: This retrospective cohort study included 422 10-year breast cancer survivors, aged 4G and CVD risk. Conclusion: Our study suggests there might be an association between the TGFβ1 29C > T polymorphism and CVD risk in long-term breast cancer survivors.

  12. R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family

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    Korvatska, Olena; Leverenz, James B.; Jayadev, Suman; McMillan, Pamela; Kurtz, Irina; Guo, Xindi; Rumbaugh, Malia; Matsushita, Mark; Girirajan, Santhosh; Dorschner, Michael O.; Kiianitsa, Kostantin; Yu, Chang-En; Brkanac, Zoran; Garden, Gwenn A.; Raskind, Wendy H.; Bird, Thomas D.

    2016-01-01

    Importance The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. Objective To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. Design, Setting, and Participants This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. Main Outcomes and Measures We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Results Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The

  13. Comprehensive evaluation of disease- and trait-specific enrichment for eight functional elements among GWAS-identified variants.

    Science.gov (United States)

    Markunas, Christina A; Johnson, Eric O; Hancock, Dana B

    2017-07-01

    Genome-wide association study (GWAS)-identified variants are enriched for functional elements. However, we have limited knowledge of how functional enrichment may differ by disease/trait and tissue type. We tested a broad set of eight functional elements for enrichment among GWAS-identified SNPs (p Enrichment analyses were conducted using logistic regression, with Bonferroni correction. Overall, a significant enrichment was observed for all functional elements, except sequence motifs. Missense SNPs showed the strongest magnitude of enrichment. eQTLs were the only functional element significantly enriched across all diseases/traits. Magnitudes of enrichment were generally similar across diseases/traits, where enrichment was statistically significant. Blood vs. brain tissue effects on enrichment were dependent on disease/trait and functional element (e.g., cardiovascular disease: eQTLs P TissueDifference  = 1.28 × 10 -6 vs. enhancers P TissueDifference  = 0.94). Identifying disease/trait-relevant functional elements and tissue types could provide new insight into the underlying biology, by guiding a priori GWAS analyses (e.g., brain enhancer elements for psychiatric disease) or facilitating post hoc interpretation.

  14. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

    DEFF Research Database (Denmark)

    Kozlitina, Julia; Smagris, Eriks; Stender, Stefan

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD, we performed an exome-wide association study of liver fat content. Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.......6 × 10(-7): two in PNPLA3, an established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a gene of unknown function. The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low...... knockdown of Tm6sf2 in mice increased liver triglyceride content by threefold and decreased very-low-density lipoprotein (VLDL) secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD....

  15. Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

    Science.gov (United States)

    Prescott, Natalie J.; Lehne, Benjamin; Stone, Kristina; Lee, James C.; Taylor, Kirstin; Knight, Jo; Papouli, Efterpi; Mirza, Muddassar M.; Simpson, Michael A.; Spain, Sarah L.; Lu, Grace; Fraternali, Franca; Bumpstead, Suzannah J.; Gray, Emma; Amar, Ariella; Bye, Hannah; Green, Peter; Chung-Faye, Guy; Hayee, Bu’Hussain; Pollok, Richard; Satsangi, Jack; Parkes, Miles; Barrett, Jeffrey C.; Mansfield, John C.; Sanderson, Jeremy; Lewis, Cathryn M.; Weale, Michael E.; Schlitt, Thomas; Mathew, Christopher G.

    2015-01-01

    The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis. PMID:25671699

  16. Characterization of variants in the promoter of BZLF1 gene of EBV in nonmalignant EBV-associated diseases in Chinese children

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    Yang Shuang

    2010-05-01

    Full Text Available Abstract Background Diseases associated with Epstein-Barr virus (EBV infections, such as infectious mononucleosis (IM, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH and chronic active EBV infection (CAEBV are not rare in Chinese children. The association of type 1 or type 2 EBV and variants of the EBV BZLF1 promoter zone (Zp with these diseases is unclear. Results The objective of this study was to investigate the relationship between EBV genotypes (Zp variants and EBV type 1 and 2 and the clinical phenotypes of EBV-associated diseases in Chinese children. The Zp region was directly sequenced in 206 EBV-positive DNA samples from the blood of patients with IM, EBV-HLH, CAEBV, and healthy controls. Type 1 or type 2 EBV was examined by PCR for EBNA2 and EBNA3C subtypes. Four polymorphic Zp variants were identified: Zp-P, Zp-V3, Zp-P4 and Zp-V1, a new variant. The Zp-V3 variant was significantly associated with CAEBV (P ≤ 0.01. The frequency of co-infection with Zp variants was higher in patients with CAEBV and EBV-HLH, compared with IM and healthy controls, mostly as Zp-P+V3 co-infection. Type 1 EBV was predominant in all categories (81.3-95% and there was no significant difference in the frequency of the EBV types 1 and 2 in different categories (P > 0.05. Conclusions Type 1 EBV and BZLF1 Zp-P of EBV were the predominant genotypes in nonmalignant EBV associated diseases in Chinese children and Zp-V3 variant may correlates with the developing of severe EBV infection diseases, such as CAEBV and EBV-HLH.

  17. Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients.

    Science.gov (United States)

    Krishnamoorthy, Soumya; Rajan, Roopa; Banerjee, Moinak; Kumar, Hardeep; Sarma, Gangadhara; Krishnan, Syam; Sarma, Sankara; Kishore, Asha

    2016-09-01

    Impulse control disorders (ICD) are reported to occur at variable frequencies in different ethnic groups. Genetic vulnerability is suspected to underlie the individual risk for ICD. We investigated whether the allelic variants of dopamine (DRD3), glutamate (GRIN2B) and serotonin (HTR2A) receptors are linked to ICD in Indian Parkinson's disease (PD) patients. We conducted a prospective, case-control study which included PD patients (70 with ICD, 100 without ICD categorized after direct psychiatric interview of patient and caregiver) and 285 healthy controls. Single nucleotide polymorphism (SNP) variants of DRD3 p.S9G (rs6280), GRIN2B c.2664C>T (rs1806201) and HTR2A c.102T>C (rs6313) were genotyped. Multivariate regression analysis revealed that DRD3 p.Ser9Gly (rs6280) heterozygous variant CT (OR = 2.22, 95% CI: 1.03-4.86, p = 0.041), higher daily Levodopa equivalent doses (LED) of drugs (for 100 mg LED, OR = 1.14, 95% CI: 1.01-1.29, p = 0.041), current dopamine agonist but not Levodopa use (OR = 2.16, 95% CI: 1.03-4.55, p = 0.042) and age of onset of motor symptoms under 50 years (OR 2.09, 95% CI: 1.05-4.18, p = 0.035) were independently associated with ICD. DRD3 p.Ser9Gly (rs6280) CT genotype is associated with ICD in Indian PD patients and this association is novel. Enhanced D3 receptor affinity due to gain-of-function conferred by the glycine residues could impair reward-risk assessment in the mesolimbic system and contribute to development of impulsive behaviour, in carriers of this genotype. Copyright © 2016. Published by Elsevier Ltd.

  18. Concordant association of insulin degrading enzyme gene (IDE variants with IDE mRNA, Abeta, and Alzheimer's disease.

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    Minerva M Carrasquillo

    2010-01-01

    Full Text Available The insulin-degrading enzyme gene (IDE is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD.We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8, fold-increase = 2.12,; the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003. Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2-C (p = 0.006 and HepG2 (p = 0.02 cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879, we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011 and total measured plasma Abeta levels (b = -0.130, p = 0.009. Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03, and the eleven IDE haplotypes (global p = 0.02 also showed significant association.Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

  19. Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity.

    Science.gov (United States)

    Katrancha, Sara M; Wu, Yi; Zhu, Minsheng; Eipper, Betty A; Koleske, Anthony J; Mains, Richard E

    2017-12-01

    Bipolar disorder, schizophrenia, autism and intellectual disability are complex neurodevelopmental disorders, debilitating millions of people. Therapeutic progress is limited by poor understanding of underlying molecular pathways. Using a targeted search, we identified an enrichment of de novo mutations in the gene encoding the 330-kDa triple functional domain (TRIO) protein associated with neurodevelopmental disorders. By generating multiple TRIO antibodies, we show that the smaller TRIO9 isoform is the major brain protein product, and its levels decrease after birth. TRIO9 contains two guanine nucleotide exchange factor (GEF) domains with distinct specificities: GEF1 activates both Rac1 and RhoG; GEF2 activates RhoA. To understand the impact of disease-associated de novo mutations and other rare sequence variants on TRIO function, we utilized two FRET-based biosensors: a Rac1 biosensor to study mutations in TRIO (T)GEF1, and a RhoA biosensor to study mutations in TGEF2. We discovered that one autism-associated de novo mutation in TGEF1 (K1431M), at the TGEF1/Rac1 interface, markedly decreased its overall activity toward Rac1. A schizophrenia-associated rare sequence variant in TGEF1 (F1538Intron) was substantially less active, normalized to protein level and expressed poorly. Overall, mutations in TGEF1 decreased GEF1 activity toward Rac1. One bipolar disorder-associated rare variant (M2145T) in TGEF2 impaired inhibition by the TGEF2 pleckstrin-homology domain, resulting in dramatically increased TGEF2 activity. Overall, genetic damage to both TGEF domains altered TRIO catalytic activity, decreasing TGEF1 activity and increasing TGEF2 activity. Importantly, both GEF changes are expected to decrease neurite outgrowth, perhaps consistent with their association with neurodevelopmental disorders. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. AprioriGWAS, a new pattern mining strategy for detecting genetic variants associated with disease through interaction effects.

    Science.gov (United States)

    Zhang, Qingrun; Long, Quan; Ott, Jurg

    2014-06-01

    Identifying gene-gene interaction is a hot topic in genome wide association studies. Two fundamental challenges are: (1) how to smartly identify combinations of variants that may be associated with the trait from astronomical number of all possible combinations; and (2) how to test epistatic interaction when all potential combinations are available. We developed AprioriGWAS, which brings two innovations. (1) Based on Apriori, a successful method in field of Frequent Itemset Mining (FIM) in which a pattern growth strategy is leveraged to effectively and accurately reduce search space, AprioriGWAS can efficiently identify genetically associated genotype patterns. (2) To test the hypotheses of epistasis, we adopt a new conditional permutation procedure to obtain reliable statistical inference of Pearson's chi-square test for the [Formula: see text] contingency table generated by associated variants. By applying AprioriGWAS to age-related macular degeneration (AMD) data, we found that: (1) angiopoietin 1 (ANGPT1) and four retinal genes interact with Complement Factor H (CFH). (2) GO term "glycosaminoglycan biosynthetic process" was enriched in AMD interacting genes. The epistatic interactions newly found by AprioriGWAS on AMD data are likely true interactions, since genes interacting with CFH are retinal genes, and GO term enrichment also verified that interaction between glycosaminoglycans (GAGs) and CFH plays an important role in disease pathology of AMD. By applying AprioriGWAS on Bipolar disorder in WTCCC data, we found variants without marginal effect show significant interactions. For example, multiple-SNP genotype patterns inside gene GABRB2 and GRIA1 (AMPA subunit 1 receptor gene). AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system. The GABRB2 mediates the fastest inhibitory synaptic transmission in the central nervous system. GRIA1 and GABRB2 are relevant to mental disorders supported by multiple

  1. Corneal epithelium expresses a variant of P2X(7 receptor in health and disease.

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    Courtney Mankus

    Full Text Available Improper wound repair of the corneal epithelium can alter refraction of light resulting in impaired vision. We have shown that ATP is released after injury, activates purinergic receptor signaling pathways and plays a major role in wound closure. In many cells or tissues, ATP activates P2X(7 receptors leading to cation fluxes and cytotoxicity. The corneal epithelium is an excellent model to study the expression of both the full-length P2X(7 form (defined as the canonical receptor and its truncated forms. When Ca(2+ mobilization is induced by BzATP, a P2X(7 agonist, it is attenuated in the presence of extracellular Mg(2+ or Zn(2+, negligible in the absence of extracellular Ca(2+, and inhibited by the competitive P2X7 receptor inhibitor, A438079. BzATP enhanced phosphorylation of ERK. Together these responses indicate the presence of a canonical or full-length P2X(7 receptor. In addition BzATP enhanced epithelial cell migration, and transfection with siRNA to the P2X(7 receptor reduced cell migration. Furthermore, sustained activation did not induce dye uptake indicating the presence of truncated or variant forms that lack the ability to form large pores. Reverse transcription-polymerase chain reaction and Northern blot analysis revealed a P2X(7 splice variant. Western blots identified a full-length and truncated form, and the expression pattern changed as cultures progressed from monolayer to stratified. Cross-linking gels demonstrated the presence of homo- and heterotrimers. We examined epithelium from age matched diabetic and non-diabetic corneas patients and detected a 4-fold increase in P2X(7 mRNA from diabetic corneal epithelium compared to non-diabetic controls and an increased trend in expression of P2X(7variant mRNA. Taken together, these data indicate that corneal epithelial cells express full-length and truncated forms of P2X(7, which ultimately allows P2X(7 to function as a multifaceted receptor that can mediate cell proliferation and

  2. Rare variants in MYD88, IRAK4 and IKBKG and susceptibility to invasive pneumococcal disease: a population-based case-control study.

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    Magda K Ellis

    Full Text Available Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD, the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.

  3. Pediatric and adult MRI atlas of bone marrow. Normal appearances, variants and diffuse disease states

    Energy Technology Data Exchange (ETDEWEB)

    Ilaslan, Hakan; Sundaram, Murali [Cleveland Clinic Lerner College of Medicine, OH (United States); Cleveland Clinic Department of Radiology, OH (United States)

    2016-08-01

    This comprehensive atlas is unique in being devoted to the MRI appearances of bone marrow in the axial and appendicular skeleton of adults and children. Normal MRI findings, including common variants and degenerative changes, are first documented. MRI appearances in the entire spectrum of neoplastic and non-neoplastic infiltrative marrow disorders are then presented, with accompanying explanatory text. Among the conditions considered are multiple myeloma, the acute and chronic leukemias, diffuse metastases, diffuse lymphomas, the anemias, polycythemia vera, myelofibrosis, storage disorders, and infections. Characteristic changes to bone marrow following various forms of treatment are also displayed and discussed. The selected images reflect the use of a variety of sequences and techniques, such as fat suppression, and contrast-enhanced imaging.

  4. Characterization of SMAD3 Gene Variants for Possible Roles in Ventricular Septal Defects and Other Congenital Heart Diseases.

    Directory of Open Access Journals (Sweden)

    Fei-Feng Li

    Full Text Available Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD or other congenital heart diseases (CHD.We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5'UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0. The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5'UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013 <0.05.The SNP rs2289263 in the SMAD3 gene is associated with VSD in Chinese Han populations.

  5. Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

    OpenAIRE

    Hensman Moss, Davina J; Pardinas, Antonio; Langbehn, Douglas; Lo, Kitty; Leavitt, Blair R; Roos, Raymund; Durr, Alexandra; Mead, Simon; Holmans, Peter; Jones, Lesley; Tabrizi, Sarah J; Coleman, A; Santos, R Dar; Decolongon, J; Sturrock, A

    2017-01-01

    Background\\ud \\ud Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure.\\ud \\ud Methods\\ud \\ud We generated a progression score on the basis of principal ...

  6. Functional analysis of variant lysosomal acid glycosidases of Anderson-Fabry and Pompe disease in a human embryonic kidney epithelial cell line (HEK 293 T).

    Science.gov (United States)

    Ebrahim, Hatim Y; Baker, Robert J; Mehta, Atul B; Hughes, Derralynn A

    2012-03-01

    The functional significance of missense mutations in genes encoding acid glycosidases of lysosomal storage disorders (LSDs) is not always clear. Here we describe a method of investigating functional properties of variant enzymes in vitro using a human embryonic kidney epithelial cell line. Site-directed mutagenesis was performed on the parental plasmids containing cDNA encoding for alpha-galactosidase A (α-Gal A) and acid maltase (α-Glu) to prepare plasmids encoding relevant point mutations. Mutant plasmids were transfected into HEK 293 T cells, and transient over-expression of variant enzymes was measured after 3 days. We have illustrated the method by examining enzymatic activities of four unknown α-Gal A and one α-Glu variants identified in our patients with Anderson-Fabry disease and Pompe diseases respectively. Comparison with control variants known to be either pathogenic or non-pathogenic together with over-expression of wild-type enzyme allowed determination of the pathogenicity of the mutation. One leader sequence novel variant of α-Gal A (p.A15T) was shown not to significantly reduce enzyme activity, whereas three other novel α-Gal A variants (p.D93Y, p.L372P and p.T410I) were shown to be pathogenic as they resulted in significant reduction of enzyme activity. A novel α-Glu variant (p.L72R) was shown to be pathogenic as this significantly reduced enzyme activity. Certain acid glycosidase variants that have been described in association with late-onset LSDs and which are known to have variable residual plasma and leukocyte enzyme activity in patients appear to show intermediate to low enzyme activity (p.N215S and p.Q279E α-Gal A respectively) in the over-expression system.

  7. Shared genetic variants suggest common pathways in allergy and autoimmune diseases

    DEFF Research Database (Denmark)

    Kreiner-Møller, Eskil; Waage, Johannes; Standl, Marie

    2017-01-01

    Background: The relationship between allergy and autoimmune disorders is complex and poorly understood. Objective: To investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. Methods: We meta-analyzed two GWAS on self-r...

  8. Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

    NARCIS (Netherlands)

    Smyth, Deborah J.; Plagnol, Vincent; Walker, Neil M.; Cooper, Jason D.; Downes, Kate; Yang, Jennie H. M.; Howson, Joanna M. M.; Stevens, Helen; McManus, Ross; Wijmenga, Cisca; Heap, Graham A.; Dubois, Patrick C.; Clayton, David G.; Hunt, Karen A.; van Heel, David A.; Todd, John A.

    2008-01-01

    Background: Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. Methods: We evaluated the

  9. Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive

    Directory of Open Access Journals (Sweden)

    Stefan Taudien

    2016-10-01

    Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course.

  10. Probable late lyme disease: a variant manifestation of untreated Borrelia burgdorferi infection

    Science.gov (United States)

    2012-01-01

    Background Lyme disease, a bacterial infection with the tick-borne spirochete Borrelia burgdorferi, can cause early and late manifestations. The category of probable Lyme disease was recently added to the CDC surveillance case definition to describe patients with serologic evidence of exposure and physician-diagnosed disease in the absence of objective signs. We present a retrospective case series of 13 untreated patients with persistent symptoms of greater than 12 weeks duration who meet these criteria and suggest a label of ‘probable late Lyme disease’ for this presentation. Methods The sample for this analysis draws from a retrospective chart review of consecutive, adult patients presenting between August 2002 and August 2007 to the author (JA), an infectious disease specialist. Patients were included in the analysis if their current illness had lasted greater than or equal to 12 weeks duration at the time of evaluation. Results Probable late Lyme patients with positive IgG serology but no history of previous physician-documented Lyme disease or appropriate Lyme treatment were found to represent 6% of our heterogeneous sample presenting with ≥ 12 weeks of symptom duration. Patients experienced a range of symptoms including fatigue, widespread pain, and cognitive complaints. Approximately one-third of this subset reported a patient-observed rash at illness onset, with a similar proportion having been exposed to non-recommended antibiotics or glucocorticosteroid treatment for their initial disease. A clinically significant response to antibiotics treatment was noted in the majority of patients with probable late Lyme disease, although post-treatment symptom recurrence was common. Conclusions We suggest that patients with probable late Lyme disease share features with both confirmed late Lyme disease and post-treatment Lyme disease syndrome. Physicians should consider the recent inclusion of probable Lyme disease in the CDC Lyme disease surveillance

  11. Comprehension of concrete and abstract words in semantic variant primary progressive aphasia and Alzheimer's disease: A behavioral and neuroimaging study.

    Science.gov (United States)

    Joubert, Sven; Vallet, Guillaume T; Montembeault, Maxime; Boukadi, Mariem; Wilson, Maximiliano A; Laforce, Robert Jr; Rouleau, Isabelle; Brambati, Simona M

    2017-07-01

    The aim of this study was to investigate the comprehension of concrete, abstract and abstract emotional words in semantic variant primary progressive aphasia (svPPA), Alzheimer's disease (AD), and healthy elderly adults (HE) Three groups of participants (9 svPPA, 12 AD, 11 HE) underwent a general neuropsychological assessment, a similarity judgment task, and structural brain MRI. The three types of words were processed similarly in the group of AD participants. In contrast, patients in the svPPA group were significantly more impaired at processing concrete words than abstract words, while comprehension of abstract emotional words was in between. VBM analyses showed that comprehension of concrete words relative to abstract words was significantly correlated with atrophy in the left anterior temporal lobe. These results support the view that concrete words are disproportionately impaired in svPPA, and that concrete and abstract words may rely upon partly dissociable brain regions. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients.

    Science.gov (United States)

    Douet, Jean Y; Lacroux, Caroline; Aron, Naima; Head, Mark W; Lugan, Séverine; Tillier, Cécile; Huor, Alvina; Cassard, Hervé; Arnold, Mark; Beringue, Vincent; Ironside, James W; Andréoletti, Olivier

    2017-06-01

    In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD.

  13. CDKL5 variants

    Science.gov (United States)

    Kalscheuer, Vera M.; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A.; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E.S.; Cobb, Stuart R.

    2017-01-01

    Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID:29264392

  14. Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease.

    Science.gov (United States)

    Sanders, Angela; Hemmelgarn, Harmony; Melrose, Heather L; Hein, Leanne; Fuller, Maria; Clarke, Lorne A

    2013-08-01

    Gaucher disease is an autosomal recessively inherited storage disorder caused by deficiency of the lysosomal hydrolase, acid β-glucosidase. The disease manifestations seen in Gaucher patients are highly heterogeneous as is the responsiveness to therapy. The elucidation of the precise factors responsible for this heterogeneity has been challenging as the development of clinically relevant animal models of Gaucher disease has been problematic. Although numerous murine models for Gaucher disease have been described each has limitations in their specific utility. We describe here, transgenic murine models of Gaucher disease that will be particularly useful for the study of pharmacological chaperones. We have produced stable transgenic mouse strains that individually express wild type, N370S and L444P containing human acid β-glucosidase and show that each of these transgenic lines rescues the lethal phenotype characteristic of acid β-glucosidase null mice. Both the N370S and L444P transgenic models show early and progressive elevations of tissue sphingolipids with L444P mice developing progressive splenic Gaucher cell infiltration. We demonstrate the potential utility of these new transgenic models for the study of Gaucher disease pathogenesis. In addition, since these mice produce only human enzyme, they are particularly relevant for the study of pharmacological chaperones that are specifically targeted to human acid β-glucosidase and the common mutations underlying Gaucher disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Biological impact of the TSH-beta splice variant in health and disease

    Directory of Open Access Journals (Sweden)

    John R. Klein

    2014-04-01

    Full Text Available Thyroid stimulating hormone (TSH, a glycoprotein hormone composed of alpha and beta chains, is produced by thryrotrope cells of the anterior pituitary. Within the conventional endocrine loop, pituitary-derived TSH binds to receptors in the thyroid, resulting in the release of the thyroid hormones thyroxine (T4 and triiodothyronine (T3. T4 and T3 in turn regulate nearly every aspect of mammalian physiology, including basal metabolism, growth and development, and mood and cognition. Although TSH-beta has been known for years to be produced by cells of the immune system, the significance of that has remained largely unclear. Recently, a splice variant of TSH-beta (TSH-beta-v, which consists of a truncated but biologically functional portion of the native form of TSH-beta, was shown to be produced by bone marrow cells and peripheral blood leukocytes, particularly cells of the myeloid/monocyte lineage. In contrast, full-length native TSH-beta is minimally produced by cells of the immune system. The present article will describe the discovery of the TSH-beta-v and will discuss its potential role in immunity and autoimmunity, inflammation, and bone remodeling.

  16. Common variants associated with plasma triglycerides and risk for coronary artery disease

    DEFF Research Database (Denmark)

    Do, R.; Willer, C. J.; Schmidt, E. M.

    2013-01-01

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common...

  17. Common variants associated with plasma triglycerides and risk for coronary artery disease

    NARCIS (Netherlands)

    Do, Ron; Willer, Cristen J.; Schmidt, Ellen M.; Sengupta, Sebanti; Gao, Chi; Peloso, Gina M.; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L.; Mora, Samia; Beckmann, Jacques S.; Bragg-Gresham, Jennifer L.; Chang, Hsing-Yi; Demirkan, Ayşe; den Hertog, Heleen M.; Donnelly, Louise A.; Ehret, Georg B.; Esko, Tõnu; Feitosa, Mary F.; Ferreira, Teresa; Fischer, Krista; Fontanillas, Pierre; Fraser, Ross M.; Freitag, Daniel F.; Gurdasani, Deepti; Heikkilä, Kauko; Hyppönen, Elina; Isaacs, Aaron; Jackson, Anne U.; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kettunen, Johannes; Kleber, Marcus E.; Li, Xiaohui; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Magnusson, Patrik K. E.; Mangino, Massimo; Mihailov, Evelin; Montasser, May E.; Müller-Nurasyid, Martina; Nolte, Ilja M.; O'Connell, Jeffrey R.; Palmer, Cameron D.; Perola, Markus; Petersen, Ann-Kristin; Sanna, Serena; Saxena, Richa; Service, Susan K.; Shah, Sonia; Shungin, Dmitry; Sidore, Carlo; Song, Ci; Strawbridge, Rona J.; Surakka, Ida; Tanaka, Toshiko; Teslovich, Tanya M.; Thorleifsson, Gudmar; van den Herik, Evita G.; Voight, Benjamin F.; Volcik, Kelly A.; Waite, Lindsay L.; Wong, Andrew; Wu, Ying; Zhang, Weihua; Absher, Devin; Asiki, Gershim; Barroso, Inês; Been, Latonya F.; Bolton, Jennifer L.; Bonnycastle, Lori L.; Brambilla, Paolo; Burnett, Mary S.; Cesana, Giancarlo; Dimitriou, Maria; Doney, Alex S. F.; Döring, Angela; Elliott, Paul; Epstein, Stephen E.; Eyjolfsson, Gudmundur Ingi; Gigante, Bruna; Goodarzi, Mark O.; Grallert, Harald; Gravito, Martha L.; Groves, Christopher J.; Hallmans, Göran; Hartikainen, Anna-Liisa; Hayward, Caroline; Hernandez, Dena; Hicks, Andrew A.; Holm, Hilma; Hung, Yi-Jen; Illig, Thomas; Jones, Michelle R.; Kaleebu, Pontiano; Kastelein, John J. P.; Khaw, Kay-Tee; Kim, Eric; Klopp, Norman; Komulainen, Pirjo; Kumari, Meena; Langenberg, Claudia; Lehtimäki, Terho; Lin, Shih-Yi; Lindström, Jaana; Loos, Ruth J. F.; Mach, François; McArdle, Wendy L.; Meisinger, Christa; Mitchell, Braxton D.; Müller, Gabrielle; Nagaraja, Ramaiah; Narisu, Narisu; Nieminen, Tuomo V. M.; Nsubuga, Rebecca N.; Olafsson, Isleifur; Ong, Ken K.; Palotie, Aarno; Papamarkou, Theodore; Pomilla, Cristina; Pouta, Anneli; Rader, Daniel J.; Reilly, Muredach P.; Ridker, Paul M.; Rivadeneira, Fernando; Rudan, Igor; Ruokonen, Aimo; Samani, Nilesh; Scharnagl, Hubert; Seeley, Janet; Silander, Kaisa; Stančáková, Alena; Stirrups, Kathleen; Swift, Amy J.; Tiret, Laurence; Uitterlinden, Andre G.; van Pelt, L. Joost; Vedantam, Sailaja; Wainwright, Nicholas; Wijmenga, Cisca; Wild, Sarah H.; Willemsen, Gonneke; Wilsgaard, Tom; Wilson, James F.; Young, Elizabeth H.; Zhao, Jing Hua; Adair, Linda S.; Arveiler, Dominique; Assimes, Themistocles L.; Bandinelli, Stefania; Bennett, Franklyn; Bochud, Murielle; Boehm, Bernhard O.; Boomsma, Dorret I.; Borecki, Ingrid B.; Bornstein, Stefan R.; Bovet, Pascal; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C.; Chen, Yii-Der Ida; Collins, Francis S.; Cooper, Richard S.; Danesh, John; Dedoussis, George; de Faire, Ulf; Feranil, Alan B.; Ferrières, Jean; Ferrucci, Luigi; Freimer, Nelson B.; Gieger, Christian; Groop, Leif C.; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hingorani, Aroon; Hirschhorn, Joel N.; Hofman, Albert; Hovingh, G. Kees; Hsiung, Chao Agnes; Humphries, Steve E.; Hunt, Steven C.; Hveem, Kristian; Iribarren, Carlos; Järvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kaprio, Jaakko; Kesäniemi, Antero; Kivimaki, Mika; Kooner, Jaspal S.; Koudstaal, Peter J.; Krauss, Ronald M.; Kuh, Diana; Kuusisto, Johanna; Kyvik, Kirsten O.; Laakso, Markku; Lakka, Timo A.; Lind, Lars; Lindgren, Cecilia M.; Martin, Nicholas G.; März, Winfried; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Metspalu, Andres; Moilanen, Leena; Morris, Andrew D.; Munroe, Patricia B.; Njølstad, Inger; Pedersen, Nancy L.; Power, Chris; Pramstaller, Peter P.; Price, Jackie F.; Psaty, Bruce M.; Quertermous, Thomas; Rauramaa, Rainer; Saleheen, Danish; Salomaa, Veikko; Sanghera, Dharambir K.; Saramies, Jouko; Schwarz, Peter E. H.; Sheu, Wayne H.-H.; Shuldiner, Alan R.; Siegbahn, Agneta; Spector, Tim D.; Stefansson, Kari; Strachan, David P.; Tayo, Bamidele O.; Tremoli, Elena; Tuomilehto, Jaakko; Uusitupa, Matti; van Duijn, Cornelia M.; Vollenweider, Peter; Wallentin, Lars; Wareham, Nicholas J.; Whitfield, John B.; Wolffenbuttel, Bruce H. R.; Altshuler, David; Ordovas, Jose M.; Boerwinkle, Eric; Palmer, Colin N. A.; Thorsteinsdottir, Unnur; Chasman, Daniel I.; Rotter, Jerome I.; Franks, Paul W.; Ripatti, Samuli; Cupples, L. Adrienne; Sandhu, Manjinder S.; Rich, Stephen S.; Boehnke, Michael; Deloukas, Panos; Mohlke, Karen L.; Ingelsson, Erik; Abecasis, Goncalo R.; Daly, Mark J.; Neale, Benjamin M.; Kathiresan, Sekar

    2013-01-01

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common

  18. Analysis of new lactotransferrin gene variants in a case-control study related to periodontal disease in dog.

    Science.gov (United States)

    Morinha, Francisco; Albuquerque, Carlos; Requicha, João; Dias, Isabel; Leitão, José; Gut, Ivo; Guedes-Pinto, Henrique; Viegas, Carlos; Bastos, Estela

    2012-04-01

    The molecular and genetic research has contributed to a better understanding of the periodontal disease (PD) in humans and has shown that many genes play a role in the predisposition and progression of this complex disease. Variations in human lactotransferrin (LTF) gene appear to affect anti-microbial functions of this molecule, influencing the PD susceptibility. PD is also a major health problem in small animal practice, being the most common inflammatory disease found in dogs. Nevertheless, the research in genetic predisposition to PD is an unexplored subject in this species. This work aims to contribute to the characterization of the genetic basis of canine PD. In order to identify genetic variations and verify its association with PD, was performed a molecular analysis of LTF gene in a case-control approach, including 40 dogs in the PD cases group and 50 dogs in the control group. In this study were detected and characterized eight new single nucleotide variations in the dog LTF gene. Genotype and allele frequencies of these variations showed no statistically significant differences between the control and PD cases groups. Our data do not give evidence for the contribution of these LTF variations to the genetic background of canine PD. Nevertheless, the sequence variant L/15_g.411C > T leads to an aminoacid change (Proline to Leucine) and was predicted to be possibly damaging to the LTF protein. Further investigations would be of extreme value to clarify the biological importance of these new findings.

  19. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls.

    Science.gov (United States)

    Bellenguez, Céline; Charbonnier, Camille; Grenier-Boley, Benjamin; Quenez, Olivier; Le Guennec, Kilan; Nicolas, Gaël; Chauhan, Ganesh; Wallon, David; Rousseau, Stéphane; Richard, Anne Claire; Boland, Anne; Bourque, Guillaume; Munter, Hans Markus; Olaso, Robert; Meyer, Vincent; Rollin-Sillaire, Adeline; Pasquier, Florence; Letenneur, Luc; Redon, Richard; Dartigues, Jean-François; Tzourio, Christophe; Frebourg, Thierry; Lathrop, Mark; Deleuze, Jean-François; Hannequin, Didier; Genin, Emmanuelle; Amouyel, Philippe; Debette, Stéphanie; Lambert, Jean-Charles; Campion, Dominique

    2017-11-01

    We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10 -6 was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a clearer insight into the classes of rare variants involved. Despite different effect sizes and varying cumulative minor allele frequencies, the rare protein-truncating and missense-predicted damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE ε4. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Uncovering the Rare Variants of DLC1 Isoform 1 and Their Functional Effects in a Chinese Sporadic Congenital Heart Disease Cohort

    Science.gov (United States)

    Wang, Zhen; Tan, Huilian; Kong, Xianghua; Shu, Yang; Zhang, Yuchao; Huang, Yun; Zhu, Yufei; Xu, Heng; Wang, Zhiqiang; Wang, Ping; Ning, Guang; Kong, Xiangyin; Hu, Guohong; Hu, Landian

    2014-01-01

    Congenital heart disease (CHD) is the most common birth defect affecting the structure and function of fetal hearts. Despite decades of extensive studies, the genetic mechanism of sporadic CHD remains obscure. Deleted in liver cancer 1 (DLC1) gene, encoding a GTPase-activating protein, is highly expressed in heart and essential for heart development according to the knowledge of Dlc1-deficient mice. To determine whether DLC1 is a susceptibility gene for sporadic CHD, we sequenced the coding region of DLC1 isoform 1 in 151 sporadic CHD patients and identified 13 non-synonymous rare variants (including 6 private variants) in the case cohort. Importantly, these rare variants (8/13) were enriched in the N-terminal region of the DLC1 isoform 1 protein. Seven of eight amino acids at the N-terminal variant positions were conserved among the primates. Among the 9 rare variants that were predicted as “damaging”, five were located at the N-terminal region. Ensuing in vitro functional assays showed that three private variants (Met360Lys, Glu418Lys and Asp554Val) impaired the ability of DLC1 to inhibit cell migration or altered the subcellular location of the protein compared to wild-type DLC1 isoform 1. These data suggest that DLC1 might act as a CHD-associated gene in addition to its role as a tumor suppressor in cancer. PMID:24587289

  1. Genetic variants of SLC11A1 are associated with both autoimmune and infectious diseases: systematic review and meta-analysis.

    Science.gov (United States)

    Archer, N S; Nassif, N T; O'Brien, B A

    2015-06-01

    A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT)n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR=0.94 (0.89-0.98)). On the basis of a stronger association of (GT)n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease (OR=1.30 (1.04-1.64)) and rheumatoid arthritis (OR=1.60 (1.20-2.13)) and between the -237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR=0.60 (0.43-0.84)). Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.

  2. Variants in TNFAIP3, STAT4 and c12orf30 loci associated with multiple auto-immune diseases are also associated with Juvenile Idiopathic Arthritis

    Science.gov (United States)

    Prahalad, Sampath; Hansen, Sterling; Whiting, April; Guthery, Stephen L.; Clifford, Bronte; McNally, Bernadette; Zeft, Andrew S.; Bohnsack, John F.; Jorde, Lynn B.

    2010-01-01

    Objectives Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA, to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. Methods Cases were 445 children with JIA, and controls were 643 healthy adults. Eight single nucleotide polymorphisms (SNPs) in 7 loci [TNFAIP3 (rs10499194 and rs6920220), RSBN1 (rs6679677), C12ORF30 (rs17696736), TRAF1 (rs3761847), IL2RA (rs2104286), PTPN2 (rs2542151), and STAT4 (rs7574865)] were genotyped by the TaqMan assay. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. Results The strongest associations were observed for TNFAIP3 variants rs10499194 (OR: 0.74 (0.61-0.91); p <0.004), and TNFAIP3 rs6920220 (OR: 1.3 (1.05-1.61); p <0.02). We also observed associations between JIA and STAT4 (OR: 1.24 (1.02-1.51); p <0.03) and C12ORF30 (OR: 1.2 (1.01-1.43); p <0.04) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1, and RSBN1 were not associated with JIA. After stratification by JIA subtype, TNFAIP3 and C12ORF30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. Conclusions We have demonstrated associations between JIA and variants in TNFAIP3, STAT4 and C12ORF30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors. PMID:19565500

  3. Association Between a Genetic Variant Related to Glutamic Acid Metabolism and Coronary Heart Disease in Type 2 Diabetes

    Science.gov (United States)

    Qi, Qibin; Prudente, Sabrina; Mendonca, Christine; Andreozzi, Francesco; di Pietro, Natalia; Sturma, Mariella; Novelli, Valeria; Mannino, Gaia Chiara; Formoso, Gloria; Gervino, Ernest V.; Hauser, Thomas H.; Muehlschlegel, Jochen D.; Niewczas, Monika A.; Krolewski, Andrzej S.; Biolo, Gianni; Pandolfi, Assunta; Rimm, Eric; Sesti, Giorgio; Trischitta, Vincenzo; Hu, Frank

    2013-01-01

    IMPORTANCE Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and non-diabetic participants. OBJECTIVE To identify genetic determinants of CHD that are specific to diabetic patients. DESIGN, SETTING, AND PARTICIPANTS We studied five independent sets of CHD cases and CHD-negative controls from the Nurses Health Study (NHS; enrolled in 1976 and followed through 2008), Health Professionals Follow-up Study (HPFS; enrolled in 1986 and followed through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1,517 CHD cases and 2,671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 non-diabetic CHD cases and 1,637 non-diabetic CHD-negative controls from the NHS and HPFS cohorts. EXPOSURE 2,543,016 common genetic variants occurring throughout the genome. MAIN OUTCOME CHD defined as fatal or non-fatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS We identified a variant on chromosome 1q25 (rs10911021) consistently associated with CHD risk among diabetic participants with an odds ratio of 1.36 (95% confidence interval [CI] 1.22-1.51, P=2×10−8). No association between this variant and CHD was detected among non-diabetic participants (OR=0.99, P=0.89), consistent with a significant gene-by-diabetes interaction on CHD risk (P=2×10−4). As compared to protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P=0.0048). They also showed a decreased ratio between plasma

  4. Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants.

    Science.gov (United States)

    Shahid, Saleem Ullah; Shabana; Cooper, Jackie A; Beaney, Katherine E; Li, Kawah; Rehman, Abdul; Humphries, Steve E

    2017-03-01

    Conventional coronary artery disease (CAD) risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of CAD risk prediction algorithms, but provide only modest discrimination. Genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors. Here we analyzed the genetic risk of CAD in subjects from Pakistan, using a GRS of 21 variants in 18 genes and examined whether the GRS is associated with blood lipid levels. 625 (405 cases and 220 controls) subjects were genotyped for variants, NOS3 rs1799983, SMAD3 rs17228212, APOB rs1042031, LPA rs3798220, LPA rs10455872, SORT1 rs646776, APOE rs429358, GLUL rs10911021, FTO rs9939609, MIA3 rs17465637, CDKN2Ars10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328, LPL rs1801177, PCSK9 rs11591147 and APOE rs7412 by TaqMan and KASPar allele discrimination techniques. Individually, the single SNPs were not associated with CAD except APOB rs1042031 and FTO rs993969 (p = 0.01 and 0.009 respectively). However, the combined GRS of 21 SNPs was significantly higher in cases than controls (19.37 ± 2.56 vs. 18.47 ± 2.45, p = 2.9 × 10 -5 ), and compared to the bottom quintile, CAD risk in the top quintile of the GRS was 2.96 (95% CI 1.71-5.13). Atherogenic blood lipids showed significant positive association with GRS. The GRS was quantitatively associated with CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be, in part at least, through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Sjögren's and plasma cell variant Castleman disease: a case report ...

    African Journals Online (AJOL)

    It classically presents as a mediastinal mass that involves the lymphatic tissue primarily but can also affect extra lymphatic sites including the lungs, larynx, parotid glands, pancreas, meninges, and muscles. In HIV and HHV8-negative patients with idiopathic multicentric Castleman disease, pathogenesis may involve ...

  6. Genetic Variants of Homocysteine Metabolizing Enzymes and the Risk of Coronary Artery Disease

    Czech Academy of Sciences Publication Activity Database

    Janošíková, B.; Pavlíková, Markéta; Kocmanová, Dora; Vítová, D.; Veselá, K.; Krupková, L.; Kahleová, R.; Krijt, J.; Kraml, P.; Hyánek, J.; Zvárová, Jana; Anděl, M.; Kožich, V.

    2003-01-01

    Roč. 79, - (2003), s. 167-175 ISSN 1096-7192 R&D Projects: GA MZd NM26; GA MZd NM6548 Keywords : coronary disease * risk factors * genes * homocysteine * metabolism Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.038, year: 2003

  7. ATP13A2 variants in early-onset Parkinson's disease patients and controls

    DEFF Research Database (Denmark)

    Djarmati, Ana; Hagenah, Johann; Reetz, Kathrin

    2009-01-01

    Four genes responsible for recessively inherited forms of Parkinson's disease (PD) have been identified, including the recently discovered ATP13A2 (PARK9) gene. Our objective was to investigate the role of this gene in a large cohort of PD patients and controls. We extensively screened all 29 exo...

  8. Variants in RET Associated With Hirschsprung's Disease Affect Binding of Transcription Factors and Gene Expression

    NARCIS (Netherlands)

    Sribudiani, Yunia; Metzger, Marco; Osinga, Jan; Rey, Amanda; Burns, Alan J.; Thapar, Nikhil; Hofstra, Robert M. W.

    BACKGROUND & AIMS: Two noncoding variations in RET-the T allele of the single nucleotide polymorphism (SNP) rs2435357 (Enh1:C>T) and the A allele of the SNP rs2506004 (Enh2:C>A)-are associated with Hirschsprung's disease. These SNPs are in strong linkage disequilibrium and located in an enhancer

  9. Sjögren's and plasma cell variant Castleman disease: a case report

    African Journals Online (AJOL)

    of Ghana School of Biomedical and Allied Health Sciences, PO Box GP 4236, Accra, Ghana, 4Department of .... moval of the involved lymph nodes or use of anti-IL6 ... disease activity at later end points. 29 ... Yoshizaki K, Honda O, et al.

  10. Identification of Splice Variants as Molecular Markers in Parkinson’s Disease

    Science.gov (United States)

    2006-09-01

    compazine, beta blockers ; e. Drugs with significant muscarinic receptor antagonist activity: Cogentin, Akineton, Artane, Ditropan, Detrol, Elavil...f. Drugs known to improve dyskinesias: amantadine, dextromethorphan, beta - blockers , fluoxitene, clozapine, quetiapine, olanzapine, buspirone, other...disease based on the presence of a characteristic clinical history and neurological findings including at least 2 of the following: resting tremor

  11. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

    Science.gov (United States)

    Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C l...

  12. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

    DEFF Research Database (Denmark)

    Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B

    2016-01-01

    Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-...

  13. Rare variants in calcium homeostasis modulator 1 (CALHM1 found in early onset Alzheimer's disease patients alter calcium homeostasis.

    Directory of Open Access Journals (Sweden)

    Fanny Rubio-Moscardo

    Full Text Available Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD. Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+-permeable channel CALHM1. A genetic polymorphism (p. P86L in CALHM1 reduces plasma membrane Ca(2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD, we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H and one (p.A213T in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T behaved as wild-type CALHM1 (CALHM1-WT, a complete abolishment of the Ca(2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H. Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.

  14. Variants in the interleukin-1 alpha and beta genes, and the risk for periodontal disease in dogs.

    Science.gov (United States)

    Albuquerque, C; Morinha, F; Magalhães, J; Requicha, J; Dias, I; Guedes-Pinto, H; Bastos, E; Viegas, C

    2015-12-01

    Elevated levels of interleukin-1 (IL-1) have been shown to amplify the inflammatory response against periodontopathogenic bacteria.In humans,polymorphisms in the IL1A and IL1B genes are the most well-studied genetic polymorphisms associated with periodontal disease (PD). In contrast to human, there is a lack of knowledge on the genetic basis of canine PD. A case-control study was conducted in which a molecular analysis of dog IL1A and IL1B genes was performed. Of the eight genetic variants identified, seven in IL1A gene and one in IL1B gene, IL1A/1_g.388A>C and IL1A /1_g.521T>A showed statistically significant differences between groups (adjusted OR (95% CI): 0.15 (0.03-0.76),P=0.022; 5.76 (1.03-32.1),P=0.046, respectively). It suggests that in the studied population the IL1A/1_g.388C allele is associated with a decreased PD risk, whereas the IL1A/1_g.521A allele can confer an increased risk. Additionally, the IL1A/2_g.515G>T variation resulted in a change of amino acid, i.e. glycine to valine. In silico analysis suggests that this change can alter protein structure and function, predicting it to be deleterious or damaging. This work suggests that IL1 genetic variants may be important in PD susceptibility in canines.

  15. Thyroid stimulating hormone receptor (TSHR intron 1 variants are major risk factors for Graves' disease in three European Caucasian cohorts.

    Directory of Open Access Journals (Sweden)

    Rafał Płoski

    2010-11-01

    Full Text Available The thyroid stimulating hormone receptor (TSHR gene is an established susceptibility locus for Graves' disease (GD, with recent studies refining association to two single nucleotide polymorphisms (SNPs, rs179247 and rs12101255, within TSHR intron 1.We aimed to validate association of rs179247 and rs12101255 in Polish and UK Caucasian GD case-control subjects, determine the mode of inheritance and to see if association correlates with specific GD clinical manifestations. We investigated three case-control populations; 558 GD patients and 520 controls from Warsaw, Poland, 196 GD patients and 198 controls from Gliwice, Poland and 2504 GD patients from the UK National collection and 2784 controls from the 1958 British Birth cohort. Both rs179247 (P = 1.2×10(-2-6.2×10(-15, OR = 1.38-1.45 and rs12101255 (P = 1.0×10(-4-3.68×10(-21, OR = 1.47-1.87 exhibited strong association with GD in all three cohorts. Logistic regression suggested association of rs179247 is secondary to rs12101255 in all cohorts. Inheritance modeling suggested a co-dominant mode of inheritance in all cohorts. Genotype-phenotype correlations provided no clear evidence of association with any specific clinical characteristics.We have validated association of TSHR intron 1 SNPs with GD in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255. Fine mapping is now required to determine the exact location of the aetiological DNA variants within the TSHR.

  16. Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study

    NARCIS (Netherlands)

    Zewinger, Stephen; Kleber, Marcus E.; Tragante Do O, V; McCubrey, Raymond O.; Schmidt, Amand F.; Direk, Kenan; Laufs, Ulrich; Werner, Christian; Koenig, Wolfgang; Rothenbacher, Dietrich; Mons, Ute; Breitling, Lutz P; Brenner, Herrmann; Jennings, Richard T.; Petrakis, Ioannis; Triem, Sarah; Klug, Mira; Filips, Alexandra; Blankenberg, Stefan; Waldeyer, Christoph; Sinning, Christoph; Schnabel, Renate B.; Lackner, Karl J.; Vlachopoulou, Efthymia; Nygård, Ottar; Svingen, Gard Frodahl Tveitevåg; Pedersen, Eva Ringdal; Tell, Grethe S.; Sinisalo, Juha; Nieminen, Markku S.; Laaksonen, Reijo; Trompet, Stella; Smit, Roelof A.J.; Sattar, Naveed; Jukema, J. Wouter; Groesdonk, Heinrich V.; Delgado, Graciela; Stojakovic, Tatjana; Pilbrow, Anna P.; Cameron, Vicky A.; Richards, A. Mark; Doughty, Robert N.; Gong, Yan; Cooper-Dehoff, Rhonda M; Johnson, Julie A; Scholz, Markus; Beutner, Frank; Thiery, Joachim; Smith, J. Gustav; Vilmundarson, Ragnar O.; McPherson, Ruth; Stewart, Alexandre F. R.; Cresci, Sharon; Lenzini, Petra A.; Spertus, John A.; Olivieri, Oliviero; Girelli, Domenico; Martinelli, Nicola I.; Leiherer, Andreas; Saely, Christoph H.; Drexel, Heinz; Mündlein, Axel; Braund, Peter S; Nelson, Christopher P.; Samani, Nilesh J.; Kofink, Daniel; Hoefer, Imo E.; Pasterkamp, Gerard; Quyyumi, Arshed A.; Ko, Yi-An; Hartiala, Jaana A.; Allayee, Hooman; Tang, W. H. Wilson; Hazen, Stanley L.; Eriksson, Niclas; Held, Claes; Hagström, Emil; Wallentin, Lars; Åkerblom, Axel; Siegbahn, Agneta; Karp, Igor; Labos, Christopher; Pilote, Louise; Engert, James C.; Brophy, James M.; Thanassoulis, George; Bogaty, Peter; Szczeklik, Wojciech; Kaczor, Marcin; Sanak, Marek; Virani, Salim S.; Ballantyne, Christie M.; Lee, Vei Vei; Boerwinkle, Eric; Holmes, Michael V.; Horne, Benjamin D; Hingorani, Aroon D.; Asselbergs, Folkert W.; Patel, Riyaz S; Krämer, Bernhard K; Scharnagl, Hubert; Fliser, Danilo; März, Winfried; Speer, Thimoteus

    Background Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods We obtained

  17. The power of gene-based rare variant methods to detect disease-associated variation and test hypotheses about complex disease.

    Directory of Open Access Journals (Sweden)

    Loukas Moutsianas

    2015-04-01

    Full Text Available Genome and exome sequencing in large cohorts enables characterization of the role of rare variation in complex diseases. Success in this endeavor, however, requires investigators to test a diverse array of genetic hypotheses which differ in the number, frequency and effect sizes of underlying causal variants. In this study, we evaluated the power of gene-based association methods to interrogate such hypotheses, and examined the implications for study design. We developed a flexible simulation approach, using 1000 Genomes data, to (a generate sequence variation at human genes in up to 10K case-control samples, and (b quantify the statistical power of a panel of widely used gene-based association tests under a variety of allelic architectures, locus effect sizes, and significance thresholds. For loci explaining ~1% of phenotypic variance underlying a common dichotomous trait, we find that all methods have low absolute power to achieve exome-wide significance (~5-20% power at α = 2.5 × 10(-6 in 3K individuals; even in 10K samples, power is modest (~60%. The combined application of multiple methods increases sensitivity, but does so at the expense of a higher false positive rate. MiST, SKAT-O, and KBAC have the highest individual mean power across simulated datasets, but we observe wide architecture-dependent variability in the individual loci detected by each test, suggesting that inferences about disease architecture from analysis of sequencing studies can differ depending on which methods are used. Our results imply that tens of thousands of individuals, extensive functional annotation, or highly targeted hypothesis testing will be required to confidently detect or exclude rare variant signals at complex disease loci.

  18. Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

    Science.gov (United States)

    Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J; Dugger, Brittany N; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Sali, Andrej; Prusiner, Stanley B

    2016-11-01

    The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP Sc , were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates. Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for

  19. Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease.

    Science.gov (United States)

    Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier; Torres, Juan María

    2017-09-01

    Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met 129 ) or valine (Val 129 ) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met 129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val 129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met 129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val 129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val 129 Hu-PrP-positive humans with the emergence of new strain features.

  20. A case-control study between interleukin-10 gene variants and periodontal disease in dogs.

    Science.gov (United States)

    Albuquerque, Carlos; Morinha, Francisco; Requicha, João; Dias, Isabel; Guedes-Pinto, Henrique; Viegas, Carlos; Bastos, Estela

    2014-04-10

    Periodontal disease (PD) refers to a group of inflammatory diseases that affect the periodontium, the organ which surrounds and supports the teeth. PD is a highly prevalent disease with a multifactorial etiology and, in humans the individual susceptibility is known to be strongly determined by genetic factors. Several candidate genes have been studied, namely genes related with molecules involved in the inflammatory response. Interleukin-10 (IL-10) is a cytokine with important anti-inflammatory and immunomodulatory roles, and several studies indicate an association between IL10 polymorphisms and PD. In dogs, an important animal model in periodontology, PD is also a highly prevalent naturally occurring disease, and only now are emerging the first studies evaluating the genetic predisposition. In this case-control study, a population of 90 dogs (40 dogs with PD and 50 healthy dogs) was used to study the IL10 gene, and seven new genetic variations in this gene were identified. No statistically significant differences were detected in genotype and allele frequencies of these variations between the PD cases and control groups. Nevertheless, one of the variations (IL10/2_g.285G>A) leads to an amino acid change (glycine to arginine) in the putative signal peptide, being predicted a potential influence on IL-10 protein functionality. Further investigations are important to clarify the biological importance of these new findings. The knowledge of these genetic determinants can help to understand properly the complex causal pathways of PD, with important clinical implications. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Genome-wide association scan in HIV-1-infected individuals identifying variants influencing disease course.

    Directory of Open Access Journals (Sweden)

    Daniëlle van Manen

    Full Text Available BACKGROUND: AIDS develops typically after 7-11 years of untreated HIV-1 infection, with extremes of very rapid disease progression (15 years. To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS. METHODS: The association of SNP genotypes with the clinical course of HIV-1 infection was tested in Cox regression survival analyses using AIDS-diagnosis and AIDS-related death as endpoints. RESULTS: Multiple, not previously identified SNPs, were identified to be strongly associated with disease progression after HIV-1 infection, albeit not genome-wide significant. However, three independent SNPs in the top ten associations between SNP genotypes and time between seroconversion and AIDS-diagnosis, and one from the top ten associations between SNP genotypes and time between seroconversion and AIDS-related death, had P-values smaller than 0.05 in the French Genomics of Resistance to Immunodeficiency Virus cohort on disease progression. CONCLUSIONS: Our study emphasizes that the use of different phenotypes in GWAS may be useful to unravel the full spectrum of host genetic factors that may be associated with the clinical course of HIV-1 infection.

  2. Genome-Wide Association Scan in HIV-1-Infected Individuals Identifying Variants Influencing Disease Course

    Science.gov (United States)

    van Manen, Daniëlle; Delaneau, Olivier; Kootstra, Neeltje A.; Boeser-Nunnink, Brigitte D.; Limou, Sophie; Bol, Sebastiaan M.; Burger, Judith A.; Zwinderman, Aeilko H.; Moerland, Perry D.; van 't Slot, Ruben; Zagury, Jean-François; van 't Wout, Angélique B.; Schuitemaker, Hanneke

    2011-01-01

    Background AIDS develops typically after 7–11 years of untreated HIV-1 infection, with extremes of very rapid disease progression (15 years). To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS) in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS. Methods The association of SNP genotypes with the clinical course of HIV-1 infection was tested in Cox regression survival analyses using AIDS-diagnosis and AIDS-related death as endpoints. Results Multiple, not previously identified SNPs, were identified to be strongly associated with disease progression after HIV-1 infection, albeit not genome-wide significant. However, three independent SNPs in the top ten associations between SNP genotypes and time between seroconversion and AIDS-diagnosis, and one from the top ten associations between SNP genotypes and time between seroconversion and AIDS-related death, had P-values smaller than 0.05 in the French Genomics of Resistance to Immunodeficiency Virus cohort on disease progression. Conclusions Our study emphasizes that the use of different phenotypes in GWAS may be useful to unravel the full spectrum of host genetic factors that may be associated with the clinical course of HIV-1 infection. PMID:21811574

  3. Common variants at five new loci associated with early-onset inflammatory bowel disease.

    Science.gov (United States)

    Imielinski, Marcin; Baldassano, Robert N; Griffiths, Anne; Russell, Richard K; Annese, Vito; Dubinsky, Marla; Kugathasan, Subra; Bradfield, Jonathan P; Walters, Thomas D; Sleiman, Patrick; Kim, Cecilia E; Muise, Aleixo; Wang, Kai; Glessner, Joseph T; Saeed, Shehzad; Zhang, Haitao; Frackelton, Edward C; Hou, Cuiping; Flory, James H; Otieno, George; Chiavacci, Rosetta M; Grundmeier, Robert; Castro, Massimo; Latiano, Anna; Dallapiccola, Bruno; Stempak, Joanne; Abrams, Debra J; Taylor, Kent; McGovern, Dermot; Silber, Gary; Wrobel, Iwona; Quiros, Antonio; Barrett, Jeffrey C; Hansoul, Sarah; Nicolae, Dan L; Cho, Judy H; Duerr, Richard H; Rioux, John D; Brant, Steven R; Silverberg, Mark S; Taylor, Kent D; Barmuda, M Michael; Bitton, Alain; Dassopoulos, Themistocles; Datta, Lisa Wu; Green, Todd; Griffiths, Anne M; Kistner, Emily O; Murtha, Michael T; Regueiro, Miguel D; Rotter, Jerome I; Schumm, L Philip; Steinhart, A Hillary; Targan, Stephen R; Xavier, Ramnik J; Libioulle, Cécile; Sandor, Cynthia; Lathrop, Mark; Belaiche, Jacques; Dewit, Olivier; Gut, Ivo; Heath, Simon; Laukens, Debby; Mni, Myriam; Rutgeerts, Paul; Van Gossum, André; Zelenika, Diana; Franchimont, Denis; Hugot, J P; de Vos, Martine; Vermeire, Severine; Louis, Edouard; Cardon, Lon R; Anderson, Carl A; Drummond, Hazel; Nimmo, Elaine; Ahmad, Tariq; Prescott, Natalie J; Onnie, Clive M; Fisher, Sheila A; Marchini, Jonathan; Ghori, Jilur; Bumpstead, Suzannah; Gwillam, Rhian; Tremelling, Mark; Delukas, Panos; Mansfield, John; Jewell, Derek; Satsangi, Jack; Mathew, Christopher G; Parkes, Miles; Georges, Michel; Daly, Mark J; Heyman, Melvin B; Ferry, George D; Kirschner, Barbara; Lee, Jessica; Essers, Jonah; Grand, Richard; Stephens, Michael; Levine, Arie; Piccoli, David; Van Limbergen, John; Cucchiara, Salvatore; Monos, Dimitri S; Guthery, Stephen L; Denson, Lee; Wilson, David C; Grant, Straun F A; Daly, Mark; Silverberg, Mark S; Satsangi, Jack; Hakonarson, Hakon

    2009-12-01

    The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

  4. Impact of T300A Variant of ATG16L1 on Antibacterial Response, Risk of Culture Positive Infections, and Clinical Course of Crohn's Disease

    DEFF Research Database (Denmark)

    Salem, Mohammad; Nielsen, Ole Haagen; Nys, Kris

    2015-01-01

    OBJECTIVES: Autophagy-related 16-like 1 (ATG16L1) deficiency leads to impaired cellular autophagy and bacterial degradation as well as an altered cytokine production. The single-nucleotide polymorphism rs2241880 (T300A) is associated with an increased risk for Crohn's disease (CD). ATG16L1...... polymorphisms could therefore have an impact on the risk of infectious complications and disease course in CD. We examined the impact of the T300A genotype on the antibacterial response toward a panel of pathogenic bacteria in vitro, as well as clinical infectious complications in vivo and the disease course...... risk variant, AG heterozygous variant, respectively). The median duration of disease was 128 months (range, 30-175). The cumulative follow-up of this cohort was 2,366 patient-years. ATG16L1 gene variations interfered with the production of IL-1β, which was significantly increased in PBMCs from GG...

  5. Characterization of Coconut cadang-cadang viroid variants from oil palm affected by orange spotting disease in Malaysia.

    Science.gov (United States)

    Wu, Y H; Cheong, L C; Meon, S; Lau, W H; Kong, L L; Joseph, H; Vadamalai, G

    2013-06-01

    A 246-nt variant of Coconut cadang-cadang viroid (CCCVd) has been identified and described from oil palms with orange spotting symptoms in Malaysia. Compared with the 246-nt form of CCCVd from coconut, the oil palm variant substituted C(31)→U in the pathogenicity domain and G(70)→C in the central conserved domain. This is the first sequence reported for a 246-nt variant of CCCVd in oil palms expressing orange spotting symptoms.

  6. DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn's disease

    DEFF Research Database (Denmark)

    Renner, Marcus; Bergmann, Gaby; Krebs, Inge

    2007-01-01

    , immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case-control sample. Dmbt1(-/-) mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium-induced colitis. RESULTS: DMBT1 levels correlate with disease...... is associated with an increased risk of CD (P = .00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1(-/-) mice display enhanced susceptibility to dextran sulfate sodium-induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. CONCLUSIONS: DMBT1 may play a role...

  7. Identification of MHCII variants associated with chlamydial disease in the koala (Phascolarctos cinereus)

    OpenAIRE

    Lau, Quintin; Griffith, Joanna E.; Higgins, Damien P.

    2014-01-01

    Chlamydiosis, the most common infectious disease in koalas, can cause chronic urogenital tract fibrosis and infertility. High titres of serum immunoglobulin G against 10 kDa and 60 kDa chlamydial heat-shock proteins (c-hsp10 and c-hsp60) are associated with fibrous occlusion of the koala uterus and uterine tube. Murine and human studies have identified associations between specific major histocompatibility complex class II (MHCII) alleles or genotypes, and higher c-hsp 60 antibody levels or c...

  8. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants

    Science.gov (United States)

    Lenassi, Eva; Vincent, Ajoy; Li, Zheng; Saihan, Zubin; Coffey, Alison J; Steele-Stallard, Heather B; Moore, Anthony T; Steel, Karen P; Luxon, Linda M; Héon, Elise; Bitner-Glindzicz, Maria; Webster, Andrew R

    2015-01-01

    Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration (‘retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one ‘retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype–phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting. PMID:25649381

  9. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.

    Directory of Open Access Journals (Sweden)

    Paola Di Meglio

    2011-02-01

    Full Text Available IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A and common (G allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.

  10. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.

    Science.gov (United States)

    Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C; Peris, Ketty; Nestle, Frank O

    2011-02-22

    IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.

  11. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity.

    Science.gov (United States)

    Hutcheson, Kelly A; Paluru, Prasuna C; Bernstein, Steven L; Koh, Jamie; Rappaport, Eric F; Leach, Richard A; Young, Terri L

    2005-07-14

    Retinopathy of prematurity (ROP) is a leading cause of visual loss in the pediatric population. Mutations in the Norrie disease gene (NDP) are associated with heritable retinal vascular disorders, and have been found in a small subset of patients with severe retinopathy of prematurity. Varying rates of progression to threshold disease in different races may have a genetic basis, as recent studies suggest that the incidence of NDP mutations may vary in different groups. African Americans, for example, are less likely to develop severe degrees of ROP. We screened a large cohort of ethnically diverse patients for mutations in the entire NDP. A total of 143 subjects of different ethnic backgrounds were enrolled in the study. Fifty-four patients had severe ROP (Stage 3 or worse). Of these, 38 were threshold in at least one eye (with a mean gestational age of 26.1 weeks and mean birth weight of 788.4 g). There were 36 patients with mild or no ROP, 31 parents with no history of retinal disease or prematurity, and 22 wild type (normal) controls. There were 70 African American subjects, 55 Caucasians, and 18 of other races. Severe ROP was noted in 29 African American subjects, 17 Caucasians, and 8 of other races. Seven polymerase chain reaction primer pairs spanning the NDP were optimized for denaturing high performance liquid chromatography and direct sequencing. Three primer pairs covered the coding region, and the remaining four spanned the 3' and 5' untranslated regions (UTR). Six of 54 (11%) infants with severe ROP had polymorphisms in the NDP. Five of the infants were African American, and one was Caucasian. Two parents were heterozygous for the same polymorphism as their child. One parent-child pair had a single base pair (bp) insertion in the 3' UTR region. Another parent-child pair had two mutations: a 14 bp deletion in the 5' UTR region of exon 1 and a single nucleotide polymorphism in the 5' UTR region of exon 2. No coding region sequence changes were found. No

  12. Functional promoter variant in zinc finger protein 202 predicts severe atherosclerosis and ischemic heart disease

    DEFF Research Database (Denmark)

    Frikke-Schmidt, R.; Nordestgaard, Børge; Grande, Peer

    2008-01-01

    Objectives This study was designed to test the hypotheses that single nucleotide polymorphisms ( SNPs), in zinc finger protein 202 ( ZNF202), predict severe atherosclerosis and ischemic heart disease ( IHD). Background ZNF202 is a transcriptional repressor controlling promoter elements in genes...... involved in vascular maintenance and lipid metabolism. Methods We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis ( ankle brachial index >0.7 vs. ...,998 controls. Finally, we determined whether g. -660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results Cross-sectionally, ZNF202 g. -660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 ( 95% confidence interval [CI]: 1.34 to 3.01). Prospectively...

  13. Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD.

    Science.gov (United States)

    Carrasquillo, Minerva M; Khan, Qurat ul Ain; Murray, Melissa E; Krishnan, Siddharth; Aakre, Jeremiah; Pankratz, V Shane; Nguyen, Thuy; Ma, Li; Bisceglio, Gina; Petersen, Ronald C; Younkin, Steven G; Dickson, Dennis W; Boeve, Bradley F; Graff-Radford, Neill R; Ertekin-Taner, Nilüfer

    2014-04-22

    To investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of "posterior AD" neuropathology. We assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies. There was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10(-17), OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk. We identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.

  14. Fluid-phase immunoradiometric assay for the detection of qualitative abnormalities of factor VIII/von Willebrand factor in variants of von Willebrand's disease

    International Nuclear Information System (INIS)

    Girma, J.P.; Ardaillou, N.; Meyer, D.; Lavergne, J.M.; Larrieu, M.J.

    1979-01-01

    Antigenic reactivity of F.VIII/WF in variants of von Willebrand's disease (vWd) was studied with both fluid-phase and solid-phase immunoradiometric assays. Two different (rabbit and goat) 125 I-labeled specific antibodies against purified F.VIII/WF were used in both their divalent (lgG) and their monovalent (Fab fragment) forms. Dose-response curves obtained by reacting a constant amount of antibody with serial dilutions of plasmas from normal or homozygous vWd demonstrated the specificity of the test. The accuracy was significantly higher with 125 I-Fab fragments of goat anti-F.VIII/WF antiserum than intact goat lgG or rabbit lgG or Fab fragments. The significant decrease of the slope of the dose-response curves obtained with plasma from variants of vWd has been interpreted as due to the presence of abnormal F.VIII/WF molecules with decreased antigenic reactivity. A similar anomaly was found in cryosupernatant prepared from normal plasma, paralleling similarities demonstrated between variants of vWd and cryosupernatant. Results of experiments performed by reacting constant plasma dilutions from control or variants of vWd and varying concentrations of anti-F.VIII/WF Fab fragments (rabbit or goat) confirmed the decreased antigenic reactivity of variant F.VIII/WF

  15. Whole-exome sequencing reveals genetic variants associated with chronic kidney disease characterized by tubulointerstitial damages in North Central Region, Sri Lanka.

    Science.gov (United States)

    Nanayakkara, Shanika; Senevirathna, S T M L D; Parahitiyawa, Nipuna B; Abeysekera, Tilak; Chandrajith, Rohana; Ratnatunga, Neelakanthi; Hitomi, Toshiaki; Kobayashi, Hatasu; Harada, Kouji H; Koizumi, Akio

    2015-09-01

    The familial clustering observed in chronic kidney disease of uncertain etiology (CKDu) characterized by tubulointerstitial damages in the North Central Region of Sri Lanka strongly suggests the involvement of genetic factors in its pathogenesis. The objective of the present study is to use whole-exome sequencing to identify the genetic variants associated with CKDu. Whole-exome sequencing of eight CKDu cases and eight controls was performed, followed by direct sequencing of candidate loci in 301 CKDu cases and 276 controls. Association study revealed rs34970857 (c.658G > A/p.V220M) located in the KCNA10 gene encoding a voltage-gated K channel as the most promising SNP with the highest odds ratio of 1.74. Four rare variants were identified in gene encoding Laminin beta2 (LAMB2) which is known to cause congenital nephrotic syndrome. Three out of four variants in LAMB2 were novel variants found exclusively in cases. Genetic investigations provide strong evidence on the presence of genetic susceptibility for CKDu. Possibility of presence of several rare variants associated with CKDu in this population is also suggested.

  16. Distinct Patterns of Association of Variants at 11q23.3 Chromosomal Region with Coronary Artery Disease and Dyslipidemia in the Population of Andhra Pradesh, India.

    Directory of Open Access Journals (Sweden)

    Rayabarapu Pranav Chand

    Full Text Available In our attempt to comprehensively understand the nature of association of variants at 11q23.3 apolipoprotein gene cluster region, we genotyped a prioritized set of 96 informative SNPs using Fluidigm customized SNP genotyping platform in a sample of 508 coronary artery disease (CAD cases and 516 controls. We found 12 SNPs as significantly associated with CAD at P <0.05, albeit only four (rs2849165, rs17440396, rs6589566 and rs633389 of these remained significant after Benjamin Hochberg correction. Of the four, while rs6589566 confers risk to CAD, the other three SNPs reduce risk for the disease. Interaction of variants that belong to regulatory genes BUD13 and ZPR1 with APOA5-APOA4 intergenic variants is also observed to significantly increase the risk towards CAD. Further, ROC analysis of the risk scores of the 12 significant SNPs suggests that our study has substantial power to confer these genetic variants as predictors of risk for CAD, as illustrated by AUC (0.763; 95% CI: 0.729-0.798, p = <0.0001. On the other hand, the protective SNPs of CAD are associated with elevated Low Density Lipoprotein Cholesterol and Total Cholesterol levels, hence with dyslipidemia, in our sample of controls, which may suggest distinct effects of the variants at 11q23.3 chromosomal region towards CAD and dyslipidemia. It may be necessary to replicate these findings in the independent and ethnically heterogeneous Indian samples in order to establish this as an Indian pattern. However, only functional analysis of the significant variants identified in our study can provide more precise understanding of the mechanisms involved in the contrasting nature of their effects in manifesting dyslipidemia and CAD.

  17. Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

    Directory of Open Access Journals (Sweden)

    Alexander M Kulminski

    2016-11-01

    Full Text Available Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC Study (N = 9,573 was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5% located in band 2q22.3 with risks of coronary heart disease (CHD, heart failure (HF, stroke, diabetes, cancer, neurodegenerative diseases (ND, and mortality in the ARIC study, the Framingham Heart Study (N = 4,434, and the Health and Retirement Study (N = 9,676. We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9, CHD by 35% (p = 8.9×10-6, HF by 55% (p = 9.7×10-5, stroke by 25% (p = 4.0×10-2, and ND by 100% (p = 1.3×10-3. This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

  18. The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk.

    Science.gov (United States)

    Hooli, Basavaraj V; Parrado, Antonio R; Mullin, Kristina; Yip, Wai-Ki; Liu, Tian; Roehr, Johannes T; Qiao, Dandi; Jessen, Frank; Peters, Oliver; Becker, Tim; Ramirez, Alfredo; Lange, Christoph; Bertram, Lars; Tanzi, Rudolph E

    2014-10-07

    Recently, 2 independent studies reported that a rare missense variant, rs75932628 (R47H), in exon 2 of the gene encoding the "triggering receptor expressed on myeloid cells 2" (TREM2) significantly increases the risk of Alzheimer disease (AD) with an effect size comparable to that of the APOE ε4 allele. In this study, we attempted to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in 2 independent Caucasian family cohorts consisting of 927 families (with 1,777 affected and 1,235 unaffected) and in 2 Caucasian case-control cohorts composed of 1,314 cases and 1,609 controls. In addition, we imputed genotypes in 3 independent Caucasian case-control cohorts containing 1,906 cases and 1,503 controls. Meta-analysis of the 2 family-based and the 5 case-control cohorts yielded a p value of 0.0029, while the overall summary estimate (using case-control data only) resulted in an odds ratio of 1.67 (95% confidence interval 0.95-2.92) for the association between the TREM2 R47H and increased AD risk. While our results serve to confirm the association between R47H and risk of AD, the observed effect on risk was substantially smaller than that previously reported. © 2014 American Academy of Neurology.

  19. Common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: a meta-analysis.

    Science.gov (United States)

    Zain, Shamsul Mohd; Mohamed, Zahurin; Mohamed, Rosmawati

    2015-01-01

    Although studies have suggested that rs780094, a common variant in the glucokinase regulatory (GCKR) gene to be associated with type 2 diabetes, obesity, and their related traits, the genetic basis of the association between GCKR rs780094 and nonalcoholic fatty liver disease (NAFLD) is still being examined. This meta-analysis was performed to evaluate the effect strength caused by GCKR rs780094 on NAFLD. We searched Medline, PubMed, Scopus, and Embase for relevant articles published up to April 2014. Data were extracted, and summary estimates of the association between GCKR rs780094 and NAFLD were examined. Heterogeneity and publication bias were also examined. This meta-analysis incorporated a total of 2091 NAFLD cases and 3003 controls from five studies. Overall, the pooled result indicated that the GCKR rs780094 was significantly associated with increased risk of NAFLD (additive: odds ratio (OR) 1.25, 95% confidence interval (CI) 1.14-1.36, P risk of NAFLD. Similar effect size was demonstrated in both Asian and non-Asian populations. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  20. Meta-Analysis of Facial Emotion Recognition in Behavioral Variant Frontotemporal Dementia: Comparison With Alzheimer Disease and Healthy Controls.

    Science.gov (United States)

    Bora, Emre; Velakoulis, Dennis; Walterfang, Mark

    2016-07-01

    Behavioral disturbances and lack of empathy are distinctive clinical features of behavioral variant frontotemporal dementia (bvFTD) in comparison to Alzheimer disease (AD). The aim of this meta-analytic review was to compare facial emotion recognition performances of bvFTD with healthy controls and AD. The current meta-analysis included a total of 19 studies and involved comparisons of 288 individuals with bvFTD and 329 healthy controls and 162 bvFTD and 147 patients with AD. Facial emotion recognition was significantly impaired in bvFTD in comparison to the healthy controls (d = 1.81) and AD (d = 1.23). In bvFTD, recognition of negative emotions, especially anger (d = 1.48) and disgust (d = 1.41), were severely impaired. Emotion recognition was significantly impaired in bvFTD in comparison to AD in all emotions other than happiness. Impairment of emotion recognition is a relatively specific feature of bvFTD. Routine assessment of social-cognitive abilities including emotion recognition can be helpful in better differentiating between cortical dementias such as bvFTD and AD. © The Author(s) 2016.

  1. Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Li, Yu-Yuan

    2012-12-07

    Nonalcoholic fatty liver disease (NAFLD) is common worldwide. The importance of genetic and epigenetic changes in etiology and pathogenesis of NAFLD has been increasingly recognized. However, the exact mechanism is largely unknown. A large number of single nucleotide polymorphisms (SNPs) related to NAFLD has been documented by candidate gene studies (CGSs). Among these genes, peroxisome proliferatoractivated receptor-γ, adiponectin, leptin and tumor necrosis factor-α were frequently reported. Since the introduction of genome-wide association studies (GWASs), there have been significant advances in our understanding of genomic variations of NAFLD. Patatin-like phospholipase domain containing family member A3 (PNPLA3, SNP rs738409, encoding I148M), also termed adiponutrin, has caught most attention. The evidence that PNPLA3 is associated with increased hepatic fat levels and hepatic inflammation has been validated by a series of studies. Epigenetic modification refers to phenotypic changes caused by an adaptive mechanism unrelated to alteration of primary DNA sequences. Epigenetic regulation mainly includes microRNAs (miRs), DNA methylation, histone modifications and ubiquitination, among which miRs are studied most extensively. miRs are small natural single stranded RNA molecules regulating mRNA degradation or translation inhibition, subsequently altering protein expression of target genes. The miR-122, a highly abundant miR accounting for nearly 70% of all miRs in the liver, is significantly under-expressed in NAFLD subjects. Inhibition of miR-122 with an antisense oligonucleotide results in decreased mRNA expression of lipogenic genes and improvement of liver steatosis. The investigation into epigenetic involvement in NAFLD pathogenesis is just at the beginning and needs to be refined. This review summarizes the roles of genetics and epigenetics in the development of NAFLD. The progress made in this field may provide novel diagnostic biomarkers and therapeutic

  2. IRGM Variants and Susceptibility to Inflammatory Bowel Disease in the German Population

    Science.gov (United States)

    Bues, Stephanie; Stallhofer, Johannes; Fries, Christoph; Olszak, Torsten; Tsekeri, Eleni; Wetzke, Martin; Beigel, Florian; Steib, Christian; Friedrich, Matthias; Göke, Burkhard; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

    2013-01-01

    Background & Aims Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study. Methodology/Principal Findings Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05–1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06–1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01–1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (passociations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction. Conclusions/Significance Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD. PMID:23365659

  3. Creutzfeldt-Jakob disease, Heidenhain variant: case report with MRI (DWI) findings

    International Nuclear Information System (INIS)

    Arruda, Walter Oleschko; Bordignon, Kelly C.; Milano, Jeronimo B.; Ramina, Ricardo

    2004-01-01

    Creutzfeldt-Jakob disease (CJD) is a pre senile dementia characterized by rapidly progressive mental deterioration, myoclonic jerking, and other less common neurological signs. Few accentuates cases have been described in Brazil. A 54-year-old white woman, was admitted in our service with a month history of progressive, bilateral cortical blindness. After admission, she developed right partial motor seizures (right facial, upper and lower limbs), she became progressively aphasic (mixed aphasia). Seizures were controlled with phenytoine, but she developed choreoathetotic movements on her right dimidium, with partial control after introduction of chlorpromazine 25 mg q/d. She could no longer stand up or walk due to severe ataxia. The first EEG (October, 2001) showed left hemisphere severe seizure activity (status epilepticus partial is). She was delivered home with enteral nutrition, phenytoine, chlorpromazine and mepacrine 100 mg q d. The following laboratory tests were negative or normal: blood series, platelets, ESR, kidney and liver function, copper, ceruloplasmin, Vedril, HIV, HTLV-1, lactate, and cerebral Dsa (performed in other service). A spinal tap with normal opening pressure was perform and CSFR examination was normal. CSFR 14-3-3 protein was positive, CSF specific neuronal enolase 7.5 ng/ml(normal). Genetic study of PRNP gene did not disclosed any known mutation. A MRI (October, 2001) showed areas of hyperintense signal (T 2 and FLAIR) without Gd-enhancement on T1, in the left temporal lobe and in both occipital lobes; basal ganglia have a normal appearance. DWI imaging showed bright areas at the same sites. An EEG (March, 2002) disclosed a periodical sharp triphasic waves pattern, suggestive of CJD. A second MRI (April, 2002) showed mild generalized atrophy, no ventricular dilatation, and the hyperintense sites disappeared. She remained clinically stable and under use of chlorpromazine and mepacrine until she died due to pulmonary complications on April

  4. Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia?

    Science.gov (United States)

    Bertoux, Maxime; de Souza, Leonardo Cruz; O'Callaghan, Claire; Greve, Andrea; Sarazin, Marie; Dubois, Bruno; Hornberger, Michael

    2016-01-01

    Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.

  5. GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease.

    Directory of Open Access Journals (Sweden)

    Yutao Liu

    Full Text Available DNA copy number variants (CNVs have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC. This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1. (p = 0.017, fisher's exact test. It was validated with array comparative genomic hybridization (arrayCGH and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio = 3.5, 95% CI -1.1-12.0. Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6-16.4. Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG.

  6. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

    Science.gov (United States)

    Quartier, Angélique; Poquet, Hélène; Gilbert-Dussardier, Brigitte; Rossi, Massimiliano; Casteleyn, Anne-Sophie; Portes, Vincent des; Feger, Claire; Nourisson, Elsa; Kuentz, Paul; Redin, Claire; Thevenon, Julien; Mosca-Boidron, Anne-Laure; Callier, Patrick; Muller, Jean; Lesca, Gaetan; Huet, Frédéric; Geoffroy, Véronique; El Chehadeh, Salima; Jung, Matthieu; Trojak, Benoit; Le Gras, Stéphanie; Lehalle, Daphné; Jost, Bernard; Maury, Stéphanie; Masurel, Alice; Edery, Patrick; Thauvin-Robinet, Christel; Gérard, Bénédicte; Mandel, Jean-Louis; Faivre, Laurence; Piton, Amélie

    2017-01-01

    Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up. PMID:28176767

  7. Cellulase variants

    Science.gov (United States)

    Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

    2015-07-14

    This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

  8. Genetic variants of genital mycoplasmas and their relation to the clinical course of inflammatory diseases of the urogenital system in women

    Directory of Open Access Journals (Sweden)

    M. R. Rakhmatulina

    2014-01-01

    Full Text Available Goal of the study. To study genetic variability of M. hominis (based on the vaa gene and M. genitalium (based on the mg192 gene derived from biological material samples taken from women with different clinical manifestations of inflammatory diseases of the urogenital system and clinically healthy women (for M. hominis. Materials and methods. Genetic variability of twenty M. hominis samples taken from patients with inflammatory diseases of the urogenital system and twenty M. hominis samples taken from patients without clinical and laboratory signs of inflammatory processes of the urogenital system was studied by the sequence analysis method. Genetic variability of eight M. genitalium samples taken from patients with different clinical signs of inflammatory diseases of the urogenital system was also examined by the sequence analysis method. Results. Three genetic variants of M. hominis based on the vaa gene were found; variant I was revealed more often in patients with clinical manifestations of inflammatory diseases (65.0%, and variant II - in clinically healthy women (60.0%. Three phylogenetic M. gentium groups based on the mg192 gene were revealed; two samples were referred to Groups I and II, and four samples were referred to Group III. Samples from each phylogenetic groups were taken from patients with clinical and laboratory manifestations of cervicitis and urethritis. Conclusion. The study data demonstrate a potential effect of the VAA surface protein on the virulence of opportunistic M. hominis pathogens.

  9. Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease

    Science.gov (United States)

    Sims, Rebecca; van der Lee, Sven J.; Naj, Adam C.; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W.; Boland, Anne; Raybould, Rachel; Bis, Joshua C.; Martin, Eden R.; Grenier-Boley, Benjamin; Heilmann-Heimbach, Stefanie; Chouraki, Vincent; Kuzma, Amanda B.; Sleegers, Kristel; Vronskaya, Maria; Ruiz, Agustin; Graham, Robert R.; Olaso, Robert; Hoffmann, Per; Grove, Megan L.; Vardarajan, Badri N.; Hiltunen, Mikko; Nöthen, Markus M.; White, Charles C.; Hamilton-Nelson, Kara L.; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W.; Dulary, Cécile; Herms, Stefan; Smith, Albert V.; Funk, Cory C.; Derbois, Céline; Forstner, Andreas J.; Ahmad, Shahzad; Li, Hongdong; Bacq, Delphine; Harold, Denise; Satizabal, Claudia L.; Valladares, Otto; Squassina, Alessio; Thomas, Rhodri; Brody, Jennifer A.; Qu, Liming; Sanchez-Juan, Pascual; Morgan, Taniesha; Wolters, Frank J.; Zhao, Yi; Garcia, Florentino Sanchez; Denning, Nicola; Fornage, Myriam; Malamon, John; Naranjo, Maria Candida Deniz; Majounie, Elisa; Mosley, Thomas H.; Dombroski, Beth; Wallon, David; Lupton, Michelle K; Dupuis, Josée; Whitehead, Patrice; Fratiglioni, Laura; Medway, Christopher; Jian, Xueqiu; Mukherjee, Shubhabrata; Keller, Lina; Brown, Kristelle; Lin, Honghuang; Cantwell, Laura B.; Panza, Francesco; McGuinness, Bernadette; Moreno-Grau, Sonia; Burgess, Jeremy D.; Solfrizzi, Vincenzo; Proitsi, Petra; Adams, Hieab H.; Allen, Mariet; Seripa, Davide; Pastor, Pau; Cupples, L. Adrienne; Price, Nathan D; Hannequin, Didier; Frank-García, Ana; Levy, Daniel; Chakrabarty, Paramita; Caffarra, Paolo; Giegling, Ina; Beiser, Alexa S.; Giedraitis, Vimantas; Hampel, Harald; Garcia, Melissa E.; Wang, Xue; Lannfelt, Lars; Mecocci, Patrizia; Eiriksdottir, Gudny; Crane, Paul K.; Pasquier, Florence; Boccardi, Virginia; Henández, Isabel; Barber, Robert C.; Scherer, Martin; Tarraga, Lluis; Adams, Perrie M.; Leber, Markus; Chen, Yuning; Albert, Marilyn S.; Riedel-Heller, Steffi; Emilsson, Valur; Beekly, Duane; Braae, Anne; Schmidt, Reinhold; Blacker, Deborah; Masullo, Carlo; Schmidt, Helena; Doody, Rachelle S.; Spalletta, Gianfranco; Longstreth, WT; Fairchild, Thomas J.; Bossù, Paola; Lopez, Oscar L.; Frosch, Matthew P.; Sacchinelli, Eleonora; Ghetti, Bernardino; Sánchez-Juan, Pascual; Yang, Qiong; Huebinger, Ryan M.; Jessen, Frank; Li, Shuo; Kamboh, M. Ilyas; Morris, John; Sotolongo-Grau, Oscar; Katz, Mindy J.; Corcoran, Chris; Himali, Jayanadra J.; Keene, C. Dirk; Tschanz, JoAnn; Fitzpatrick, Annette L.; Kukull, Walter A.; Norton, Maria; Aspelund, Thor; Larson, Eric B.; Munger, Ron; Rotter, Jerome I.; Lipton, Richard B.; Bullido, María J; Hofman, Albert; Montine, Thomas J.; Coto, Eliecer; Boerwinkle, Eric; Petersen, Ronald C.; Alvarez, Victoria; Rivadeneira, Fernando; Reiman, Eric M.; Gallo, Maura; O’Donnell, Christopher J.; Reisch, Joan S.; Bruni, Amalia Cecilia; Royall, Donald R.; Dichgans, Martin; Sano, Mary; Galimberti, Daniela; St George-Hyslop, Peter; Scarpini, Elio; Tsuang, Debby W.; Mancuso, Michelangelo; Bonuccelli, Ubaldo; Winslow, Ashley R.; Daniele, Antonio; Wu, Chuang-Kuo; Peters, Oliver; Nacmias, Benedetta; Riemenschneider, Matthias; Heun, Reinhard; Brayne, Carol; Rubinsztein, David C; Bras, Jose; Guerreiro, Rita; Hardy, John; Al-Chalabi, Ammar; Shaw, Christopher E; Collinge, John; Mann, David; Tsolaki, Magda; Clarimón, Jordi; Sussams, Rebecca; Lovestone, Simon; O’Donovan, Michael C; Owen, Michael J; Behrens, Timothy W.; Mead, Simon; Goate, Alison M.; Uitterlinden, Andre G.; Holmes, Clive; Cruchaga, Carlos; Ingelsson, Martin; Bennett, David A.; Powell, John; Golde, Todd E.; Graff, Caroline; De Jager, Philip L.; Morgan, Kevin; Ertekin-Taner, Nilufer; Combarros, Onofre; Psaty, Bruce M.; Passmore, Peter; Younkin, Steven G; Berr, Claudine; Gudnason, Vilmundur; Rujescu, Dan; Dickson, Dennis W.; Dartigues, Jean-Francois; DeStefano, Anita L.; Ortega-Cubero, Sara; Hakonarson, Hakon; Campion, Dominique; Boada, Merce; Kauwe, John “Keoni”; Farrer, Lindsay A.; Van Broeckhoven, Christine; Ikram, M. Arfan; Jones, Lesley; Haines, Johnathan; Tzourio, Christophe; Launer, Lenore J.; Escott-Price, Valentina; Mayeux, Richard; Deleuze, Jean-François; Amin, Najaf; Holmans, Peter A; Pericak-Vance, Margaret A.; Amouyel, Philippe; van Duijn, Cornelia M.; Ramirez, Alfredo; Wang, Li-San; Lambert, Jean-Charles; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D.

    2017-01-01

    Introduction We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development. PMID:28714976

  10. Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans

    Science.gov (United States)

    Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Mayeux, Richard

    2013-01-01

    Importance Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. Objective To identify genetic loci associated with late-onset Alzheimer disease in African Americans. Design, Setting, and Participants The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. Main Outcomes and Measures Presence of Alzheimer disease according to standardized criteria. Results Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses

  11. Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.

    Science.gov (United States)

    Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B; Graff-Radford, Neill R; Evans, Denis; De Jager, Philip L; Crane, Paul K; Buxbaum, Joseph D; Murrell, Jill R; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T; Green, Robert C; Barnes, Lisa L; Cantwell, Laura B; Fallin, M Daniele; Go, Rodney C P; Griffith, Patrick; Obisesan, Thomas O; Manly, Jennifer J; Lunetta, Kathryn L; Kamboh, M Ilyas; Lopez, Oscar L; Bennett, David A; Hendrie, Hugh; Hall, Kathleen S; Goate, Alison M; Byrd, Goldie S; Kukull, Walter A; Foroud, Tatiana M; Haines, Jonathan L; Farrer, Lindsay A; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Mayeux, Richard

    2013-04-10

    Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. To identify genetic loci associated with late-onset Alzheimer disease in African Americans. The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. Presence of Alzheimer disease according to standardized criteria. Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional

  12. Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease

    NARCIS (Netherlands)

    Vermeiren, Yannick; Janssens, Jana; Aerts, Tony; Martin, Jean-Jacques; Sieben, Anne; Van Dam, Debby; De Deyn, Peter P.

    2016-01-01

    Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non) cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative,

  13. The Role of RNF213 4810G>A and 4950G>A Variants in Patients with Moyamoya Disease in Korea

    Directory of Open Access Journals (Sweden)

    Young Seok Park

    2017-11-01

    Full Text Available Although a founder variant of RNF213 4810G>A is a major genetic risk factor for moyamoya disease (MMD in East Asians, the frequency and disease susceptibility of RNF213 variants remain largely unknown. This study investigated the mutation analysis of RNF213 (4448, 4810, 4863, and 4950 between Korean MMD and healthy controls. We performed a polymerase chain reaction-restriction fragment length polymorphism analysis. To identify the association between RNF213 gene polymorphisms and MMD disease, we performed statistical analyses such as multivariable logistic regression and Fisher’s exact test. Genetic data from 117 MMD patients were analyzed and compared with 253 healthy controls. We assessed and compared single nucleotide polymorphisms of RNF213 (4448, 4810, 4863, and 4950 between MMD and control groups. We performed genome-wide association studies to investigate the genetic pathophysiology of MMD. Among the RNF213 variants (4448G>A, 4810G>A, 4863G>A, and 4950G>A, RNF213 4810G>A and 4950G>A variants were more frequent in MMD patients. In a subgroup analysis, the RNF213 4810G>A was more frequent in moyamoya disease, and the comparison with GG+AA genotype was also significantly different in moyamoya patients. These results confirm that RNF213 4810G>A and RNF213 4950G>A were more frequent in MMD patients. We have confirmed that RNF213 4810G>A and 4950G>A are strongly associated with Korean MMD in children and adults as well as for the ischemic and hemorrhagic types.

  14. Frontal and temporal lobe contributions to emotional enhancement of memory in behavioural-variant frontotemporal dementia and Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Fiona eKumfor

    2014-06-01

    Full Text Available Emotional events gain special priority in how they are remembered, with emotionally arousing events typically recalled more vividly and with greater confidence than non-emotional events. In dementia, memory and emotion processing are affected to varying degrees, however, whether emotional enhancement of memory for complex ecologically valid events is differentially affected across dementia syndromes remains unclear, with previous studies examining effects of emotion on simple visual recognition only. Here, we examined memory for an emotionally arousing short story and a closely matched, emotionally neutral story in behavioural-variant frontotemporal dementia (bvFTD (n = 13 and Alzheimer’s disease (AD (n = 14, and contrasted their performance with healthy controls (n = 12. Multiple-choice recognition memory for specific details of the story was assessed after a 1-hour delay. While AD and control groups showed enhanced memory for the emotional story, the bvFTD group recalled a similar number of details from the emotional and neutral stories. Voxel-based morphometry analyses revealed emotional enhancement of memory correlated with distinct brain regions in each patient group. In AD, emotional enhancement was associated with integrity of the bilateral hippocampus, parahippocampal gyri, temporal fusiform gyrus and frontal pole, regions implicated in memory processes. In contrast in bvFTD, integrity of emotion processing regions, including the orbitofrontal cortex, right amygdala and right insula, correlated with the extent emotion enhanced memory. Our results reveal that integrity of frontal and temporal regions determine the quality and nature of emotional memories. While emotional enhancement of memory is present in mild AD, in bvFTD emotion does not facilitate memory retrieval for complex realistic events. This attenuation of emotional enhancement is due to degradation of emotion processing regions, which may be important for modulating levels

  15. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality

    Energy Technology Data Exchange (ETDEWEB)

    Hitomi, Toshiaki [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Habu, Toshiyuki [Radiation Biology Center, Kyoto University, Kyoto (Japan); Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H. [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Osafune, Kenji [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Taura, Daisuke; Sone, Masakatsu [Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Hashikata, Hirokuni; Takagi, Yasushi [Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Morito, Daisuke [Faculty of Life Sciences, Kyoto Sangyo University, Kyoto (Japan); Miyamoto, Susumu [Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Nakao, Kazuwa [Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto (Japan); Koizumi, Akio, E-mail: koizumi.akio.5v@kyoto-u.ac.jp [Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan)

    2013-10-04

    Highlights: •Overexpression of RNF213 R4810K inhibited cell proliferation. •Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. •R4810K formed a complex with MAD2 more readily than wild-type. •iPSECs from the MMD patients had elevated mitotic failure compared from the control. •RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n = 3, 61.0 ± 8.2%) compared with wild-type subjects (n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts (p < 0.01) and induced pluripotent stem cells (iPSCs) (p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls (p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls (p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability.

  16. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality

    International Nuclear Information System (INIS)

    Hitomi, Toshiaki; Habu, Toshiyuki; Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H.; Osafune, Kenji; Taura, Daisuke; Sone, Masakatsu; Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko; Hashikata, Hirokuni; Takagi, Yasushi; Morito, Daisuke; Miyamoto, Susumu; Nakao, Kazuwa; Koizumi, Akio

    2013-01-01

    Highlights: •Overexpression of RNF213 R4810K inhibited cell proliferation. •Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. •R4810K formed a complex with MAD2 more readily than wild-type. •iPSECs from the MMD patients had elevated mitotic failure compared from the control. •RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. -- Abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n = 3, 61.0 ± 8.2%) compared with wild-type subjects (n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts (p < 0.01) and induced pluripotent stem cells (iPSCs) (p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls (p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls (p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability

  17. Alzheimer Disease and Behavioral Variant Frontotemporal Dementia: Automatic Classification Based on Cortical Atrophy for Single-Subject Diagnosis.

    Science.gov (United States)

    Möller, Christiane; Pijnenburg, Yolande A L; van der Flier, Wiesje M; Versteeg, Adriaan; Tijms, Betty; de Munck, Jan C; Hafkemeijer, Anne; Rombouts, Serge A R B; van der Grond, Jeroen; van Swieten, John; Dopper, Elise; Scheltens, Philip; Barkhof, Frederik; Vrenken, Hugo; Wink, Alle Meije

    2016-06-01

    Purpose To investigate the diagnostic accuracy of an image-based classifier to distinguish between Alzheimer disease (AD) and behavioral variant frontotemporal dementia (bvFTD) in individual patients by using gray matter (GM) density maps computed from standard T1-weighted structural images obtained with multiple imagers and with independent training and prediction data. Materials and Methods The local institutional review board approved the study. Eighty-four patients with AD, 51 patients with bvFTD, and 94 control subjects were divided into independent training (n = 115) and prediction (n = 114) sets with identical diagnosis and imager type distributions. Training of a support vector machine (SVM) classifier used diagnostic status and GM density maps and produced voxelwise discrimination maps. Discriminant function analysis was used to estimate suitability of the extracted weights for single-subject classification in the prediction set. Receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were calculated for image-based classifiers and neuropsychological z scores. Results Training accuracy of the SVM was 85% for patients with AD versus control subjects, 72% for patients with bvFTD versus control subjects, and 79% for patients with AD versus patients with bvFTD (P ≤ .029). Single-subject diagnosis in the prediction set when using the discrimination maps yielded accuracies of 88% for patients with AD versus control subjects, 85% for patients with bvFTD versus control subjects, and 82% for patients with AD versus patients with bvFTD, with a good to excellent AUC (range, 0.81-0.95; P ≤ .001). Machine learning-based categorization of AD versus bvFTD based on GM density maps outperforms classification based on neuropsychological test results. Conclusion The SVM can be used in single-subject discrimination and can help the clinician arrive at a diagnosis. The SVM can be used to distinguish disease-specific GM patterns in patients with AD

  18. PGC1α −1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals

    Directory of Open Access Journals (Sweden)

    Tara M. Henagan

    2014-01-01

    Full Text Available PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α. CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α  −1 nucleosome (−1N position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the −1N position revealed that those individuals with a −1N phased further upstream from the transcriptional start site (UP expressed lower levels of NTPGC1α than those with the −1N more proximal to TSS (DN. UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the −1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and −1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.

  19. A double mutation in exon 6 of the [beta]-hexosaminidase [alpha] subunit in a patient with the B1 variant of Tay-Sachs disease

    Energy Technology Data Exchange (ETDEWEB)

    Ainsworth, P.J. (Univ. of Western Ontario, Ontario (Canada) Child Health Research Institute, London, Ontario (Canada)); Coulter-Mackie, M.B. (Univ. of Western Ontario, Ontario (Canada) Child Health Research Institute, London, Ontario (Canada) Children' s Psychiatric Research Institute, London, Ontario (Canada))

    1992-10-01

    The B1 variant form of Tay-Sachs disease is enzymologically unique in that the causative mutation(s) appear to affect the active site in the [alpha] subunit of [beta]-hexosaminidase A without altering its ability to associate with the [beta] subunit. Most previously reported B1 variant mutations were found in exon 5 within codon 178. The coding sequence of the [alpha] subunit gene of a patient with the B1 variant form was examined with a combination of reverse transcription of mRNA to cDNA, PCR, and dideoxy sequencing. A double mutation in exon 6 has been identified: a G[sub 574][yields]C transversion causing a val[sub 192][yields]leu change and a G[sub 598][yields] A transition resulting in a val[sub 200][yields]met alteration. The amplified cDNAs were otherwise normal throughout their sequence. The 574 and 598 alterations have been confirmed by amplification directly from genomic DNA from the patient and her mother. Transient-expression studies of the two exon 6 mutations (singly or together) in COS-1 cells show that the G[sub 574][yields]C change is sufficient to cause the loss of enzyme activity. The biochemical phenotype of the 574 alteration in transfection studies is consistent with that expected for a B1 variant mutation. As such, this mutation differs from previously reported B1 variant mutations, all of which occur in exon 5. 31 refs., 2 figs., 2 tabs.

  20. Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene

    Directory of Open Access Journals (Sweden)

    Michael V. Zaragoza

    2017-11-01

    Full Text Available Dupuytren’s disease (palmar fibromatosis involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the LMNA mutation. Fibroblast RNA studies revealed monoallelic expression of the normal LMNA allele and reduced lamin A/C mRNAs consistent with LMNA haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala in the Asteroid Homolog 1 (ASTE1 gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four LMNA mutation carriers with fibromatosis and one individual without the LMNA mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling, ASTE1 may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.

  1. Carcinoma papilífero da tireoide e suas variantes histológicas associados à tireoidite de Hashimoto Thyroid papillary carcinoma and histologic variants linked to Hashimoto disease

    Directory of Open Access Journals (Sweden)

    Murilo Pedreira Neves Junior

    2009-10-01

    BRAS, RAS, P53 (mutations. Whereas Hashimoto's thyroiditis is an autoimmune disease characterized by auto-immune destruction followed by thyroid failure and it presents RET/PTC, RAS and FAS alterations. This study aims to describe the association of Hashimoto's thyroiditis with papillary carcinoma thyroid, correlating them with demographic data and histological variants. METHODS: It was conducted a case series study of 466 patients diagnosed with thyroid papillary carcinoma from January 2000 to December 2008. Case forms were filled up with the aim to collect demographic data and histological variants. RESULTS: The present study showed a coexistence of 30% of Hashimoto's thyroiditis in patients with papillary thyroid carcinoma. Among female patients there was a higher number of Hashimoto's thyroiditis cases, p = 0.046. CONCLUSION: The case series study showed a frequency of 30% of Hashimoto's thyroiditis in cases with papillary thyroid carcinoma suggesting a noncoincidental association, which raises the possibility of a cause and effect relation between thyroiditis and carcinoma development.

  2. PGC1? ?1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals

    OpenAIRE

    Henagan, Tara M.; Stewart, Laura K.; Forney, Laura A.; Sparks, Lauren M.; Johannsen, Neil; Church, Timothy S.

    2014-01-01

    PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically re...

  3. Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes*

    Science.gov (United States)

    Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W.; Mohri, Shirou; Kitamoto, Tetsuyuki

    2013-01-01

    To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype. PMID:23792955

  4. Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes.

    Science.gov (United States)

    Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W; Mohri, Shirou; Kitamoto, Tetsuyuki

    2013-07-26

    To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.

  5. Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases.

    Science.gov (United States)

    Itoh, Masayuki; Ide, Shuhei; Iwasaki, Yuji; Saito, Takashi; Narita, Keishi; Dai, Hongmei; Yamakura, Shinji; Furue, Takeki; Kitayama, Hirotsugu; Maeda, Keiko; Takahashi, Eihiko; Matsui, Kiyoshi; Goto, Yu-Ichi; Takeda, Sen; Arima, Masataka

    2018-04-01

    Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  6. Intestinal DMBT1 expression is modulated by Crohn's disease-associated IL23R variants and by a DMBT1 variant which influences binding of the transcription factors CREB1 and ATF-2.

    Directory of Open Access Journals (Sweden)

    Julia Diegelmann

    Full Text Available OBJECTIVES: DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs regarding inflammatory bowel disease (IBD susceptibility and examined their functional impact on transcription factor binding and downstream gene expression. METHODS: Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn's disease (CD patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays. RESULTS: IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0 × 10(-7, OR 1.42; 95% CI 1.24-1.63. All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1 × 10(-18. The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele. CONCLUSION: We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important

  7. Intestinal DMBT1 expression is modulated by Crohn's disease-associated IL23R variants and by a DMBT1 variant which influences binding of the transcription factors CREB1 and ATF-2.

    Science.gov (United States)

    Diegelmann, Julia; Czamara, Darina; Le Bras, Emmanuelle; Zimmermann, Eva; Olszak, Torsten; Bedynek, Andrea; Göke, Burkhard; Franke, Andre; Glas, Jürgen; Brand, Stephan

    2013-01-01

    DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs) regarding inflammatory bowel disease (IBD) susceptibility and examined their functional impact on transcription factor binding and downstream gene expression. Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn's disease (CD) patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays. IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0 × 10(-7), OR 1.42; 95% CI 1.24-1.63). All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1 × 10(-18)). The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele. We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important role of DMBT1 in CD pathogenesis.

  8. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease' in Italy

    Science.gov (United States)

    Nemethova, Martina; Radvanszky, Jan; Kadasi, Ludevit; Ascher, David B; Pires, Douglas E V; Blundell, Tom L; Porfirio, Berardino; Mannoni, Alessandro; Santucci, Annalisa; Milucci, Lia; Sestini, Silvia; Biolcati, Gianfranco; Sorge, Fiammetta; Aurizi, Caterina; Aquaron, Robert; Alsbou, Mohammed; Marques Lourenço, Charles; Ramadevi, Kanakasabapathi; Ranganath, Lakshminarayan R; Gallagher, James A; van Kan, Christa; Hall, Anthony K; Olsson, Birgitta; Sireau, Nicolas; Ayoob, Hana; Timmis, Oliver G; Le Quan Sang, Kim-Hanh; Genovese, Federica; Imrich, Richard; Rovensky, Jozef; Srinivasaraghavan, Rangan; Bharadwaj, Shruthi K; Spiegel, Ronen; Zatkova, Andrea

    2016-01-01

    Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650–85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy. PMID:25804398

  9. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.

    Science.gov (United States)

    Nemethova, Martina; Radvanszky, Jan; Kadasi, Ludevit; Ascher, David B; Pires, Douglas E V; Blundell, Tom L; Porfirio, Berardino; Mannoni, Alessandro; Santucci, Annalisa; Milucci, Lia; Sestini, Silvia; Biolcati, Gianfranco; Sorge, Fiammetta; Aurizi, Caterina; Aquaron, Robert; Alsbou, Mohammed; Lourenço, Charles Marques; Ramadevi, Kanakasabapathi; Ranganath, Lakshminarayan R; Gallagher, James A; van Kan, Christa; Hall, Anthony K; Olsson, Birgitta; Sireau, Nicolas; Ayoob, Hana; Timmis, Oliver G; Sang, Kim-Hanh Le Quan; Genovese, Federica; Imrich, Richard; Rovensky, Jozef; Srinivasaraghavan, Rangan; Bharadwaj, Shruthi K; Spiegel, Ronen; Zatkova, Andrea

    2016-01-01

    Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.

  10. MMS exposure promotes increased MtDNA mutagenesis in the presence of replication-defective disease-associated DNA polymerase γ variants.

    Science.gov (United States)

    Stumpf, Jeffrey D; Copeland, William C

    2014-10-01

    Mitochondrial DNA (mtDNA) encodes proteins essential for ATP production. Mutant variants of the mtDNA polymerase cause mutagenesis that contributes to aging, genetic diseases, and sensitivity to environmental agents. We interrogated mtDNA replication in Saccharomyces cerevisiae strains with disease-associated mutations affecting conserved regions of the mtDNA polymerase, Mip1, in the presence of the wild type Mip1. Mutant frequency arising from mtDNA base substitutions that confer erythromycin resistance and deletions between 21-nucleotide direct repeats was determined. Previously, increased mutagenesis was observed in strains encoding mutant variants that were insufficient to maintain mtDNA and that were not expected to reduce polymerase fidelity or exonuclease proofreading. Increased mutagenesis could be explained by mutant variants stalling the replication fork, thereby predisposing the template DNA to irreparable damage that is bypassed with poor fidelity. This hypothesis suggests that the exogenous base-alkylating agent, methyl methanesulfonate (MMS), would further increase mtDNA mutagenesis. Mitochondrial mutagenesis associated with MMS exposure was increased up to 30-fold in mip1 mutants containing disease-associated alterations that affect polymerase activity. Disrupting exonuclease activity of mutant variants was not associated with increased spontaneous mutagenesis compared with exonuclease-proficient alleles, suggesting that most or all of the mtDNA was replicated by wild type Mip1. A novel subset of C to G transversions was responsible for about half of the mutants arising after MMS exposure implicating error-prone bypass of methylated cytosines as the predominant mutational mechanism. Exposure to MMS does not disrupt exonuclease activity that suppresses deletions between 21-nucleotide direct repeats, suggesting the MMS-induce mutagenesis is not explained by inactivated exonuclease activity. Further, trace amounts of CdCl2 inhibit mtDNA replication but

  11. Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Anil K Giri

    Full Text Available A recent genome-wide association study (GWAS identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525-OR 1.71, P = 1.38 x 10-09; rs12008279-OR 1.56, P = 1.53 x 10-04 and 2 variants in MORC4 gene (rs12688220-OR 1.72, P = 9.20 x 10-09; rs6622126-OR 1.75, P = 4.04x10-05 in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06 and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31-0.78], P = 0.0027. A variant in the gene MORC4 (rs12688220 showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068 suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14. Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.

  12. Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease

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    Erik van der Wal

    2017-06-01

    Full Text Available The most common variant causing Pompe disease is c.-32-13T>G (IVS1 in the acid α-glucosidase (GAA gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA-based AONs. This resulted in the identification of a splicing regulatory element in GAA intron 1. We designed phosphorodiamidate morpholino oligomer-based AONs to this element, and these promoted exon 2 inclusion and enhanced GAA enzyme activity to levels above the disease threshold. These results indicate that the common IVS1 GAA splicing variant in Pompe disease is subject to negative regulation, and inhibition of a splicing regulatory element using AONs is able to restore canonical GAA splicing and endogenous GAA enzyme activity.

  13. Insights into the evolution of the new variant rabbit haemorrhagic disease virus (GI.2) and the identification of novel recombinant strains.

    Science.gov (United States)

    Silvério, D; Lopes, A M; Melo-Ferreira, J; Magalhães, M J; Monterroso, P; Serronha, A; Maio, E; Alves, P C; Esteves, P J; Abrantes, J

    2018-02-11

    Rabbit haemorrhagic disease (RHD) is a viral disease that affects the European rabbit. RHD was detected in 1984 in China and rapidly disseminated worldwide causing a severe decline in wild rabbit populations. The aetiological agent, rabbit haemorrhagic disease virus (RHDV), is an RNA virus of the family Caliciviridae, genus Lagovirus. Pathogenic (G1-G6 or variants GI.1a-GI.1d) and non-pathogenic strains (GI.4) have been characterized. In 2010, a new variant of RHDV, RHDV2/RHDVb/GI.2, was detected in France. GI.2 arrived to the Iberian Peninsula in 2011, and several recombination events were reported. Here, we sequenced full genomes of 19 samples collected in Portugal between 2014 and 2016. New GI.2 recombinant strains were detected, including triple recombinants. These recombinants possess a non-structural protein p16 related to a non-pathogenic strain. Evolutionary analyses were conducted on GI.2 VP60 sequences. Estimated time to the most recent common ancestor (tMRCA) suggests an emergence of GI.2 in July 2008, not distant from its first detection in 2010. This is the first study on GI.2 evolution and highlights the need of continued monitoring and characterization of complete genome sequences when studying lagoviruses' evolution. © 2018 Blackwell Verlag GmbH.

  14. Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.

    Science.gov (United States)

    Melchionda, Laura; Fang, Mingyan; Wang, Hairong; Fugnanesi, Valeria; Morbin, Michela; Liu, Xuanzhu; Li, Wenyan; Ceccherini, Isabella; Farina, Laura; Savoiardo, Mario; D'Adamo, Pio; Zhang, Jianguo; Costa, Alfredo; Ravaglia, Sabrina; Ghezzi, Daniele; Zeviani, Massimo

    2013-05-01

    We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander's disease (AOAD), suggesting different expression of the same, genetically determined, condition. Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-α, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells. Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-ϵ, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene. Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.

  15. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.

    Science.gov (United States)

    Nikopoulos, Konstantinos; Venselaar, Hanka; Collin, Rob W J; Riveiro-Alvarez, Rosa; Boonstra, F Nienke; Hooymans, Johanna M M; Mukhopadhyay, Arijit; Shears, Deborah; van Bers, Marleen; de Wijs, Ilse J; van Essen, Anthonie J; Sijmons, Rolf H; Tilanus, Mauk A D; van Nouhuys, C Erik; Ayuso, Carmen; Hoefsloot, Lies H; Cremers, Frans P M

    2010-06-01

    Wnt signaling is a crucial component of the cell machinery orchestrating a series of physiological processes such as cell survival, proliferation, and migration. Among the plethora of roles that Wnt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. Mutations in the genes encoding the low density lipoprotein receptor protein 5 (LRP5) and frizzled 4 (FZD4), acting as coreceptors for Wnt ligands, cause familial exudative vitreoretinopathy (FEVR). Moreover, mutations in the gene encoding NDP, a ligand for these Wnt receptors, cause Norrie disease and FEVR. Both FEVR and Norrie disease share similar phenotypic characteristics, including abnormal vascularization of the peripheral retina and formation of fibrovascular masses in the eye that can lead to blindness. In this mutation update, we report 21 novel variants for FZD4, LRP5, and NDP, and discuss the putative functional consequences of missense mutations. In addition, we provide a comprehensive overview of all previously published variants in the aforementioned genes and summarize the phenotypic characteristics in mouse models carrying mutations in the orthologous genes. The increasing molecular understanding of Wnt signaling, related to ocular development and blood supply, offers more tools for accurate disease diagnosis that may be important in the development of therapeutic interventions.

  16. A Variant in COX-2 Gene Is Associated with Left Main Coronary Artery Disease and Clinical Outcomes of Coronary Artery Bypass Grafting

    Directory of Open Access Journals (Sweden)

    Hanning Liu

    2017-01-01

    Full Text Available As a particular severe phenotype of coronary artery disease (CAD, left main coronary artery disease (LMCAD is heritable. Genetic variants related to prostaglandin metabolism are associated with LMCAD. Cyclooxygenase-2 (COX-2, a key synthase in prostaglandin pathways, displays high density in atherosclerotic lesions and promotes early atherosclerosis in CAD progression. We hypothesized that genetic variants in COX-2 gene contribute to LMCAD phenotype susceptibility compared to more peripheral coronary artery disease (MPCAD. In this study, we genotyped COX-2 rs5275, rs5277, and rs689466 of 1544 CAD patients undergoing coronary artery bypass grafting (CABG and found that rs5277 C allele carriage was associated with LMCAD (adjusted OR: 1.590; 95% CI: 1.103~2.291; p=0.013. Furtherly, long-term follow-up data suggested that rs5277 C allele carriage increased risk of major adverse cardiac and cerebrovascular events (MACCE in the whole cohort (adjusted HR: 1.561; 95% CI: 1.025~2.377; p=0.038 and LMCAD subgroup (adjusted HR: 2.014; 95% CI: 1.036~3.913; p=0.039 but not in MPCAD subgroup (adjusted HR: 1.375; 95% CI: 0.791~2.392; p=0.259. In conclusion, we demonstrate that COX-2 rs5277 C allele increases the risk of left main coronary artery lesion and is also correlated with poor prognosis of LMCAD patients with CABG therapy.

  17. Acantholytic dermatosis of the crural folds with ATP2C1 mutation is a possible variant of Hailey-Hailey Disease.

    Science.gov (United States)

    Lipoff, Jules B; Mudgil, Adarsh V; Young, Saryna; Chu, Paul; Cohen, Steven R

    2009-01-01

    We describe a patient with acantholytic dermatosis of the crural folds (ADCF) that was misdiagnosed and treated as condyloma acuminata for 13 years. After many skin biopsies consistently showed epidermal acantholysis and negative human papillomavirus serotyping excluded condyloma acuminata, a diagnosis of ADCF was considered most likely. Acitretin effectively suppressed the symptomatic hyperkeratosis. Subsequent genetic testing revealed a deletion in the ATP2C1 gene that led us to conclude that this case of ADCF is probably a variant of familial benign chronic pemphigus (Hailey-Hailey disease).

  18. Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer’s disease cohorts

    OpenAIRE

    Tan, Lin; Wang, Hui-Fu; Tan, Meng-Shan; Tan, Chen-Chen; Zhu, Xi-Chen; Miao, Dan; Yu, Wan-Jiang; Jiang, Teng; Tan, Lan; Yu, Jin-Tai; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William

    2016-01-01

    The Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer’s disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in β-amyloid (Aβ) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify ...

  19. The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires' disease in humans.

    Directory of Open Access Journals (Sweden)

    Juan S Ruiz-Moreno

    2018-01-01

    Full Text Available The cyclic GMP-AMP synthase (cGAS-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ TMEM173/STING were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs. In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model of Legionnaires' disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires' disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila in mice and men, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection.ClinicalTrials.gov DRKS00005274, German Clinical Trials Register.

  20. The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires' disease in humans.

    Science.gov (United States)

    Ruiz-Moreno, Juan S; Hamann, Lutz; Shah, Javeed A; Verbon, Annelies; Mockenhaupt, Frank P; Puzianowska-Kuznicka, Monika; Naujoks, Jan; Sander, Leif E; Witzenrath, Martin; Cambier, John C; Suttorp, Norbert; Schumann, Ralf R; Jin, Lei; Hawn, Thomas R; Opitz, Bastian

    2018-01-01

    The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ TMEM173/STING were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model of Legionnaires' disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires' disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila in mice and men, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection. ClinicalTrials.gov DRKS00005274, German Clinical Trials Register.

  1. The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans

    Science.gov (United States)

    Hamann, Lutz; Verbon, Annelies; Mockenhaupt, Frank P.; Puzianowska-Kuznicka, Monika; Naujoks, Jan; Sander, Leif E.; Witzenrath, Martin; Schumann, Ralf R.; Hawn, Thomas R.

    2018-01-01

    The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ TMEM173/STING were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model of Legionnaires’ disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires’ disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila in mice and men, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection. Trial registration ClinicalTrials.gov DRKS00005274, German Clinical Trials Register PMID:29298342

  2. Pleiotropic Associations of RARRES2 Gene Variants and Circulating Chemerin Levels: Potential Roles of Chemerin Involved in the Metabolic and Inflammation-Related Diseases

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    Leay-Kiaw Er

    2018-01-01

    Full Text Available Chemerin, an adipokine and inflammatory mediator, is associated with metabolic, inflammation- and immune-mediated diseases. The genetic, clinical, and biomarker correlates of circulating chemerin levels have not been completely elucidated. We analyzed the determinants and correlates of retinoic acid receptor responder 2 (RARRES2; encoding chemerin gene variants and chemerin levels in the Taiwanese population. In total, 612 individuals were recruited. Clinical and metabolic phenotypes, 13 inflammatory markers, 5 adipokines, and 6 single-nucleotide polymorphisms (SNPs covering the RARRES2 region were analyzed. High chemerin levels and chemerin level tertiles were positively associated with multiple metabolic phenotypes and circulating inflammatory marker and adipokine levels and negatively associated with high-density lipoprotein cholesterol and adiponectin levels and estimated glomerular filtration rates (eGFRs. Genotype and haplotype analyses showed that RARRES2 SNPs were significantly associated with chemerin, fibrinogen, interleukin 6, and lipocalin 2 levels. Stepwise logistic regression analysis showed that C-reactive protein level, leptin level, triglyceride level, eGFR, rs3735167 genotypes, sex, and soluble P-selectin level were independently associated with chemerin levels. In conclusion, pleiotropic associations were noted between RARRES2 variants, circulating chemerin levels and multiple metabolic phenotypes and inflammatory marker levels. This study provides further evidence for the potential roles of chemerin in metabolic and inflammation-related diseases.

  3. Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus

    DEFF Research Database (Denmark)

    von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael

    2013-01-01

    The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from...... Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing....... Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance...

  4. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.

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    Yi Lu

    2010-05-01

    Full Text Available Central corneal thickness (CCT, one of the most highly heritable human traits (h(2 typically>0.9, is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058. Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1 had an overall meta-analysis p-value for all the individually genotyped samples of 4.6x10(-10. The locus on chromosome 16 was associated with CCT with p = 8.95x10(-11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS, a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.

  5. Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood.

    Science.gov (United States)

    Proitsi, Petroula; Lee, Sang Hyuck; Lunnon, Katie; Keohane, Aoife; Powell, John; Troakes, Claire; Al-Sarraj, Safa; Furney, Simon; Soininen, Hilkka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Hodges, Angela

    2014-02-01

    An increased risk of developing Alzheimer's disease (AD) has previously been found to be associated with variants at the MS4A6A locus. We sought to identify which genes and transcripts in this region have altered expression in AD and mild cognitive impairment (MCI) and are influenced by the AD risk variant(s), as a first step to understanding the molecular basis of AD susceptibility at this locus. Common variants located within highly expressed MS4A6A transcripts were significantly associated with AD and MS4A6A expression levels in blood from MCI and AD subjects (p < 0.05, rs610932, rs7232, rs583791). More copies of the protective (minor) allele were associated with lower MS4A6A expression of each transcript (e.g., p = 0.019; rs610932-total MS4A6A). Furthermore, in heterozygous AD subjects, relative expression of the protective allele of V4-MS4A6A transcripts was lower (p < 0.008). Irrespective of genotype, MS4A6A transcripts were increased in blood from people with AD (p < 0.003), whereas lower expression of full length V1-MS4A6A (p = 0.002) and higher expression of V4-MS4A6A (p = 1.8 × 10(-4)) were observed in MCI, relative to elderly controls. The association between genotype and expression was less consistent in brain, although BA9 did have a similar genotype association with V4-MS4A6A transcripts as in blood. MS4A6A transcripts were widely expressed in tissues and cells, with the exception of V4-MS4A6A, which was not expressed in neuronal cells. Together these results suggest that high levels of MS4A6A in emerging AD pathology are detrimental. Persons with MCI may lower MS4A6A expression to minimize detrimental disease associated MS4A6A activity. However, those with the susceptibility allele appear unable to decrease expression sufficiently, which may explain their increased risk for developing AD. Inhibiting MS4A6A may therefore promote a more neuroprotective phenotype, although further work is needed to establish whether this is the case. Copyright © 2014

  6. Holoprosencephaly Variant

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    J Gordon Millichap

    2003-01-01

    Full Text Available The clinical manifestations in 15 patients (6 boys and 9 girls with middle interhemispheric variant (MIH of holoprosencephaly (HPE were compared with classic subtypes (alobar, semilobar, and lobar of HPE in a multicenter study at Stanford University School of Medicine and Lucile Packard Children’s Hospital; Children’s Hospital of Philadelphia; University of California at San Francisco; Texas Scottish Rite Hospital, Dallas; and Kennedy Krieger Institute, Baltimore, MD.

  7. Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening.

    Science.gov (United States)

    Almannai, Mohammed; Marom, Ronit; Divin, Kristian; Scaglia, Fernando; Sutton, V Reid; Craigen, William J; Lee, Brendan; Burrage, Lindsay C; Graham, Brett H

    2017-09-01

    Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant. A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted. 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening. The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Genetic variant in the 3'-untranslated region of VEGFR1 gene influences chronic obstructive pulmonary disease and lung cancer development in Chinese population.

    Science.gov (United States)

    Wang, Hui; Yang, Lei; Deng, Jieqiong; Wang, Bo; Yang, Xiaorong; Yang, Rongrong; Cheng, Mei; Fang, Wenxiang; Qiu, Fuman; Zhang, Xin; Ji, Weidong; Ran, Pixin; Zhou, Yifeng; Lu, Jiachun

    2014-09-01

    Lung inflammation and epithelial to mesenchymal transition (EMT) are two pathogenic features for the two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. VEGFR1 (or FLT1) plays a certain role in promoting tumour growth, inflammation and EMT. To simultaneously test the association between the single nucleotide polymorphisms (SNPs) in VEGFR1 and risk of COPD and lung cancer would reveal genetic mechanisms shared by these two diseases and joint aetiology. We conducted a two-population hospital-based case-control study. Three potential functional SNPs (rs664393, rs7326277 and rs9554314) were genotyped in southern Chinese and validated in eastern Chinese to explore their associations with COPD risk in 1511 COPD patients and 1677 normal lung function controls, and with lung cancer risk in 1559 lung cancer cases and 1679 cancer-free controls. We also detected the function of the promising SNP. Individuals carrying the rs7326277C (CT+CC) variant genotypes of VEGFR1 had a significant decrease in risk of both COPD (OR = 0.78; 95% CI = 0.68-0.90) and lung cancer (OR = 0.79; 95% CI = 0.64-0.98), compared with those carrying the rs7326277TT genotype. Functional assays further showed that the rs7326277C genotypes had lower transcriptional activity and caused decreased VEGFR expression, compared with the rs7326277TT genotype. However, no significant association was observed for the other two SNPs (rs664393 and rs9554314) and either COPD or lung cancer risk. Our data suggested that the rs7326277C variant of VEGFR1 could reduce both COPD and lung cancer risk by lowering VEGFR1 mRNA expression; the SNP might be a common susceptible locus for both COPD and lung cancer. © The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases

    Science.gov (United States)

    Coppola, Giovanni; Chinnathambi, Subashchandrabose; Lee, Jason JiYong; Dombroski, Beth A.; Baker, Matt C.; Soto-Ortolaza, Alexandra I.; Lee, Suzee E.; Klein, Eric; Huang, Alden Y.; Sears, Renee; Lane, Jessica R.; Karydas, Anna M.; Kenet, Robert O.; Biernat, Jacek; Wang, Li-San; Cotman, Carl W.; DeCarli, Charles S.; Levey, Allan I.; Ringman, John M.; Mendez, Mario F.; Chui, Helena C.; Le Ber, Isabelle; Brice, Alexis; Lupton, Michelle K.; Preza, Elisavet; Lovestone, Simon; Powell, John; Graff-Radford, Neill; Petersen, Ronald C.; Boeve, Bradley F.; Lippa, Carol F.; Bigio, Eileen H.; Mackenzie, Ian; Finger, Elizabeth; Kertesz, Andrew; Caselli, Richard J.; Gearing, Marla; Juncos, Jorge L.; Ghetti, Bernardino; Spina, Salvatore; Bordelon, Yvette M.; Tourtellotte, Wallace W.; Frosch, Matthew P.; Vonsattel, Jean Paul G.; Zarow, Chris; Beach, Thomas G.; Albin, Roger L.; Lieberman, Andrew P.; Lee, Virginia M.; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Bird, Thomas D.; Galasko, Douglas R.; Masliah, Eliezer; White, Charles L.; Troncoso, Juan C.; Hannequin, Didier; Boxer, Adam L.; Geschwind, Michael D.; Kumar, Satish; Mandelkow, Eva-Maria; Wszolek, Zbigniew K.; Uitti, Ryan J.; Dickson, Dennis W.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Ross, Owen A.; Rademakers, Rosa; Schellenberg, Gerard D.; Miller, Bruce L.; Mandelkow, Eckhard; Geschwind, Daniel H.

    2012-01-01

    Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated. PMID:22556362

  10. Infantile onset Vanishing White Matter disease associated with a novel EIF2B5 variant, remarkably long life span, severe epilepsy, and hypopituitarism.

    Science.gov (United States)

    Woody, April L; Hsieh, David T; McIver, Harkirtin K; Thomas, Linda P; Rohena, Luis

    2015-04-01

    Vanishing White Matter disease (VWM) is an inherited progressive leukoencephalopathy caused by mutations in the genes EIF2B1-5, which encode for the 5 subunits of the eukaryotic initiation factor 2B (eIF2B), a regulator of protein synthesis. VWM typically presents with acute neurological decline following febrile infections or minor head trauma, and subsequent progressive neurological and cognitive regression. There is a varied clinical spectrum of VWM, with earlier onset associated with more severe phenotypes. Brain magnetic resonance imaging is usually diagnostic with diffusely abnormal white matter, progressing over time to cystic degeneration. We are reporting on a patient with infantile onset VWM associated with three heterozygous missense variants in EIF2B5, including a novel missense variant on exon 6 of EIF2B5 (D262N), as well as an interstitial duplication at 7q21.12. In addition, our case is unusual because of a severe epilepsy course, a novel clinical finding of hypopituitarism manifested by hypothyroidism and adrenal insufficiency, and a prolonged life span with current age of survival of 4 years and 11 months. © 2015 Wiley Periodicals, Inc.

  11. Variants of cognitive deficiency depending on the clinical characteristics of the disease in patients with paranoid schizophrenia

    Directory of Open Access Journals (Sweden)

    G. G. Lebedeva

    2015-01-01

    Full Text Available Pecific aspects of cognitive impairments in patients with paranoid schizophrenia depending on the clinical characteristics of the disease have been studied. One hundred and thirty patients were examined. A clinico-psychological, experimental psychological and statistical methods were used. Three main types of cognitive deficiency with paranoid schizophrenia, associated with the onset, disease duration, and severity of psychiatric symptomology : 1 long-term course of the disease accompanied by the average level of clinical symptomology associated with abnormal attention and visuospatial functions; 2 late onset of the disease and unexpressed clinical symptomology combined with memory impairments; 3 acute onset and early age combined with the absence of cognitive impairments.

  12. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

    NARCIS (Netherlands)

    Rivas, Manuel A.; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Desch, A. Nicole; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; Mucha, Soeren; Kurki, Mitja I.; Li, Dalin; D'Amato, Mauro; Annese, Vito; Vermeire, Severine; Weersma, Rinse K.; Halfvarson, Jonas; Paavola-Sakki, Paulina; Lappalainen, Maarit; Lek, Monkol; Cummings, Beryl; Tukiainen, Taru; Haritunians, Talin; Halme, Leena; Koskinen, Lotta L. E.; Ananthakrishnan, Ashwin N.; Luo, Yang; Heap, Graham A.; Visschedijk, Marijn C.; MacArthur, Daniel G.; Neale, Benjamin M.; Ahmad, Tariq; Anderson, Carl A.; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Cho, Judy H.; Palotie, Aarno; Saavalainen, Paivi; Kontula, Kimmo; Farkkila, Martti; McGovern, Dermot P. B.; Franke, Andre; Stefansson, Kari; Rioux, John D.; Xavier, Ramnik J.; Daly, Mark J.

    Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants

  13. Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein

    NARCIS (Netherlands)

    Meade-White, K.; Race, B.; Trifilo, M.; Bossers, A.; Favara, C.; Lacasse, R.; Miller, M.; Williams, E.; Oldstone, M.; Race, R.; Chesebro, B.

    2007-01-01

    Prion protein (PrP) is a required factor for susceptibility to transmissible spongiform encephalopathy or prion diseases. In transgenic mice, expression of prion protein (PrP) from another species often confers susceptibility to prion disease from that donor species. For example, expression of deer

  14. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

    NARCIS (Netherlands)

    Gupta, Rajat M.; Hadaya, Joseph; Trehan, Aditi; Zekavat, Seyedeh M.; Roselli, Carolina; Klarin, Derek; Emdin, Connor A.; Hilvering, Catharina R.E.; Bianchi, Valerio; Mueller, Christian; Khera, Amit V.; Ryan, Russell J.H.; Engreitz, Jesse M.; Issner, Robbyn; Shoresh, Noam; Epstein, Charles B.; de Laat, Wouter; Brown, Jonathan D.; Schnabel, Renate B.; Bernstein, Bradley E.; Kathiresan, Sekar

    2017-01-01

    Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common

  15. Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis.

    Science.gov (United States)

    Müller, Hans-Peter; Agosta, Federica; Riva, Nilo; Spinelli, Edoardo G; Comi, Giancarlo; Ludolph, Albert C; Filippi, Massimo; Kassubek, Jan

    2018-01-01

    The criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant. The study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy). DTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a 'classical' phenotype to identify white matter structural alterations. The analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls. This study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

  16. The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants

    Directory of Open Access Journals (Sweden)

    Antoinesha L. Hollman

    2016-03-01

    Full Text Available Exposure to environmental hazards has been associated with diseases in humans. The identification of single nucleotide polymorphisms (SNPs in human populations exposed to different environmental hazards, is vital for detecting the genetic risks of some important human diseases. Several studies in this field have been conducted on glutathione S-transferases (GSTs, a phase II detoxification superfamily, to investigate its role in the occurrence of diseases. Human GSTs consist of cytosolic and microsomal superfamilies that are further divided into subfamilies. Based on scientific search engines and a review of the literature, we have found a large amount of published articles on human GST super- and subfamilies that have greatly assisted in our efforts to examine their role in health and disease. Because of its polymorphic variations in relation to environmental hazards such as air pollutants, cigarette smoke, pesticides, heavy metals, carcinogens, pharmaceutical drugs, and xenobiotics, GST is considered as a significant biomarker. This review examines the studies on gene-environment interactions related to various diseases with respect to single nucleotide polymorphisms (SNPs found in the GST superfamily. Overall, it can be concluded that interactions between GST genes and environmental factors play an important role in human diseases.

  17. ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A>G and c.5461-10T>C cause Stargardt disease due to defective splicing.

    Science.gov (United States)

    Jonsson, Frida; Westin, Ida Maria; Österman, Lennart; Sandgren, Ola; Burstedt, Marie; Holmberg, Monica; Golovleva, Irina

    2018-02-20

    Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP-binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing. The splicing of the ABCA4 gene was studied in human embryonic kidney cells, HEK293T, and in human retinal pigment epithelium cells, ARPE-19, using a minigene system containing variants c.4773+3A>G and c.5461-10T>C. We showed that both ABCA4 variants, c.4773+3A>G and c.5461-10T>C, cause aberrant splicing of the ABCA4 minigene resulting in exon skipping. We also demonstrated that splicing of ABCA4 has different outcomes depending on transfected cell type. Two intronic variants c.4773+3A>G and c.5461-10T>C, both predicted to affect splicing, are indeed disease-causing mutations due to skipping of exons 33, 34, 39 and 40 of ABCA4 gene. The experimental proof that ABCA4 mutations in STGD patients affect protein function is crucial for their inclusion to future clinical trials; therefore, functional testing of all ABCA4 intronic variants associated with Stargardt disease by minigene technology is desirable. © 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  18. IgG4-related Hashimoto’s thyroiditis – A new variant of a well known disease

    OpenAIRE

    Luiz, Henrique Vara; Gonçalves, Diogo; Silva, Tiago Nunes da; Nascimento, Isabel; Ribeiro, Ana; Mafra, Manuela; Manita, Isabel; Portugal, Jorge

    2014-01-01

    Hashimoto’s thyroiditis (HT) has been characterized for many years as a well-defined clinicopathologic entity, but is now considered a heterogeneous disease. IgG4-related HT is a new subtype characterized by thyroid inflammation rich in IgG4-positive plasma cells and marked fibrosis. It may be part of the systemic IgG4-related disease. We report a case of a 56-year-old Portuguese man who presented with a one-month history of progressive neck swelling and dysphagia. Laboratory testing revealed...

  19. Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models

    NARCIS (Netherlands)

    Karpinar, D.P.; Giller, K.; Becker, S.; Baldus, M.

    2009-01-01

    The relation of -synuclein (S) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated S species have in neurotoxicity in

  20. Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation

    DEFF Research Database (Denmark)

    Danesh, J.; Hingorani, A.; Wensley, F.

    2008-01-01

    Many prospective studies have reported associations between circulating C-reactive protein (CRP) levels and risk of coronary heart disease (CHD), but causality remains uncertain. Studies of CHD are being conducted that involve measurement of common polymorphisms of the CRP gene known to be associ...

  1. A point of view: quantitative and qualitative imbalance in disease pathogenesis; pulmonary surfactant protein A genetic variants as a model.

    Science.gov (United States)

    Floros, J; Wang, G

    2001-05-01

    The high degree of similarity at the molecular level, between humans and other species, has provided the rationale for the use of a variety of species as model systems in research, resulting in enormous advances in biological sciences and medicine. In contrast, the individual variability observed among humans, for example, in external physique, organ functionality and others, is accounted for, by only a fraction of 1% of differences at the DNA level. These small differences, which are essential for understanding disease pathogenesis, have posed enormous challenges in medicine, as we try to understand why patients may respond differently to drugs or why one patient has complications and another does not. Differences in outcome are most likely the result of interactions among genetic components themselves and/or the environment at the molecular, cellular, organ, or organismal level, or the macroenvironment. In this paper: (1) we consider some issues for multifactorial disease pathogenesis; (2) we provide a review of human SP-A and how the knowledge gained and the characteristics of the hSP-A system may serve as a model in the study of disease with multifactorial etiology; and (3) we describe examples where hSP-A has been used in the study of disease.

  2. in silico identification of genetic variants in glucocerebrosidase (GBA gene involved in Gaucher’s disease using multiple software tools.

    Directory of Open Access Journals (Sweden)

    Madhumathi eManickam

    2014-05-01

    Full Text Available Gaucher’s disease is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalysis the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Polymorphisms in GBA gene have been associated with the development of Gaucher disease. We hypothesize that prediction of SNPs using multiple state of the art software tools will help in increasing the confidence in identification of SNPs involved in Gaucher's disease. Enzyme replacement therapy is the only option for GD. Our goal is to use several state of art SNP algorithms to predict/address harmful SNPs using comparative studies. In this study seven different algorithms (SIFT, MutPred, nsSNP Analyzer, PANTHER, PMUT, PROVEAN and SNPs&GO were used to predict the harmful polymorphisms. Among the 7 programs, SIFT found 47 nsSNPs as deleterious, MutPred found 46 nsSNPs as harmful. nsSNP Analyzer program found 43 out of 47 nsSNPs are disease causing SNPs whereas PANTHER found 32 out of 47 as highly deleterious, 22 out of 47 are classified as pathological mutations by PMUT, 44 out of 47 were predicted to be deleterious by PROVEAN server, all 47 shows the disease related mutations by SNPs&GO. Twenty two nsSNPs were commonly predicted by all the seven different algorithms. The common 22 targeted mutations are F251L, C342G, W312C, P415R, R463C, D127V, A309V, G46E, G202E, P391L, Y363C, Y205C, W378C, I402T, S366R, F397S, Y418C, P401L, G195E, W184R, R48W and T43R.

  3. PARP-1 Variant Rs1136410 Confers Protection against Coronary Artery Disease in a Chinese Han Population: A Two-Stage Case-Control Study Involving 5643 Subjects

    Directory of Open Access Journals (Sweden)

    Xue-bin Wang

    2017-11-01

    Full Text Available Inhibition of poly(ADP-ribose polymerase (PARP may protect against coronary artery disease (CAD in animal models, and rs1136410, a non-synonymous single nucleotide polymorphism (SNP in PARP-1, has a potential impact on PARP activities in vitro. This two-stage case-control study, involving 2803 CAD patients and 2840 controls, aimed to investigate the associations of PARP-1 rs1136410 with CAD development, lipid levels, PARP activities, 8-hydroxy-2′-dexyguanosine (8-OHdG, and interleukin (IL-6 levels in a Chinese Han population. Assuming a recessive model, the variant genotype GG of SNP rs1136410 showed a significantly inverse association with CAD risk (adjusted odds ratio (OR = 0.73, P < 0.001, left main coronary artery (LMCA lesions (P = 0.003, vessel scores (P = 0.003, and modified Gensini scores (P < 0.001. There were significant correlations of SNP rs1136410 with higher levels of total cholesterol (TC and lower levels of high-density lipoprotein cholesterol (HDL-c. In gene-environment interaction analyses, participants with the variant genotype GG, but without smoking habit, type 2 diabetes mellitus, and hyperlipidemia, conferred an 84% (P < 0.001 decreased risk of CAD. The genotype-phenotype correlation analyses further supported the functional roles of SNP rs1136410 in decreasing PARP activities and 8-OHdG levels. Taken together, our data suggest that SNP rs1136410 may confer protection against CAD through modulation of PARP activities and gene-environment interactions in a Chinese Han population.

  4. Integrated Enrichment Analysis of Variants and Pathways in Genome-Wide Association Studies Indicates Central Role for IL-2 Signaling Genes in Type 1 Diabetes, and Cytokine Signaling Genes in Crohn's Disease

    Science.gov (United States)

    Carbonetto, Peter; Stephens, Matthew

    2013-01-01

    Pathway analyses of genome-wide association studies aggregate information over sets of related genes, such as genes in common pathways, to identify gene sets that are enriched for variants associated with disease. We develop a model-based approach to pathway analysis, and apply this approach to data from the Wellcome Trust Case Control Consortium (WTCCC) studies. Our method offers several benefits over existing approaches. First, our method not only interrogates pathways for enrichment of disease associations, but also estimates the level of enrichment, which yields a coherent way to promote variants in enriched pathways, enhancing discovery of genes underlying disease. Second, our approach allows for multiple enriched pathways, a feature that leads to novel findings in two diseases where the major histocompatibility complex (MHC) is a major determinant of disease susceptibility. Third, by modeling disease as the combined effect of multiple markers, our method automatically accounts for linkage disequilibrium among variants. Interrogation of pathways from eight pathway databases yields strong support for enriched pathways, indicating links between Crohn's disease (CD) and cytokine-driven networks that modulate immune responses; between rheumatoid arthritis (RA) and “Measles” pathway genes involved in immune responses triggered by measles infection; and between type 1 diabetes (T1D) and IL2-mediated signaling genes. Prioritizing variants in these enriched pathways yields many additional putative disease associations compared to analyses without enrichment. For CD and RA, 7 of 8 additional non-MHC associations are corroborated by other studies, providing validation for our approach. For T1D, prioritization of IL-2 signaling genes yields strong evidence for 7 additional non-MHC candidate disease loci, as well as suggestive evidence for several more. Of the 7 strongest associations, 4 are validated by other studies, and 3 (near IL-2 signaling genes RAF1, MAPK14

  5. Detection and Localization of PrPSc in the Skeletal Muscle of Patients with Variant, Iatrogenic, and Sporadic Forms of Creutzfeldt-Jakob Disease

    Science.gov (United States)

    Peden, Alexander H.; Ritchie, Diane L.; Head, Mark W.; Ironside, James W.

    2006-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) differs from other human prion diseases in that the pathogenic prion protein PrPSc can be detected to a greater extent at extraneuronal sites throughout the body, principally within lymphoid tissues. However, a recent study using a high-sensitivity Western blotting technique revealed low levels of PrPSc in skeletal muscle from a quarter of Swiss patients with sporadic CJD (sCJD). This posed the question of whether PrPSc in muscle could also be detected in vCJD, sCJD, and iatrogenic (iCJD) patients from other populations. Therefore, we have used the same high-sensitivity Western blotting technique, in combination with paraffin-embedded tissue blotting, to screen for PrPSc in muscle tissue specimens taken at autopsy from 49 CJD patients in the United Kingdom. These techniques identified muscle PrPSc in 8 of 17 vCJD, 7 of 26 sCJD, and 2 of 5 iCJD patients. Paraffin-embedded tissue blotting analysis showed PrPSc in skeletal muscle in localized anatomical structures that had the morphological and immunohistochemical characteristics of nerve fibers. The detection of PrPSc in muscle tissue from all forms of CJD indicates the possible presence of infectivity in these tissues, suggesting important implications for assessing the potential risk of iatrogenic spread via contaminated surgical instruments. PMID:16507908

  6. Integrated Genomics of Crohn’s Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy

    Directory of Open Access Journals (Sweden)

    Jakob Begun

    2015-06-01

    Full Text Available The polymorphism ATG16L1 T300A, associated with increased risk of Crohn’s disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1∗300A risk allele. Clec12a−/− mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease.

  7. The role of common variants of the cholesteryl ester transfer protein gene in left main coronary artery disease

    Directory of Open Access Journals (Sweden)

    Giannakopoulou Vasiliki

    2011-09-01

    Full Text Available Abstract Background The cholesteryl ester transfer protein (CETP has a central role in the lipid metabolism and therefore may alter the susceptibility to atherosclerosis. Methods The DNA of 471 subjects [133 subjects with angiographically documented left main coronary artery disease (LMCAD, 241 subjects with more peripheral coronary artery disease (MPCAD and 97 subjects self reported healthy (Controls] was analyzed for the frequency of TaqIB and I405V polymorphisms in the gene coding CETP. Results There is no significant difference in CETP allele frequency or genotype distribution among LMCAD and MPCAD patients although there is statistical difference between LMCAD and Controls (p = 0.001. Specifically, patients with LMCAD and B1B1 genotype of TaqIB polymorphism were more frequent present compared to Controls (33.8% vs 22.9%, respectively. The frequency of B2B2 genotype was 3 times lower in the LMCAD group compared to Controls (10.5% vs 30.2%, respectively. In the LMCAD group the frequency of B1 allele compared to Controls was higher (62% vs 46%, respectively, p = 0.001. The relationship between TaqIB gene polymorphism and the LMCAD was independent of lipid profile, with the exception of apolipoprotein A. Conclusions These findings indicate that the TaqIB polymorphism may have potential importance in screening individuals at high risk for developing CAD. However, this polymorphism cannot distinguish between LMCAD and MPCAD. Further prospective investigations in larger populations are required to confirm these findings.

  8. Implications of ACE (I/D) Gene Variants to the Genetic Susceptibility of Coronary Artery Disease in Asian Indians.

    Science.gov (United States)

    Bhatti, G K; Bhatti, J S; Vijayvergiya, R; Singh, B

    2017-06-01

    Angiotensin-1-converting enzyme (ACE) gene has established substantial attention in the recent years as a candidate gene for hypertension, cardiovascular diseases and type 2 diabetes. The aim of the present study was to investigate the association of ACE (I/D) polymorphism with coronary artery disease (CAD) in a north Indian population. A total of 662 subjects (330 CAD patients and 332 healthy controls) were examined for association of ACE gene (I/D) polymorphism and environmental risk factors. The mean age of the CAD patients and control subjects was 60.53 ± 8.6 years and 56.55 ± 7.7 years, respectively ( p  = 0.000). Anthropometric and demographic data showed BMI values significantly higher among CAD patients and control subjects (26.98 ± 4.9 vs 24.04 ± 4.7, p  = 0.000). We observed pronounced central obesity in both CAD patients and controls, even at the lowest BMI values (ACE gene. In conclusion, DD genotype of ACE gene may be associated with increased risk of CAD in Asian Indian population.

  9. MMP3 and TIMP1 variants contribute to chronic periodontitis and may be implicated in disease progression.

    Science.gov (United States)

    Letra, Ariadne; Silva, Renato M; Rylands, Ryan J; Silveira, Elcia M; de Souza, Ana P; Wendell, Steven K; Garlet, Gustavo P; Vieira, Alexandre R

    2012-08-01

    Matrix metalloproteinases (MMPs) play a key role in the tissue destruction characteristic of chronic periodontitis. The purpose of this study was to investigate the association of MMP and TIMP polymorphisms with chronic periodontitis in two populations. A total of 34 polymorphisms spanning 12 MMP and 2 TIMP genes were genotyped in 401 individuals from Brazil (99 cases with chronic periodontitis and 302 controls), and 274 individuals from the US (70 cases and 204 controls). Individuals were considered cases if presenting at least three teeth exhibiting sites of clinical attachment loss ≥ 5 mm in two different quadrants. Controls were characterized by absence of clinical attachment loss and no sites with probing depth >3 mm. MMP3 and TIMP1 mRNA expression was evaluated in healthy and diseased periodontal tissues. TIMP1 showed association with chronic periodontitis in the Brazilian population (for rs5906435, p = 0.0004), whereas MMP3 showed association in the US population (for rs679620, p = 0.0003; and rs650108, p = 0.002) and in the Brazilian population (for rs639752, p = 0.005). MMP3 and TIMP1 mRNA expression was significantly higher in diseased tissues when compared to control tissues. Our results further support a role for variations in MMP3 in chronic periodontitis and report a novel association with TIMP1. These genes may be considered additional candidate genes for chronic periodontitis. © 2012 John Wiley & Sons A/S.

  10. The surface glycoprotein of a natural feline leukemia virus subgroup A variant, FeLV-945, as a determinant of disease outcome.

    Science.gov (United States)

    Bolin, Lisa L; Ahmad, Shamim; Levy, Laura S

    2011-10-15

    Feline leukemia virus (FeLV) is a natural retrovirus of domestic cats associated with degenerative, proliferative and malignant diseases. Studies of FeLV infection in a cohort of naturally infected cats were undertaken to examine FeLV variation, the selective pressures operative in FeLV infection that lead to predominance of natural variants, and the consequences for infection and disease progression. A unique variant, designated FeLV-945, was identified as the predominant isolate in the cohort and was associated with non-T-cell diseases including multicentric lymphoma. FeLV-945 was assigned to the FeLV-A subgroup based on sequence analysis and receptor utilization, but was shown to differ in sequence from a prototype member of FeLV-A, designated FeLV-A/61E, in the long terminal repeat (LTR) and the surface glycoprotein gene (SU). A unique sequence motif in the FeLV-945 LTR was shown to function as a transcriptional enhancer and to confer a replicative advantage. The FeLV-945 SU protein was observed to differ in sequence as compared to FeLV-A/61E within functional domains known to determine receptor selection and binding. Experimental infection of newborn cats was performed using wild type FeLV-A/61E or recombinant FeLV-A/61E in which the LTR (61E/945L) or LTR and SU (61E/945SL) were exchanged for that of FeLV-945. Infection with either FeLV-A/61E or 61E/945L resulted in T-cell lymphoma of the thymus, although 61E/945L caused disease significantly more rapidly. In contrast, infection with 61E/945SL resulted in the rapid induction of a multicentric lymphoma of B-cell origin, thus recapitulating the outcome of natural infection and implicating FeLV-945 SU as a determinant of disease outcome. Recombinant FeLV-B was detected infrequently and at low levels in multicentric lymphomas, and was thereby not implicated in disease induction. Preliminary studies of receptor interaction indicated that virus particles bearing FeLV-945 SU bind to the FeLV-A receptor more

  11. Social influence on associative learning: double dissociation in high-functioning autism, early-stage behavioural variant frontotemporal dementia and Alzheimer's disease.

    Science.gov (United States)

    Kéri, Szabolcs

    2014-05-01

    Most of our learning activity takes place in a social context. I examined how social interactions influence associative learning in neurodegenerative diseases and atypical neurodevelopmental conditions primarily characterised by social cognitive and memory dysfunctions. Participants were individuals with high-functioning autism (HFA, n = 18), early-stage behavioural variant frontotemporal dementia (bvFTD, n = 16) and Alzheimer's disease (AD, n = 20). The leading symptoms in HFA and bvFTD were social and behavioural dysfunctions, whereas AD was characterised by memory deficits. Participants received three versions of a paired associates learning task. In the game with boxes test, objects were hidden in six candy boxes placed in different locations on the computer screen. In the game with faces, each box was labelled by a photo of a person. In the real-life version of the game, participants played with real persons. Individuals with HFA and bvFTD performed well in the computer games, but failed on the task including real persons. In contrast, in patients with early-stage AD, social interactions boosted paired associates learning up to the level of healthy control volunteers. Worse performance in the real life game was associated with less successful recognition of complex emotions and mental states in the Reading the Mind in the Eyes Test. Spatial span did not affect the results. When social cognition is impaired, but memory systems are less compromised (HFA and bvFTD), real-life interactions disrupt associative learning; when disease process impairs memory systems but social cognition is relatively intact (early-stage AD), social interactions have a beneficial effect on learning and memory. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Whole exome sequencing of a consanguineous family identifies the possible modifying effect of a globally rare AK5 allelic variant in celiac disease development among Saudi patients.

    Directory of Open Access Journals (Sweden)

    Jumana Yousuf Al-Aama

    Full Text Available Celiac disease (CD, a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family. Sequence validation of 200 chromosomes each of sporadic CD cases and controls, revealed that this extremely rare (EXac MAF 0.000008 mutation is highly penetrant among general Saudi populations (MAF is 0.62. Genotype and allelic distribution analysis have indicated that this AK5 (c.1683_1684insATT mutation is negatively selected among patient groups and positively selected in the control group, in whom it may modify the risk against CD development [p<0.002]. Our observation gains additional support from computational analysis which predicted that Iso561 insertion shifts the existing H-bonds between 400th and 556th amino acid residues lying near the functional domain of adenylate kinase. This shuffling of amino acids and their H-bond interactions is likely to disturb the secondary structure orientation of the polypeptide and induces the gain-of-function in nucleoside phosphate kinase activity of AK5, which may eventually down-regulates the reactivity potential of CD4+ T-cells against gluten antigens. Our study underlines the need to have population-specific genome databases to avoid false leads and to identify true candidate causal genes for the familial form of celiac disease.

  13. Definite behavioral variant of frontotemporal dementia with C9ORF72 expansions despite positive Alzheimer's disease cerebrospinal fluid biomarkers.

    Science.gov (United States)

    Wallon, David; Rovelet-Lecrux, Anne; Deramecourt, Vincent; Pariente, Jeremie; Auriacombe, Sophie; Le Ber, Isabelle; Schraen, Suzanna; Pasquier, Florence; Campion, Dominique; Hannequin, Didier

    2012-01-01

    Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer's disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the dementia diagnostic algorithm.

  14. Outbreak of variant hand-foot-and-mouth disease caused by coxsackievirus A6 in Auckland, New Zealand.

    Science.gov (United States)

    Hayman, Rebecca; Shepherd, Michael; Tarring, Claire; Best, Emma

    2014-10-01

    Hand-foot-and-mouth disease is a common, usually mild childhood illness caused by enteroviruses. Over the last five years, coxsackievirus A6 has been identified as a causative agent in outbreaks in Europe, South-East Asia and America. It has an atypical presentation compared with other enteroviruses, with more widespread rash, larger blisters and subsequent skin peeling and/or nail shedding. We give the first description of an outbreak of coxsackievirus A6 in New Zealand and how health-care communication networks enabled detection of and dissemination of information about this emergent strain. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  15. Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer's Disease with Emphasis on Atypical Disease Variants.

    Science.gov (United States)

    Abu Rumeileh, Samir; Lattanzio, Francesca; Stanzani Maserati, Michelangelo; Rizzi, Romana; Capellari, Sabina; Parchi, Piero

    2017-01-01

    According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer's disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the "atypical" disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.

  16. Computational analysis of candidate disease genes and variants for Salt-sensitive hypertension in indigenous Southern Africans

    KAUST Repository

    Tiffin, Nicki

    2010-09-27

    Multiple factors underlie susceptibility to essential hypertension, including a significant genetic and ethnic component, and environmental effects. Blood pressure response of hypertensive individuals to salt is heterogeneous, but salt sensitivity appears more prevalent in people of indigenous African origin. The underlying genetics of salt-sensitive hypertension, however, are poorly understood. In this study, computational methods including text- and data-mining have been used to select and prioritize candidate aetiological genes for salt-sensitive hypertension. Additionally, we have compared allele frequencies and copy number variation for single nucleotide polymorphisms in candidate genes between indigenous Southern African and Caucasian populations, with the aim of identifying candidate genes with significant variability between the population groups: identifying genetic variability between population groups can exploit ethnic differences in disease prevalence to aid with prioritisation of good candidate genes. Our top-ranking candidate genes include parathyroid hormone precursor (PTH) and type-1angiotensin II receptor (AGTR1). We propose that the candidate genes identified in this study warrant further investigation as potential aetiological genes for salt-sensitive hypertension. © 2010 Tiffin et al.

  17. Anatomical variants of tympanic compartments and their aeration pathways involved in the pathogenesis of middle ear inflammatory disease

    Science.gov (United States)

    MANIU, ALMA; CATANA, IULIU V.; HARABAGIU, OANA; PETRI, MARIA; COSGAREA, MARCEL

    2013-01-01

    Aim The aim of this article is to review the anatomy of middle ear compartments and folds and to demonstrate through anatomical evidence their presence at birth. Additionally, their role in the obstructions of middle ear ventilatory pathway is highlighted. Methods Ninety-eight adult temporal bones, with no history of auricular disease and fifteen newborn temporal bones were studied by micro dissection. Documentation was done by color photography using the operation microscope Results Our micro-dissections have showed that mucosal folds from the middle ear are steadily present since birth, given that they were found in all newborn temporal bones. The mucosal folds in our normal adult material, showed some variations including membrane defects but they were constantly present. Our micro dissections showed that the epitympanic diaphragm consisted, in addition to malleal ligamental folds and ossicles, of only two constantly present folds: the tensor tympani fold and the incudomalleal fold. When the tensor fold is complete the only ventilation pathway to the anterior epitympanic space is through the isthmus, whereas its absence creates an efficient additional aeration route from the Eustachian tube to the epitympanum. Conclusions The goal of surgery in the chronic pathology of the middle ear should be restoration of normal ventilation of the attical-mastoid area. This is possible by removing the tensor fold and restoring the functionality of the isthmus tympani. PMID:26527977

  18. Longitudinal assessment of short-term memory deterioration in a logopenic variant primary progressive aphasia with post-mortem confirmed Alzheimer's Disease pathology.

    Science.gov (United States)

    Tree, Jeremy; Kay, Janice

    2015-09-01

    In the field of dementia research, there are reports of neurodegenerative cases with a focal loss of language, termed primary progressive aphasia (PPA). Currently, this condition has been further sub-classified, with the most recent sub-type dubbed logopenic variant (PPA-LV). As yet, there remains somewhat limited evaluation of the characteristics of this condition, with no studies providing longitudinal assessment accompanied by post-mortem examination. Moreover, a key characteristic of the PPA-LV case is a deterioration of phonological short-term memory, but again little work has scrutinized the nature of this impairment over time. The current study seeks to redress these oversights and presents detailed longitudinal examination of language and memory function in a case of PPA-LV, with special focus on tests linked to components of phonological short-term memory function. Our findings are then considered with reference to a contemporary model of the neuropsychology of phonological short-term memory. Additionally, post-mortem examinations indicated Alzheimer's disease type pathology, providing further evidence that the PPA-LV presentation may reflect an atypical presentation of this condition. © 2014 The British Psychological Society.

  19. Gain-of-function variants in NLRP1 protect against the development of diabetic kidney disease: NLRP1 inflammasome role in metabolic stress sensing?

    Science.gov (United States)

    Soares, Jaine L S; Fernandes, Fernanda Pereira; Patente, Thiago Andrade; Monteiro, Maria B; Parisi, Maria C; Giannella-Neto, Daniel; Corrêa-Giannella, Maria L; Pontillo, Alessandra

    2018-02-01

    Although inflammasome plays a well-known role in animal models of renal injury, limited studies in humans are available, and its participation in diabetic kidney disease (DKD) remains unknown. Aim of this study was to elucidate the contribution of inflammasome genetics in the development of DKD in type-1 diabetes (T1D). The association of functional variants in inflammasome genes with DKD was assessed by multivariate analysis in a retrospective and in a prospective cohort. NLRP1 rs2670660 and rs11651270 polymorphisms were significantly associated with a decrease risk to develop DKD (p adj <0.01), and rs11651270 also with a lower risk of new renal events during follow-up (p adj =0.01). Supporting these findings, diabetes metabolites (glycated albumin and high glucose) were able to modulate NLRP1 expression. This study is the first to suggest a protective role of NLRP1 in DKD, highlighting an emerging role of NLRP1 as a homeostatic factor against metabolic stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Validation of inverse seasonal peak mortality in medieval plagues, including the Black Death, in comparison to modern Yersinia pestis-variant diseases.

    Science.gov (United States)

    Welford, Mark R; Bossak, Brian H

    2009-12-22

    Recent studies have noted myriad qualitative and quantitative inconsistencies between the medieval Black Death (and subsequent "plagues") and modern empirical Y. pestis plague data, most of which is derived from the Indian and Chinese plague outbreaks of A.D. 1900+/-15 years. Previous works have noted apparent differences in seasonal mortality peaks during Black Death outbreaks versus peaks of bubonic and pneumonic plagues attributed to Y. pestis infection, but have not provided spatiotemporal statistical support. Our objective here was to validate individual observations of this seasonal discrepancy in peak mortality between historical epidemics and modern empirical data. We compiled and aggregated multiple daily, weekly and monthly datasets of both Y. pestis plague epidemics and suspected Black Death epidemics to compare seasonal differences in mortality peaks at a monthly resolution. Statistical and time series analyses of the epidemic data indicate that a seasonal inversion in peak mortality does exist between known Y. pestis plague and suspected Black Death epidemics. We provide possible explanations for this seasonal inversion. These results add further evidence of inconsistency between historical plagues, including the Black Death, and our current understanding of Y. pestis-variant disease. We expect that the line of inquiry into the disputed cause of the greatest recorded epidemic will continue to intensify. Given the rapid pace of environmental change in the modern world, it is crucial that we understand past lethal outbreaks as fully as possible in order to prepare for future deadly pandemics.

  1. Validation of inverse seasonal peak mortality in medieval plagues, including the Black Death, in comparison to modern Yersinia pestis-variant diseases.

    Directory of Open Access Journals (Sweden)

    Mark R Welford

    Full Text Available BACKGROUND: Recent studies have noted myriad qualitative and quantitative inconsistencies between the medieval Black Death (and subsequent "plagues" and modern empirical Y. pestis plague data, most of which is derived from the Indian and Chinese plague outbreaks of A.D. 1900+/-15 years. Previous works have noted apparent differences in seasonal mortality peaks during Black Death outbreaks versus peaks of bubonic and pneumonic plagues attributed to Y. pestis infection, but have not provided spatiotemporal statistical support. Our objective here was to validate individual observations of this seasonal discrepancy in peak mortality between historical epidemics and modern empirical data. METHODOLOGY/PRINCIPAL FINDINGS: We compiled and aggregated multiple daily, weekly and monthly datasets of both Y. pestis plague epidemics and suspected Black Death epidemics to compare seasonal differences in mortality peaks at a monthly resolution. Statistical and time series analyses of the epidemic data indicate that a seasonal inversion in peak mortality does exist between known Y. pestis plague and suspected Black Death epidemics. We provide possible explanations for this seasonal inversion. CONCLUSIONS/SIGNIFICANCE: These results add further evidence of inconsistency between historical plagues, including the Black Death, and our current understanding of Y. pestis-variant disease. We expect that the line of inquiry into the disputed cause of the greatest recorded epidemic will continue to intensify. Given the rapid pace of environmental change in the modern world, it is crucial that we understand past lethal outbreaks as fully as possible in order to prepare for future deadly pandemics.

  2. Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study.

    Science.gov (United States)

    Daly, Martina E; Dawood, Ban B; Lester, William A; Peake, Ian R; Rodeghiero, Francesco; Goodeve, Anne C; Makris, Michael; Wilde, Jonathan T; Mumford, Andrew D; Watson, Stephen P; Mundell, Stuart J

    2009-04-23

    We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY12) contribute to the bleeding tendency in 92 index cases enrolled in the European MCMDM-1VWD study. A heterozygous mutation, predicting a lysine to glutamate (K174E) substitution in P2Y(12), was identified in one case with mild type 1 von Willebrand disease (VWD) and a VWF defect. Platelets from the index case and relatives carrying the K174E defect changed shape in response to ADP, but showed reduced and reversible aggregation in response to 10 muM ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [(3)H]2MeS-ADP to P2Y(12), whereas binding to the P2Y(1) receptor was normal. A hemagglutinin-tagged K174E P2Y(12) variant showed surface expression in CHO cells, markedly reduced binding to [(3)H]2MeS-ADP, and minimal ADP-mediated inhibition of forskolin-induced adenylyl cyclase activity. Our results provide further evidence for locus heterogeneity in type 1 VWD.

  3. Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease.

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    Ani Manichaikul

    Full Text Available Previous studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP rs4238001 with incident coronary heart disease (CHD.Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR] = 1.49, 95% CI [1.04, 2.14], P = 0.028. Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events and African Americans (total n = 5,962 with 355 CHD events and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013, in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], P = 0.019, in males (HR of 1.29 with 95% CI [1.08, 1.54], P = 4.91 x 10(-3 and in White males (HR of 1.24 with 95% CI [1.03, 1.51], P = 0.026.SCARB1 missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.

  4. The pattern of verbal, visuospatial and procedural learning in Richardson variant of progressive supranuclear palsy in comparison to Parkinson's disease.

    Science.gov (United States)

    Sitek, Emilia J; Wieczorek, Dariusz; Konkel, Agnieszka; Dąbrowska, Magda; Sławek, Jarosław

    2017-08-29

    Progressive supranuclear palsy (PSP) is regarded either within spectrum of atypical parkinsonian syndromes or frontotemporal lobar degeneration. We compared the verbal, visuospatial and procedural learning profiles in patients with PSP and Parkinson's disease (PD). Furthermore, the relationship between executive factors (initiation and inhibition) and learning outcomes was analyzed. Thirty-three patients with the clinical diagnosis of PSP-Richardson's syndrome (PSP-RS), 39 patients with PD and 29 age -and education -matched controls were administered Mini-Mental State Examination (MMSE), phonemic and semantic fluency tasks, Auditory Verbal Learning Test (AVLT), Visual Learning and Memory Test for Neuropsychological Assessment by Lamberti and Weidlich (Diagnosticum für Cerebralschädigung, DCS), Tower of Toronto (ToT) and two motor sequencing tasks. Patients with PSP-RS and PD were matched in terms of MMSE scores and mood. Performance on DCS was lower in PSP-RS than in PD. AVLT delayed recall was better in PSP-RS than PD. Motor sequencing task did not differentiate between patients. Scores on AVLT correlated positively with phonemic fluency scores in both PSP-RS and PD. ToT rule violation scores were negatively associated with DCS performance in PSP-RS and PD as well as with AVLT performance in PD. Global memory performance is relatively similar in PSP-RS and PD. Executive factors (initiation and inhibition) are closely related to memory performance in PSP-RS and PD. Visuospatial learning impairment in PSP-RS is possibly linked to impulsivity and failure to inhibit automatic responses.

  5. Interleukin‑1 gene cluster variants in hemodialysis patients with end stage renal disease: An association and meta‑analysis

    Directory of Open Access Journals (Sweden)

    G Tripathi

    2015-01-01

    Full Text Available We evaluated whether polymorphisms in interleukin (IL-1 gene cluster (IL-1 alpha [IL-1A], IL-1 beta [IL-1B], and IL-1 receptor antagonist [IL-1RN] are associated with end stage renal disease (ESRD. A total of 258 ESRD patients and 569 ethnicity matched controls were examined for IL-1 gene cluster. These were genotyped for five single-nucleotide gene polymorphisms in the IL-1A, IL-1B and IL-1RN genes and a variable number of tandem repeats (VNTR in the IL-1RN. The IL-1B − 3953 and IL-1RN + 8006 polymorphism frequencies were significantly different between the two groups. At IL-1B, the T allele of − 3953C/T was increased among ESRD (P = 0.0001. A logistic regression model demonstrated that two repeat (240 base pair [bp] of the IL-1Ra VNTR polymorphism was associated with ESRD (P = 0.0001. The C/C/C/C/C/1 haplotype was more prevalent in ESRD = 0.007. No linkage disequilibrium (LD was observed between six loci of IL-1 gene. We further conducted a meta-analysis of existing studies and found that there is a strong association of IL-1 RN VNTR 86 bp repeat polymorphism with susceptibility to ESRD (odds ratio = 2.04, 95% confidence interval = 1.48-2.82; P = 0.000. IL-1B − 5887, +8006 and the IL-1RN VNTR polymorphisms have been implicated as potential risk factors for ESRD. The meta-analysis showed a strong association of IL-1RN 86 bp VNTR polymorphism with susceptibility to ESRD.

  6. A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans.

    Science.gov (United States)

    Pazderska, Agnieszka; Oftedal, Bergithe E; Napier, Catherine M; Ainsworth, Holly F; Husebye, Eystein S; Cordell, Heather J; Pearce, Simon H S; Mitchell, Anna L

    2016-11-01

    Autoimmune Addison's disease (AAD) is a rare but highly heritable condition. The BACH2 protein plays a crucial role in T lymphocyte maturation, and allelic variation in its gene has been associated with a number of autoimmune conditions. We aimed to determine whether alleles of the rs3757247 single nucleotide polymorphism (SNP) in the BACH2 gene are associated with AAD. This case-control association study was performed in two phases using Taqman chemistry. In the first phase, the rs3757247 SNP was genotyped in 358 UK AAD subjects and 166 local control subjects. Genotype data were also available from 5154 healthy UK controls from the Wellcome Trust (WTCCC2) for comparison. In the second phase, the SNP was genotyped in a validation cohort comprising 317 Norwegian AAD subjects and 365 controls. The frequency of the minor T allele was significantly higher in subjects with AAD from the United Kingdom compared to both the local and WTCCC2 control cohorts (58% vs 45 and 48%, respectively) (local controls, P = 1.1 × 10 -4 ; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.29-2.18; WTCCC2 controls, P = 1.4 × 10 -6 ; OR, 1.44; 95% CI, 1.23-1.69). This finding was replicated in the Norwegian validation cohort (P = .0015; OR, 1.41; 95% CI, 1.14-1.75). Subgroup analysis showed that this association is present in subjects with both isolated AAD (OR, 1.53; 95% CI, 1.22-1.92) and autoimmune polyglandular syndrome type 2 (OR, 1.37; 95% CI, 1.12-1.69) in the UK cohort, and with autoimmune polyglandular syndrome type 2 in the Norwegian cohort (OR, 1.58; 95% CI, 1.22-2.06). We have demonstrated, for the first time, that allelic variability at the BACH2 locus is associated with susceptibility to AAD. Given its association with multiple autoimmune conditions, BACH2 can be considered a "universal" autoimmune susceptibility locus.

  7. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    2008-01-01

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

  8. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

  9. Insights into the management of emerging infections: regulating variant Creutzfeldt-Jakob disease transfusion risk in the UK and the US.

    Science.gov (United States)

    Ponte, Maya L

    2006-10-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible

  10. Insights into the management of emerging infections: regulating variant Creutzfeldt-Jakob disease transfusion risk in the UK and the US.

    Directory of Open Access Journals (Sweden)

    Maya L Ponte

    2006-10-01

    Full Text Available Variant Creutzfeldt-Jakob disease (vCJD is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case.A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood

  11. Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease.

    Science.gov (United States)

    Karumuthil-Melethil, Subha; Nagabhushan Kalburgi, Sahana; Thompson, Patrick; Tropak, Michael; Kaytor, Michael D; Keimel, John G; Mark, Brian L; Mahuran, Don; Walia, Jagdeep S; Gray, Steven J

    2016-07-01

    GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), a substrate-specific cofactor for HexA. In their infantile, acute forms, these diseases rapidly progress with mental and psychomotor deterioration resulting in death by approximately 4 years of age. After gene transfer that overexpresses one of the deficient subunits, the amount of HexA heterodimer formed would empirically be limited by the availability of the other endogenous Hex subunit. The present study used a new variant of the human HexA α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM gene. Also, a previously published capsid mutant, AAV9.47, was used to deliver the gene to brain and spinal cord while having restricted biodistribution to the liver. The novel capsid and cassette design combination was characterized in vivo in TSD mice for its ability to efficiently transduce cells in the central nervous system when delivered intravenously in both adult and neonatal mice. This study demonstrates that the modified HexM is capable of degrading long-standing GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.

  12. Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers.

    Science.gov (United States)

    Dodich, Alessandra; Cerami, Chiara; Cappa, Stefano F; Marcone, Alessandra; Golzi, Valeria; Zamboni, Michele; Giusti, Maria Cristina; Iannaccone, Sandro

    2018-01-01

    Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult. In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups. We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD. Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD. Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

  13. A strain-specific multiplex RT-PCR for Australian rabbit haemorrhagic disease viruses uncovers a new recombinant virus variant in rabbits and hares.

    Science.gov (United States)

    Hall, R N; Mahar, J E; Read, A J; Mourant, R; Piper, M; Huang, N; Strive, T

    2018-04-01

    Rabbit haemorrhagic disease virus (RHDV, or GI.1) is a calicivirus in the genus Lagovirus that has been widely utilized in Australia as a biological control agent for the management of overabundant wild European rabbit (Oryctolagus cuniculus) populations since 1996. Recently, two exotic incursions of pathogenic lagoviruses have been reported in Australia; GI.1a-Aus, previously called RHDVa-Aus, is a GI.1a virus detected in January 2014, and the novel lagovirus GI.2 (previously known as RHDV2). Furthermore, an additional GI.1a strain, GI.1a-K5 (also known as 08Q712), was released nationwide in March 2017 as a supplementary tool for wild rabbit management. To discriminate between these lagoviruses, a highly sensitive strain-specific multiplex RT-PCR assay was developed, which allows fast, cost-effective and sensitive detection of the four pathogenic lagoviruses currently known to be circulating in Australia. In addition, we developed a universal RT-qPCR assay to be used in conjunction with the multiplex assay that broadly detects all four viruses and facilitates quantification of viral RNA load in samples. These assays enable rapid detection, identification and quantification of pathogenic lagoviruses in the Australian context. Using these assays, a novel recombinant lagovirus was detected in rabbit tissue samples, which contained the non-structural genes of GI.1a-Aus and the structural genes of GI.2. This variant was also recovered from the liver of a European brown hare (Lepus europaeus). The impact of this novel recombinant on Australian wild lagomorph populations and its competitiveness in relation to circulating field strains, particularly GI.2, requires further studies. © 2017 Blackwell Verlag GmbH.

  14. Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia.

    Science.gov (United States)

    Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R; Irish, Muireann

    2016-05-30

    Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

  15. Geographic exposure risk of variant Creutzfeldt-Jakob disease in US blood donors: a risk-ranking model to evaluate alternative donor-deferral policies.

    Science.gov (United States)

    Yang, Hong; Huang, Yin; Gregori, Luisa; Asher, David M; Bui, Travis; Forshee, Richard A; Anderson, Steven A

    2017-04-01

    Variant Creutzfeldt-Jakob disease (vCJD) has been transmitted by blood transfusion (TTvCJD). The US Food and Drug Administration (FDA) recommends deferring blood donors who resided in or traveled to 30 European countries where they may have been exposed to bovine spongiform encephalopathy (BSE) through beef consumption. Those recommendations warrant re-evaluation, because new cases of BSE and vCJD have markedly abated. The FDA developed a risk-ranking model to calculate the geographic vCJD risk using country-specific case rates and person-years of exposure of US blood donors. We used the reported country vCJD case rates, when available, or imputed vCJD case rates from reported BSE and UK beef exports during the risk period. We estimated the risk reduction and donor loss should the deferral be restricted to a few high-risk countries. We also estimated additional risk reduction by leukocyte reduction (LR) of red blood cells (RBCs). The United Kingdom, Ireland, and France had the greatest vCJD risk, contributing approximately 95% of the total risk. The model estimated that deferring US donors who spent extended periods of time in these three countries, combined with currently voluntary LR (95% of RBC units), would reduce the vCJD risk by 89.3%, a reduction similar to that achieved under the current policy (89.8%). Limiting deferrals to exposure in these three countries would potentially allow donations from an additional 100,000 donors who are currently deferred. Our analysis suggests that a deferral option focusing on the three highest risk countries would achieve a level of blood safety similar to that achieved by the current policy. © 2016 AABB.

  16. Rapid and Highly Sensitive Detection of Variant Creutzfeldt-Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies.

    Directory of Open Access Journals (Sweden)

    Maxime Belondrade

    Full Text Available The prevalence of variant Creutzfeldt-Jakob disease (vCJD in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA. This assay allowed the specific detection of minute quantities (10-8 brain dilution of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions.

  17. Genome-wide association analysis and replication of coronary artery disease in South Korea suggests a causal variant common to diverse populations

    Science.gov (United States)

    Cho, Eun Young; Jang, Yangsoo; Shin, Eun Soon; Jang, Hye Yoon; Yoo, Yeon-Kyeong; Kim, Sook; Jang, Ji Hyun; Lee, Ji Yeon; Yun, Min Hye; Park, Min Young; Chae, Jey Sook; Lim, Jin Woo; Shin, Dong Jik; Park, Sungha; Lee, Jong Ho; Han, Bok Ghee; Rae, Kim Hyung; Cardon, Lon R; Morris, Andrew P; Lee, Jong Eun; Clarke, Geraldine M

    2010-01-01

    Background Recent genome-wide association (GWA) studies have identified and replicated several genetic loci associated with the risk of development of coronary artery disease (CAD) in samples from populations of Caucasian and Asian descent. However, only chromosome 9p21 has been confirmed as a major susceptibility locus conferring risk for development of CAD across multiple ethnic groups. The authors aimed to find evidence of further similarities and differences in genetic risk of CAD between Korean and other populations. Methods The authors performed a GWA study comprising 230 cases and 290 controls from a Korean population typed on 490 032 single nucleotide polymorphisms (SNPs). A total of 3148 SNPs were taken forward for genotyping in a subsequent replication study using an independent sample of 1172 cases and 1087 controls from the same population. Results The association previously observed on chromosome 9p21 was independently replicated (p=3.08e–07). Within this region, the same risk haplotype was observed in samples from both Korea and of Western European descent, suggesting that the causal mutation carried on this background occurred on a single ancestral allele. Other than 9p21, the authors were unable to replicate any of the previously reported signals for association with CAD. Furthermore, no evidence of association was found at chromosome 1q41 for risk of myocardial infarction, previously identified as conferring risk in a Japanese population. Conclusion A common causal variant is likely to be responsible for risk of CAD in Korean and Western European populations at chromosome 9p21.3. Further investigations are required to confirm non-replication of any other cross-race genetic risk factors. PMID:27325954

  18. The Effect of Turmeric (Curcuma longa Extract on the Functionality of the Solute Carrier Protein 22 A4 (SLC22A4 and Interleukin-10 (IL-10 Variants Associated with Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Mark J. McCann

    2014-10-01

    Full Text Available Inflammatory bowel disease (IBD is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual’s capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152 and interleukin-10 (IL-10, rs1800896 associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F and increasing anti-inflammatory cytokine gene promoter activity (IL-10, −1082A. The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions.

  19. The effect of turmeric (Curcuma longa) extract on the functionality of the solute carrier protein 22 A4 (SLC22A4) and interleukin-10 (IL-10) variants associated with inflammatory bowel disease.

    Science.gov (United States)

    McCann, Mark J; Johnston, Sarah; Reilly, Kerri; Men, Xuejing; Burgess, Elaine J; Perry, Nigel B; Roy, Nicole C

    2014-10-13

    Inflammatory bowel disease (IBD) is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual's capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae) has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152) and interleukin-10 (IL-10, rs1800896) associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene promoter activity (IL-10, -1082A). The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions.

  20. Genomic analysis reveals Nairobi sheep disease virus to be highly diverse and present in both Africa, and in India in the form of the Ganjam virus variant.

    Science.gov (United States)

    Yadav, Pragya D; Vincent, Martin J; Khristova, Marina; Kale, Charuta; Nichol, Stuart T; Mishra, Akhilesh C; Mourya, Devendra T

    2011-07-01

    Nairobi sheep disease (NSD) virus, the prototype tick-borne virus of the genus Nairovirus, family Bunyaviridae is associated with acute hemorrhagic gastroenteritis in sheep and goats in East and Central Africa. The closely related Ganjam virus found in India is associated with febrile illness in humans and disease in livestock. The complete S, M and L segment sequences of Ganjam and NSD virus and partial sequence analysis of Ganjam viral RNA genome S, M and L segments encoding regions (396 bp, 701 bp and 425 bp) of the viral nucleocapsid (N), glycoprotein precursor (GPC) and L polymerase (L) proteins, respectively, was carried out for multiple Ganjam virus isolates obtained from 1954 to 2002 and from various regions of India. M segments of NSD and Ganjam virus encode a large ORF for the glycoprotein precursor (GPC), (1627 and 1624 amino acids in length, respectively) and their L segments encode a very large L polymerase (3991 amino acids). The complete S, M and L segments of NSD and Ganjam viruses were more closely related to one another than to other characterized nairoviruses, and no evidence of reassortment was found. However, the NSD and Ganjam virus complete M segment differed by 22.90% and 14.70%, for nucleotide and amino acid respectively, and the complete L segment nucleotide and protein differing by 9.90% and 2.70%, respectively among themselves. Ganjam and NSD virus, complete S segment differed by 9.40-10.40% and 3.2-4.10 for nucleotide and proteins while among Ganjam viruses 0.0-6.20% and 0.0-1.4%, variation was found for nucleotide and amino acids. Ganjam virus isolates differed by up to 17% and 11% at the nucleotide level for the partial S and L gene fragments, respectively, with less variation observed at the deduced amino acid level (10.5 and 2%, S and L, respectively). However, the virus partial M gene fragment (which encodes the hypervariable mucin-like domain) of these viruses differed by as much as 56% at the nucleotide level. Phylogenetic

  1. Genetic variant SLC2A2 [corrected] Is associated with risk of cardiovascular disease – assessing the individual and cumulative effect of 46 type 2 diabetes related genetic variants.

    Directory of Open Access Journals (Sweden)

    Anders Borglykke

    Full Text Available To assess the individual and combined effect of 46 type 2 diabetes related risk alleles on incidence of a composite CVD endpoint.Data from the first Danish MONICA study (N = 3523 and the Inter99 study (N = 6049 was used. Using Cox proportional hazard regression the individual effect of each risk allele on incident CVD was analyzed. Risk was presented as hazard ratios (HR per risk allele.During 80,859 person years 1441 incident cases of CVD (fatal and non-fatal occurred in the MONICA study. In Inter99 942 incident cases were observed during 61,239 person years. In the Danish MONICA study four gene variants were significantly associated with incident CVD independently of known diabetes status at baseline; SLC2A2 rs11920090 (HR 1.147, 95% CI 1.027-1.283 , P = 0.0154, C2CD4A rs7172432 (1.112, 1.027-1.205 , P = 0.0089, GCKR rs780094 (1.094, 1.007-1.188 , P = 0.0335 and C2CD4B rs11071657 (1.092, 1.007-1.183 , P = 0.0323. The genetic score was significantly associated with increased risk of CVD (1.025, 1.010-1.041, P = 0.0016. In Inter99 two gene variants were associated with risk of CVD independently of diabetes; SLC2A2 (HR 1.180, 95% CI 1.038-1.341 P = 0.0116 and FTO (0.909, 0.827-0.998, P = 0.0463. Analysing the two populations together we found SLC2A2 rs11920090 (HR 1.164, 95% CI 1.070-1.267, P = 0.0004 meeting the Bonferroni corrected threshold for significance. GCKR rs780094 (1.076, 1.010-1.146, P = 0.0229, C2CD4B rs11071657 (1.067, 1.003-1.135, P = 0.0385 and NOTCH2 rs10923931 (1.104 (1.001 ; 1.217 , P = 0.0481 were found associated with CVD without meeting the corrected threshold. The genetic score was significantly associated with increased risk of CVD (1.018, 1.006-1.031, P = 0.0043.This study showed that out of the 46 genetic variants examined only the minor risk allele of SLC2A2 rs11920090 was significantly (P = 0.0005 associated with a composite endpoint of incident CVD below the threshold for statistical significance corrected for

  2. The Val{sup 192}Leu mutation in the {alpha}-subunit of {beta}-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Y.; Vavougios, G.; Hinek, A. [Univ. of Toronto (Canada)] [and others

    1996-07-01

    Substitution mutations adversely affecting the {alpha}-subunit of {beta}-hexosaminidase A ({alpha}{beta}) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-{alpha} chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an {open_quotes}active-site{close_quotes} residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all {alpha}-specific activity. This biochemical phenotype is referred to as the {open_quotes}B1-variant form{close_quotes} of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and both subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, {alpha}-Val{sup 192}Leu. Chinese hamster ovary cells were permanently cotransfected with an {alpha}-cDNA-construct encoding the substitution and a mutant {beta}-cDNA ({beta}-Arg{sup 211}Lys), encoding a {beta}-subunit that is inactive but normal in all other respects. We were surprised to find that the Val{sup 192}Leu substitution produced a pro-{alpha} chain that did not form {alpha}-{beta} dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val{sup 192}Leu substitution does not specifically affect the {alpha}-active site. 23 refs., 4 figs., 2 tabs.

  3. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene

    2017-04-17

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  4. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

    2017-01-01

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  5. Genetics Home Reference: GM2-gangliosidosis, AB variant

    Science.gov (United States)

    ... Resources Genetic Testing (1 link) Genetic Testing Registry: Tay-Sachs disease, variant AB General Information from MedlinePlus (5 links) ... AB variant Activator Deficiency/GM2 Gangliosidosis Activator-deficient Tay-Sachs disease GM2 Activator Deficiency Disease GM2 gangliosidosis, type AB ...

  6. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    Science.gov (United States)

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  7. Use of 14-3-3 and other brain-specific proteins in CSF in the diagnosis of variant Creutzfeldt-Jakob disease

    Science.gov (United States)

    Green, A; Thompson, E; Stewart, G; Zeidler, M; McKenzie, J; MacLeod, M; Ironside, J; Will, R; Knight, R

    2001-01-01

    OBJECTIVES—The detection of the protein 14-3-3 in the CSF has been shown to be a reliable and sensitive marker for sporadic Creutzfeldt-Jakob disease (CJD). Other brain-specific proteins such as neuron specific enolase (NSE), S-100b, and tau protein have also been reported to be increased in the CSF of patients with sporadic CJD. In 1996a variant of CJD (vCJD) was described which is likely to be causally linked to the bovine spongiform encephalopathy agent. This study reports and compares the findings of CSF brain specific protein analysis in 45 patients with vCJD and in 34 control patients.
METHODS—The CSF from 45 patients with vCJD and 34 controls were investigated for the presence of 14-3-3 by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting with chemiluminescent detection. Tau protein, S-100b, and NSE concentrations in CSF were measured using enzyme immunoassays.
RESULTS—Protein 14-3-3 was detected in the CSF of 22/45 patients with vCJD and in 3/34 controls. The mean concentrations of NSE, S-100b, and tau protein in CSF were significantly raised in patients with vCJD compared with controls. The positive predictive value of CSF 14-3-3 was 86% and the negative predictive value was 63%. These values are lower than those reported for sporadic CJD. An increased CSF tau had a positive predictive value of 93% and a negative predictive value of 81%. The combination of CSF 14-3-3 and/or increased CSF tau had a positive predictive value of 91% and a negative predictive value of 84%.
CONCLUSIONS—CSF protein 14-3-3 is not as useful a marker for vCJD as it is for sporadic CJD. Increased concentration of CSF tau was found to be a sensitive marker of vCJD but as concentrations may be increased in many forms of non-CJD dementia, this may limit its usefulness as a diagnostic test.

 PMID:11385008

  8. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    Directory of Open Access Journals (Sweden)

    Julie Nemecek

    Full Text Available Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA to amplify abnormal prion protein (PrP(TSE from highly diluted variant Creutzfeldt-Jakob disease (vCJD-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrP(TSE in tissues and blood. Macaque vCJD PrP(TSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA. Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV, a close relative of the bank vole, seeded with macaque vCJD PrP(TSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N. We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrP(TSE. Meadow vole brain (170N/N PrP genotype was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrP(TSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrP(TSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrP(TSE was more permissive than human PrP(TSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrP(TSE from brains of humans and macaques with vCJD. PrP(TSE signals were reproducibly detected by Western blot in dilutions through 10⁻¹² of vCJD-infected 10% brain homogenates. This is the first report showing PrP(TSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect Pr

  9. Congenital anomalies and normal skeletal variants

    International Nuclear Information System (INIS)

    Guebert, G.M.; Yochum, T.R.; Rowe, L.J.

    1987-01-01

    Congenital anomalies and normal skeletal variants are a common occurrence in clinical practice. In this chapter a large number of skeletal anomalies of the spine and pelvis are reviewed. Some of the more common skeletal anomalies of the extremities are also presented. The second section of this chapter deals with normal skeletal variants. Some of these variants may simulate certain disease processes. In some instances there are no clear-cut distinctions between skeletal variants and anomalies; therefore, there may be some overlap of material. The congenital anomalies are presented initially with accompanying text, photos, and references, beginning with the skull and proceeding caudally through the spine to then include the pelvis and extremities. The normal skeletal variants section is presented in an anatomical atlas format without text or references

  10. The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans

    NARCIS (Netherlands)

    Ruiz-Moreno, J.S. (Juan S.); Hamann, L. (Lutz); Shah, J.A. (Javeed A.); A. Verbon (Annelies); Mockenhaupt, F.P. (Frank P.); Puzianowska-Kuznicka, M. (Monika); Naujoks, J. (Jan); Sander, L.E. (Leif E.); Witzenrath, M. (Martin); Cambier, J.C. (John C.); Suttorp, N. (Norbert); Schumann, R.R. (Ralf R.); Jin, L. (Lei); T.R. Hawn; Opitz, B. (Bastian)

    2018-01-01

    textabstractThe cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary

  11. Annotating pathogenic non-coding variants in genic regions.

    Science.gov (United States)

    Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi; Ren, Zhong; La Carpia, Francesca; Halvorsen, Matt; Schoch, Kelly; Ratzon, Fanni; Heinzen, Erin L; Boland, Michael J; Petrovski, Slavé; Goldstein, David B

    2017-08-09

    Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

  12. Power and type I error results for a bias-correction approach recently shown to provide accurate odds ratios of genetic variants for the secondary phenotypes associated with primary diseases.

    Science.gov (United States)

    Wang, Jian; Shete, Sanjay

    2011-11-01

    We recently proposed a bias correction approach to evaluate accurate estimation of the odds ratio (OR) of genetic variants associated with a secondary phenotype, in which the secondary phenotype is associated with the primary disease, based on the original case-control data collected for the purpose of studying the primary disease. As reported in this communication, we further investigated the type I error probabilities and powers of the proposed approach, and compared the results to those obtained from logistic regression analysis (with or without adjustment for the primary disease status). We performed a simulation study based on a frequency-matching case-control study with respect to the secondary phenotype of interest. We examined the empirical distribution of the natural logarithm of the corrected OR obtained from the bias correction approach and found it to be normally distributed under the null hypothesis. On the basis of the simulation study results, we found that the logistic regression approaches that adjust or do not adjust for the primary disease status had low power for detecting secondary phenotype associated variants and highly inflated type I error probabilities, whereas our approach was more powerful for identifying the SNP-secondary phenotype associations and had better-controlled type I error probabilities. © 2011 Wiley Periodicals, Inc.

  13. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    OpenAIRE

    Torres, Anthony R.; Sweeten, Thayne L.; Johnson, Randall C.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Davies, Christopher J.; Thomas, Aaron J.; Croen, Lisa A.; Benson, Michael

    2016-01-01

    The common variant - common disease hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased versus matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare va...

  14. Genetic variants of ghrelin in metabolic disorders.

    Science.gov (United States)

    Ukkola, Olavi

    2011-11-01

    An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. S447X variant of the lipoprotein lipase gene, lipids, and risk of coronary heart disease in 3 prospective cohort studies

    DEFF Research Database (Denmark)

    Jensen, M.K.; Rimm, E.B.; Rader, D.

    2009-01-01

    ; the association was weaker in the HPFS and not statistically significant in the DCH women and men. The pooled relative risk per minor allele was 0.74 (0.56-1.00). There was a suggestion that the associations of the S447X variant with plasma lipids and CHD risk were more pronounced in obese individuals in the NHS...... study, but this finding was not consistent across the studies. Conclusions The LPL S447X variant tended to be associated with lower TG and higher HDL-C levels, and lower risk of CHD in all 3 cohorts. Lipoprotein lipase is an attractive target for clinical intervention, but studies are needed to clarify...

  16. One Size Does Not Fit All: Face Emotion Processing Impairments in Semantic Dementia, Behavioural-Variant Frontotemporal Dementia and Alzheimer?s Disease Are Mediated by Distinct Cognitive Deficits

    OpenAIRE

    Miller, Laurie A.; Hsieh, Sharpley; Lah, Suncica; Savage, Sharon; Hodges, John R.; Piguet, Olivier

    2011-01-01

    Patients with frontotemporal dementia (both behavioural variant [bvFTD] and semantic dementia [SD]) as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (n = 17), SD (n = 12) or AD (n = 20) to an age- and education-matched group of healthy control subjects (n = 36) on three face emotion processing tasks (Ekman 60, Emotion Matching and E...

  17. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease.

    Science.gov (United States)

    Ward, Lucas D; Kellis, Manolis

    2016-01-04

    More than 90% of common variants associated with complex traits do not affect proteins directly, but instead the circuits that control gene expression. This has increased the urgency of understanding the regulatory genome as a key component for translating genetic results into mechanistic insights and ultimately therapeutics. To address this challenge, we developed HaploReg (http://compbio.mit.edu/HaploReg) to aid the functional dissection of genome-wide association study (GWAS) results, the prediction of putative causal variants in haplotype blocks, the prediction of likely cell types of action, and the prediction of candidate target genes by systematic mining of comparative, epigenomic and regulatory annotations. Since first launching the website in 2011, we have greatly expanded HaploReg, increasing the number of chromatin state maps to 127 reference epigenomes from ENCODE 2012 and Roadmap Epigenomics, incorporating regulator binding data, expanding regulatory motif disruption annotations, and integrating expression quantitative trait locus (eQTL) variants and their tissue-specific target genes from GTEx, Geuvadis, and other recent studies. We present these updates as HaploReg v4, and illustrate a use case of HaploReg for attention deficit hyperactivity disorder (ADHD)-associated SNPs with putative brain regulatory mechanisms. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  18. Phenotypic and genotypic characterization of Salmonella Typhimurium variant 5- isolates associated with an outbreak of food-borne disease in Paz de Rio, Boyacá, Colombia, in 2010 = Caracterización fenotípica y genotípica de Salmonella Typhimurium variante 5- asociada a un brote de enfermedad transmitida por alimentos en el municipio de Paz de Río, Boyacá, 2010 = Caracterización fenotípica y genotípica de Salmonella Typhimurium variante 5- asociada a un brote de enfermedad transmitida por alimentos en el municipio de Paz de Río, Boyacá, 2010

    Directory of Open Access Journals (Sweden)

    Díaz Osorio, Miguel Ángel

    2014-01-01

    Full Text Available Introduction: Salmonella enterica serotype Typhimuri-um variant 5- is a pathogen closely related to animals, especially pigeons, which has been also associ- ated in rare cases with sporadic infections in humans. However, epidemiological surveillance systems have enabled the detection of this variant in human out- breaks. Objective: To characterize by means of phenotypic and genotypic techniques the isolates of Salmonella Typhimurium variant 5- associated with an outbreak of food-borne disease in Paz de Rio, Boyacá, Colombia (2010, in order to establish their molecular relationships. Materials and methods: Twelve isolates of Salmonella -spp., were analyzed by biochemical, serotyping and antimicrobial susceptibility tests. Pulsed-field gel electrophoresis (PFGE with Xball Blnl enzymes was used to establish their molecular relationships Results: All isolates were confirmed as Salmonella spp. They were resistant to tetracycline and streptomycin and sensitive to the rest of antibiotics tested. Eleven isolates were identified as Salmonella Typhimurium variant 5- and grouped in COIN10.JPX.X01.0168 pattern using the enzyme Xball two isolates in this group were confirmed using the enzyme Blnl with the COIN10.JPX.A26.0002 pattern. One isolate was identified as Salmonella Typhimurium with COIN10.JPX.X01.0221 pattern with the enzyme Xbal Conclusion: This is the first outbreak in Colombia of foodborne illness epidemiologically associated with isolates of Typhimurium variant 5 -, which Epidemiologic Sur were phenotypically and genetically related.

  19. Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

    Science.gov (United States)

    Jaumain, Emilie; Quadrio, Isabelle; Herzog, Laetitia; Reine, Fabienne; Rezaei, Human; Andréoletti, Olivier; Laude, Hubert; Perret-Liaudet, Armand; Haïk, Stéphane; Béringue, Vincent

    2016-12-01

    Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP C ) and the infecting pathological PrP assemblies (PrP Sc ) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP C and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP Sc signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  20. Variants of cellobiohydrolases

    Energy Technology Data Exchange (ETDEWEB)

    Bott, Richard R.; Foukaraki, Maria; Hommes, Ronaldus Wilhelmus; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Nikolaev, Igor; Sandgren, Mats; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

    2018-04-10

    Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

  1. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    Nalls, M.A.; Plagnol, V.; Hernandez, D.G.; Sharma, M.; Sheerin, U.M.; Saad, M.; Simon-Sanchez, J.; Schulte, C.; Lesage, S.; Sveinbjornsdottir, S.; Stefansson, K.; Martinez, M.; Hardy, J.; Heutink, P.; Brice, A.; Gasser, T.; Singleton, A.B.; Wood, N.W.; Bloem, B.R.; Post, B.; Scheffer, H.; Warrenburg, B.P.C. van de; et al.,

    2011-01-01

    BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA

  2. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    Nalls, Michael A.; Plagnol, Vincent; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una-Marie; Saad, Mohamad; Simon-Sanchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjornsdottir, Sigurlaug; Arepalli, Sampath; Barker, Roger; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M. A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean-Francois; Deloukas, Panos; Deuschl, Guenther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Duerr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gustafsson, Omar; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jonsson, Palmi V.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R.; Morrison, Karen E.; Mudanohwo, Ese; O'Sullivan, Sean S.; Pearson, Justin; Perlmutter, Joel S.; Petursson, Hjoervar; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Sidransky, Ellen; Smith, Colin; Spencer, Chris C. A.; Stefansson, Hreinn; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Tison, Francois; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, Andre G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefansson, Kari; Martinez, Maria; Hardy, John; Heutink, Peter; Brice, Alexis; Gasser, Thomas; Singleton, Andrew B.; Wood, Nicholas W.

    2011-01-01

    Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and

  3. A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus.

    Directory of Open Access Journals (Sweden)

    Young Jae Woo

    Full Text Available Copy number variants (CNVs at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2 are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG, a cortical structure implicated in speech and language in independent discovery (n = 100 and validation cohorts (n = 2621. In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.

  4. A study assessing the association of glycated hemoglobin A1C (HbA1C) associated variants with HbA1C, chronic kidney disease and diabetic retinopathy in populations of Asian ancestry.

    Science.gov (United States)

    Chen, Peng; Ong, Rick Twee-Hee; Tay, Wan-Ting; Sim, Xueling; Ali, Mohammad; Xu, Haiyan; Suo, Chen; Liu, Jianjun; Chia, Kee-Seng; Vithan