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Sample records for diabetes-associated gene variant

  1. Three-dimensional structure of β-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W

    Directory of Open Access Journals (Sweden)

    Weijers Rob NM

    2010-06-01

    to the correct sites in the pancreatic islet cells and are consistent with the observation that the SLC30A8 gene variant R325W has a low predicted value for future type 2 diabetes at population-based level.

  2. Type 2 diabetes associated variants of KCNQ1 strongly confer the risk of cardiovascular disease among the Saudi Arabian population

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    Maha S. Al-Shammari

    2017-08-01

    Full Text Available Abstract Genome-wide association studies have identified several loci associated with an increased risk for cardiovascular disease (CVD and type 2 diabetes (T2D. Polymorphisms within the KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1 gene are consistently associated with T2D in a number of populations. The current study was undertaken to evaluate the association of 3 polymorphisms of KCNQ1 (rs2237892, rs151290 and rs2237895 with T2D and/or CVD. Patients diagnosed with either T2D (320 patients, CVD (250 patients or both (60 patients and 516 healthy controls were genotyped by TaqMan assay run on a real time PCR thermocycler. A statistically significant association was found for SNPs rs151290 (OR = 1.76; 95%CI = 1.02-3.05; p = 0.0435 and rs2237895 (OR = 2.49; 95%CI = 1.72-3.61; p < 0.0001 with CVD. SNP rs151290 (OR = 7.43; 95%CI = 1.00-55.22; p = 0.0499 showed a strong association in patients with both T2D and CVD. None of the SNPs showed any significant association with T2D. Haploview analysis showed that the ACC (rs151290, rs2237892 and rs2237895 haplotype is the most significant risk allele combination for CVD, while CCA is the most significant risk haplotype for co-morbidity with T2D. KCNQ1 polymorphism at SNPs rs151290 and rs2237895 is strongly associated with CVD in this population, but presented no association with T2D.

  3. Apolipoprotein gene variants and susceptibility to essential ...

    African Journals Online (AJOL)

    Apolipoprotein gene variants and susceptibility to essential hypertension in Cameroon. ... Results: Whereas advanced age, SBP, DBP, lack of exercise and family history constituted risk factors of EH, sex, body mass index (BMI), Fasting blood sugar (FBS), lipid profile, smoking, excessive alcohol consumption did not.

  4. Human AZU-1 gene, variants thereof and expressed gene products

    Science.gov (United States)

    Chen, Huei-Mei; Bissell, Mina

    2004-06-22

    A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

  5. Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

    Directory of Open Access Journals (Sweden)

    Bryony A. Thompson

    2015-03-01

    Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

  6. Myostatin: genetic variants, therapy and gene doping

    Directory of Open Access Journals (Sweden)

    André Katayama Yamada

    2012-09-01

    Full Text Available Since its discovery, myostatin (MSTN has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.Desde sua descoberta, a miostatina (MSTN entrou na linha de frente em pesquisas relacionadas às terapias musculares porque mutações intrínsecas ou inibição desta proteína tanto por abordagens farmacológicas como genéticas resultam em hipertrofia muscular e hiperplasia. Além do aumento da massa muscular, a inibição de MSTN potencialmente prejudica o tecido conectivo, modula a força muscular, facilita o transplante de mioblastos, promove regeneração tecidual, induz termogênese no tecido adiposo e aumenta a oxidação na musculatura esquelética. É também sabido que os atuais avanços em terapia gênica têm uma relação com o esporte devido ao uso ilícito de tal método. Os efeitos adversos de tal abordagem, seus efeitos no desempenho de atletas e métodos para detectar doping genético s

  7. Growth differentiation factor 9 gene variants in Sudanese desert ...

    African Journals Online (AJOL)

    Certain variants in the growth differentiation factor 9 (GDF9) gene have major effects on the ovulation rate in sheep. The aim of this study was to analyse GDF9 variability in the Sudanese desert sheep ecotypes Ashgar, Dubasi and Watish, and to test identified variants for association with litter size. For this purpose, ewes of ...

  8. Common Gene Variants Account for Most Genetic Risk for Autism

    Science.gov (United States)

    ... gene variants account for most genetic risk for autism Roles of heritability, mutations, environment estimated – NIH-funded study. The bulk of risk, or liability, for autism spectrum disorders (ASD) was traced to inherited variations ...

  9. Germline variants in the ATM gene and breast cancer susceptibility ...

    African Journals Online (AJOL)

    Germline variants in the ATM gene and breast cancer susceptibility in Moroccan women: A meta-analysis. Chaymaa Marouf, Omar Hajji, Amal Tazzite, Hassan Jouhadi, Abdellatif Benider, Sellama Nadifi ...

  10. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all...

  11. Pathological assessment of mismatch repair gene variants in Lynch syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D; Royer-Pokora, Brigitte

    2012-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose...

  12. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

    International Nuclear Information System (INIS)

    Calò, Valentina; Bruno, Loredana; Paglia, Laura La; Perez, Marco; Margarese, Naomi; Gaudio, Francesca Di; Russo, Antonio

    2010-01-01

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance

  13. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

    Energy Technology Data Exchange (ETDEWEB)

    Calò, Valentina; Bruno, Loredana; Paglia, Laura La; Perez, Marco; Margarese, Naomi [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy); Gaudio, Francesca Di [Department of Medical Biotechnologies and Legal Medicine, University of Palermo, Palermo (Italy); Russo, Antonio, E-mail: lab-oncobiologia@usa.net [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy)

    2010-09-10

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.

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

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    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

  15. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

    DEFF Research Database (Denmark)

    Neve, Bernadette; Fernandez-Zapico, Martin E; Ashkenazi-Katalan, Vered

    2005-01-01

    KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first...

  16. BRCA Share: A Collection of Clinical BRCA Gene Variants.

    Science.gov (United States)

    Béroud, Christophe; Letovsky, Stanley I; Braastad, Corey D; Caputo, Sandrine M; Beaudoux, Olivia; Bignon, Yves Jean; Bressac-De Paillerets, Brigitte; Bronner, Myriam; Buell, Crystal M; Collod-Béroud, Gwenaëlle; Coulet, Florence; Derive, Nicolas; Divincenzo, Christina; Elzinga, Christopher D; Garrec, Céline; Houdayer, Claude; Karbassi, Izabela; Lizard, Sarab; Love, Angela; Muller, Danièle; Nagan, Narasimhan; Nery, Camille R; Rai, Ghadi; Revillion, Françoise; Salgado, David; Sévenet, Nicolas; Sinilnikova, Olga; Sobol, Hagay; Stoppa-Lyonnet, Dominique; Toulas, Christine; Trautman, Edwin; Vaur, Dominique; Vilquin, Paul; Weymouth, Katelyn S; Willis, Alecia; Eisenberg, Marcia; Strom, Charles M

    2016-12-01

    As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world. © 2016 WILEY PERIODICALS, INC.

  17. Combined effects of thrombosis pathway gene variants predict cardiovascular events.

    Directory of Open Access Journals (Sweden)

    Kirsi Auro

    2007-07-01

    Full Text Available The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5, intercellular adhesion molecule 1 (ICAM1, protein C (PROC, and thrombomodulin (THBD in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141, we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%, 54 single nucleotide polymorphisms (SNPs were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 x THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs-acting either in combination or as single variants--predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level.

  18. Melanoma risk associated with MC1R gene variants in Latvia and the functional analysis of rare variants.

    Science.gov (United States)

    Ozola, Aija; Azarjana, Kristīne; Doniņa, Simona; Proboka, Guna; Mandrika, Ilona; Petrovska, Ramona; Cēma, Ingrīda; Heisele, Olita; Eņģele, Ludmila; Streinerte, Baiba; Pjanova, Dace

    2013-03-01

    To evaluate the association of melanocortin 1 receptor gene (MC1R) variants with melanoma risk in a Latvian population, the MC1R gene was sequenced in 200 melanoma patients and 200 control persons. A functional study of previously uncharacterized, rare MC1R variants was also performed. In total, 26 different MC1R variants, including two novel variants Val165Ile and Val188Ile, were detected. The highest risk of melanoma was associated with the Arg151Cys variant (odds ratio (OR) 4.47, 95% confidence interval (CI) 2.19-9.14, PLatvia. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Sequence variants of the LCORL gene and its association with ...

    Indian Academy of Sciences (India)

    Y. J. HAN

    [Han Y. J., Chen Y., Liu Y. and Liu X. L. 2017 Sequence variants of the LCORL gene and its association with growth and carcass traits in. Qinchuan cattle in China. J. Genet. 96, xx–xx]. Introduction. Genetically selecting is a better way to satisfy the growing customer requirement with the development of beef cattle industry ...

  20. Germline variants in the ATM gene and breast cancer susceptibility ...

    African Journals Online (AJOL)

    Chaymaa Marouf

    2017-03-06

    Mar 6, 2017 ... investigate the associations between the c.7271T > G and c.1066–. 6T > G ATM gene variants and breast cancer risk in case-control ser- ies from Moroccan population. 2. Subjects and methods. 2.1. Study population. Cases were 163 female patients affected with breast cancer as the first diagnosed cancer.

  1. Sequence variants of the LCORL gene and its association with ...

    Indian Academy of Sciences (India)

    Sequence variants of the LCORL gene and its association with growth and carcass traits in Qinchuan cattle in China. Y. J. HAN, Y. CHEN, Y. LIU and X. L. LIU. ∗. College of Animal Science and Technology, Northwest A&F University, No. 22, Xinong Road, Yangling,. Shaanxi 712100, People's Republic of China. Abstract.

  2. RESEARCH ARTICLE Sequence variants of the LCORL gene and ...

    Indian Academy of Sciences (India)

    Navya

    1. RESEARCH ARTICLE. Sequence variants of the LCORL gene and its association with growth and carcass traits in Qinchuan cattle in China. Y.J. HAN, Y. CHEN, Y. LIU AND X.L. LIU*. College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong. Road, Yangling, Shaanxi 712100, P. R. China.

  3. Screening for common copy-number variants in cancer genes.

    Science.gov (United States)

    Tyson, Jess; Majerus, Tamsin M O; Walker, Susan; Armour, John A L

    2010-12-01

    For most cases of colorectal cancer that arise without a family history of the disease, it is proposed that an appreciable heritable component of predisposition is the result of contributions from many loci. Although progress has been made in identifying single nucleotide variants associated with colorectal cancer risk, the involvement of low-penetrance copy number variants is relatively unexplored. We have used multiplex amplifiable probe hybridization (MAPH) in a fourfold multiplex (QuadMAPH), positioned at an average resolution of one probe per 2 kb, to screen a total of 1.56 Mb of genomic DNA for copy number variants around the genes APC, AXIN1, BRCA1, BRCA2, CTNNB1, HRAS, MLH1, MSH2, and TP53. Two deletion events were detected, one upstream of MLH1 in a control individual and the other in APC in a colorectal cancer patient, but these do not seem to correspond to copy number polymorphisms with measurably high population frequencies. In summary, by means of our QuadMAPH assay, copy number measurement data were of sufficient resolution and accuracy to detect any copy number variants with high probability. However, this study has demonstrated a very low incidence of deletion and duplication variants within intronic and flanking regions of these nine genes, in both control individuals and colorectal cancer patients. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Management of Gene Variants of Unknown Significance

    DEFF Research Database (Denmark)

    Alosi, Daniela; Bisgaard, Marie Luise; Hemmingsen, Sophie Nowak

    2017-01-01

    by germline mutations in the VHL gene, which predispose to the development of multiple tumors such as central nervous system hemangioblastomas and renal cell carcinoma (RCC). Objective: We propose a method for the evaluation of VUS pathogenicity through our experience with the VHL missense mutation c.241C...... (IHC); 3) Assessment of the variant’s impact on protein structure and function, using multiple databases, in silico algorithms, and reports of functional studies. Results: Only one family member had clinical signs of vHL with early-onset RCC. IHC analysis showed no VHL protein expressed in the tumor...

  5. Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk.

    Science.gov (United States)

    Di Lucca, Julie; Guedj, Mickael; Lacapère, Jean-Jacques; Fargnoli, Maria Concetta; Bourillon, Agnes; Dieudé, Philippe; Dupin, Nicolas; Wolkenstein, Pierre; Aegerter, Philippe; Saiag, Philippe; Descamps, Vincent; Lebbe, Celeste; Basset-Seguin, Nicole; Peris, Ketty; Grandchamp, Bernard; Soufir, Nadem

    2009-12-01

    Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to multiple early onset skin cancers, including melanoma. XPV results from mutations of the POLH gene that encodes a DNA translesion polymerase. In this work, we tested the hypothesis that POLH variants could be associated with melanoma risk. A common non-synonymous POLH variant, c.1783A>G p.M595V, was genotyped in 1075 melanoma patients and in 1091 ethnic-matched controls from France. In addition, we searched for rare POLH variants by sequencing the entire coding sequence in 201 patients having a familial history of melanoma (n=123), sporadic multiple melanomas (n=65) and a melanoma associated with a skin carcinoma (n=13). Overall, the c.1783G, p.595V allele was statistically associated with melanoma (respective allelic frequencies, 0.040 versus 0.022, P-value=1.17 x 10(-3), odds ratio (OR)=1.86 [1.27-2.71]), which was further confirmed by a meta-analysis including 274 patients and 174 matched controls from Italy (P-value=7.7 x 10(-4), OR=1.84 [1.29-2.63]). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.I272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects. Besides severe deficiencies in translesion synthesis which are major risks factors for skin carcinomas and melanomas, less deleterious POLH variants could act as low penetrance melanoma predisposing alleles. The ongoing identification of genetic markers implied in skin cancer predisposition could help to identify high-risk subjects as targets for clinical follow-up. Replication studies in other populations are awaited to assess these data.

  6. Gene-environment interactions involving functional variants

    DEFF Research Database (Denmark)

    Barrdahl, Myrto; Rudolph, Anja; Hopper, John L

    2017-01-01

    epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER.......01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint  = 0.77, 95% CI: 0.67-0.88, pint  = 1.8 × 10(-4) ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.......36, 95% CI: 1.16-1.59, pint  = 1.9 × 10(-5) ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint  = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10...

  7. Integrated analysis of unclassified variants in mismatch repair genes.

    Science.gov (United States)

    Pastrello, Chiara; Pin, Elisa; Marroni, Fabio; Bedin, Chiara; Fornasarig, Mara; Tibiletti, Maria Grazia; Oliani, Cristina; Ponz de Leon, Maurizio; Urso, Emanuele Damiano; Della Puppa, Lara; Agostini, Marco; Viel, Alessandra

    2011-02-01

    Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study. We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system. The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain. Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers.

  8. Genetic Variants Contribute to Gene Expression Variability in Humans

    Science.gov (United States)

    Hulse, Amanda M.; Cai, James J.

    2013-01-01

    Expression quantitative trait loci (eQTL) studies have established convincing relationships between genetic variants and gene expression. Most of these studies focused on the mean of gene expression level, but not the variance of gene expression level (i.e., gene expression variability). In the present study, we systematically explore genome-wide association between genetic variants and gene expression variability in humans. We adapt the double generalized linear model (dglm) to simultaneously fit the means and the variances of gene expression among the three possible genotypes of a biallelic SNP. The genomic loci showing significant association between the variances of gene expression and the genotypes are termed expression variability QTL (evQTL). Using a data set of gene expression in lymphoblastoid cell lines (LCLs) derived from 210 HapMap individuals, we identify cis-acting evQTL involving 218 distinct genes, among which 8 genes, ADCY1, CTNNA2, DAAM2, FERMT2, IL6, PLOD2, SNX7, and TNFRSF11B, are cross-validated using an extra expression data set of the same LCLs. We also identify ∼300 trans-acting evQTL between >13,000 common SNPs and 500 randomly selected representative genes. We employ two distinct scenarios, emphasizing single-SNP and multiple-SNP effects on expression variability, to explain the formation of evQTL. We argue that detecting evQTL may represent a novel method for effectively screening for genetic interactions, especially when the multiple-SNP influence on expression variability is implied. The implication of our results for revealing genetic mechanisms of gene expression variability is discussed. PMID:23150607

  9. Common and rare gene variants affecting plasma LDL cholesterol.

    Science.gov (United States)

    Burnett, John R; Hooper, Amanda J

    2008-02-01

    The plasma level of LDL cholesterol is clinically important and genetically complex. LDL cholesterol levels are in large part determined by the activity of LDL receptors (LDLR) in the liver. Autosomal dominant familial hypercholesterolaemia (FH) - with its high LDL cholesterol levels, xanthomas, and premature atherosclerosis - is caused by mutations in either the LDLR or in APOB - the protein in LDL recognised by the LDLR. A third, rare form - autosomal recessive hypercholesterolaemia - arises from mutations in the gene encoding an adaptor protein involved in the internalisation of the LDLR. A fourth variant of inherited hypercholesterolaemia was recently found to be associated with missense mutations in PCSK9, which encodes a serine protease that degrades LDLR. Whereas the gain-of-function mutations in PCSK9 are rare, a spectrum of more frequent loss-of-function mutations in PCSK9 associated with low LDL cholesterol levels has been identified in selected populations and could protect against coronary heart disease. Heterozygous familial hypobetalipoproteinaemia (FHBL) - with its low LDL cholesterol levels and resistance to atherosclerosis - is caused by mutations in APOB. In contrast to other inherited forms of severe hypocholesterolaemia such as abetalipoproteinaemia - caused by mutations in MTP - and homozygous FHBL, a deficiency of PCSK9 appears to be benign. Rare variants of NPC1L1, the gene encoding the putative intestinal cholesterol receptor, have shown more modest effects on plasma LDL cholesterol than PCSK9 variants, similar in magnitude to the effect of common APOE variants. Taken together, these findings indicate that heritable variation in plasma LDL cholesterol is conferred by sequence variation in various loci, with a small number of common and multiple rare gene variants contributing to the phenotype.

  10. 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.

  11. 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.

  12. MC1R gene variants involvement in human OCA phenotype

    Directory of Open Access Journals (Sweden)

    Saleha Shamim

    2016-01-01

    Full Text Available Oculocutaneous albinism (OCA is a genetic disorder of melanin synthesis that results in hypopigmentation in hair, skin and eyes. OCA has been reported in individuals from all ethnic backgrounds but it is more common among those with Europeans ancestry. OCA is heterogeneous group of disorders and seven types of OCA are caused by mutations in TYR (OCA1, OCA2 (OCA2, TYRP1 (OCA3, SLC45A2 (OCA4, SLC24A5 (OCA6 and C10oRF11 (OCA7 genes. However, MC1R gene variants have been reported that modify OCA2 phenotype but the knowledge about the function ofMC1R gene in melanogenesis, and genotype-phenotype association, in case of OCA, is limited. In this review article we present a comprehensive description of classification of OCA, role of MSH-R in melanin synthesis, the sequence variations in MC1R and their association with OCA. This review will enhance our understanding of MC1R gene variants involved in human OCA2 phenotype.

  13. Variants of the ADRB2 Gene in COPD

    DEFF Research Database (Denmark)

    Nielsen, Anne Orholm; Steen Jensen, Camilla; Arredouani, Mohamed Simo

    2017-01-01

    The β2-adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone in chronic obstructive pulmonary disease (COPD). Variants that impair ADRB2 function could increase disease risk or reduce the response to endogenous and inhaled adrenergic agonists in COPD. We performed...... a systematic review and three meta-analyses to assess whether three functional variants (Thr164Ile, Arg16Gly, and Gln27Glu) in the ADRB2 gene are associated with elevated risk of disease or reduced therapeutic response to inhaled β2-agonists in COPD. We searched the medical literature from 1966 to 2017...... and found 16 relevant studies comprising 85381 study subjects. The meta-analyses found no significant association between ADRB2 genotype and COPD risk. The summary odds ratios (ORs) for COPD in Thr164Ile homozygotes and heterozygotes were 2.57 (95% confidence interval (CI): 0.54-12.4) and 1.17 (95% CI: 0...

  14. Novel genetic variants in the TPO gene cause congenital hypothyroidism.

    Science.gov (United States)

    Ma, Shao-Gang; Qiu, Ya-Li; Zhu, Hong; Liu, Hong; Li, Qing; Ji, Chun-Mei

    2015-01-01

    Mutations in the dual oxidase maturation factor 2 (DUOXA2) and thyroid peroxidase (TPO) genes have been reported to cause goitrous congenital hypothyroidism (GCH). The aim of this study was to determine the genetic basis of GCH in affected children. Thirty children with GCH were enrolled for molecular analysis of the DUOXA2 and TPO genes. All subjects underwent clinical examination and laboratory testing. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen for DUOXA2 and TPO gene mutations in the exon fragments amplified from the extracted DNA. Family members of those patients with mutations were also enrolled and evaluated. Analysis of the TPO gene revealed six genetic variants, including two novel heterozygous mutations, c.1970T> C (p.I657T) and c.2665G> T (p.G889X), and four mutations that have been reported previously (c.670_672del, c.2268dup, c.2266T> C and c.2647C> T). Three patients harbored the same mutation c.2268dup. The germline mutations from four unrelated families were consistent with an autosomal recessive inheritance pattern. Conversely, no mutations in the DUOXA2 gene were detected. Two novel inactivating mutations (c.1970T> C and c.2665G> T) in the TPO gene were identified. The c.2268dup mutation occurred frequently. No mutations in the DUOXA2 gene were detected in this study.

  15. Human genes with a greater number of transcript variants tend to show biological features of housekeeping and essential genes

    DEFF Research Database (Denmark)

    Ryu, Jae Yong; Kim, Hyun Uk; Lee, Sang Yup

    2015-01-01

    found to have a single transcript, and the remaining genes had 2 to 77 transcript variants. The genes with more transcript variants exhibited greater frequencies of acting as housekeeping and essential genes rather than tissue-selective and non-essential genes. They were found to be more conserved among...

  16. Multiple common variants for celiac disease influencing immune gene expression

    OpenAIRE

    MCMANUS, ROSS; KELLEHER, DERMOT

    2010-01-01

    PUBLISHED We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMI...

  17. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

    Directory of Open Access Journals (Sweden)

    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats with the asymptomatic infection of BN (Brown Norway. Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains, displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus named Hse6 towards the end of chromosome 4 (160.89-174Mb containing the Vwf (von Willebrand factor gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism. Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008 after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

  18. Distribution of KIR genes and KIR2DS4 gene variants in two Mexican Mestizo populations.

    Science.gov (United States)

    Machado-Sulbaran, Andrea Carolina; Muñoz-Valle, José Francisco; Ramírez-Dueñas, María Guadalupe; Baños-Hernández, Christian Johana; Graciano-Machuca, Omar; Velarde-De la Cruz, Erandi Enif; Parra-Rojas, Isela; Sánchez-Hernández, Pedro Ernesto

    2017-10-01

    Killer immunoglobulin-like receptors (KIR) are transmembrane proteins that regulate NK and T cell subsets by recognizing HLA-I molecules as ligands. The KIR gene family consists of 16 genes, located at chromosome 19q13.4. KIR gene frequencies vary among populations. In Mexico, HLA and genetic ancestry studies show that Mestizo populations have different genetic backgrounds based on admixture with European, African, and Asian ancestry. This study aimed to evaluate the frequencies of KIR genes and genotypes in Guerrero and Jalisco, two Mexican Mestizo populations located in the south and the west of the country, respectively, and to compare these frequencies with those of other populations. KIR genotyping was performed by SSP-PCR. We observed that KIR gene frequencies were similar in both populations. There were 24 genotypes observed in Guerrero, 38 genotypes observed in Jalisco, 15 genotypes shared in both populations and 32 genotypes unique to one population or the other. In 10 individuals, nine novel genotypes were identified. KIR2DS4 gene variants showed significant differences: The KIR2DS4full gene was more common in Guerrero (pKIR2DS4del variant was more common in Jalisco (pKIR2DS4 gene variants and genotypic profiles could be influenced by the genetic admixture in both regions. Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  19. Gene variants associated with antisocial behaviour: a latent variable approach.

    Science.gov (United States)

    Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V; Lee, Maria; Yrigollen, Carolyn M; Pakstis, Andrew J; Katsovich, Liliya; Olds, David L; Grigorenko, Elena L; Leckman, James F

    2013-10-01

    The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation programme in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed. Eight single-nucleotide polymorphisms (SNPs) from eight genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all eight genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid and cholinergic signalling as well as stress response pathways in mediating susceptibility to antisocial behaviour. This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential 'co-action' of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the aetiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a

  20. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Iversen, Edwin S; Tyrer, Jonathan

    2015-01-01

    genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association...

  1. GxGrare: gene-gene interaction analysis method for rare variants from high-throughput sequencing data.

    Science.gov (United States)

    Kwon, Minseok; Leem, Sangseob; Yoon, Joon; Park, Taesung

    2018-03-19

    With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications. Also, the recent advancement of high-throughput sequencing technologies makes it possible to conduct rare variant analysis. However, little progress has been made in gene-gene interaction analysis for rare variants. Here, we propose GxGrare which is a new gene-gene interaction method for the rare variants in the framework of the multifactor dimensionality reduction (MDR) analysis. The proposed method consists of three steps; 1) collapsing the rare variants, 2) MDR analysis for the collapsed rare variants, and 3) detect top candidate interaction pairs. GxGrare can be used for the detection of not only gene-gene interactions, but also interactions within a single gene. The proposed method is illustrated with 1080 whole exome sequencing data of the Korean population in order to identify causal gene-gene interaction for rare variants for type 2 diabetes. The proposed GxGrare performs well for gene-gene interaction detection with collapsing of rare variants. GxGrare is available at http://bibs.snu.ac.kr/software/gxgrare which contains simulation data and documentation. Supported operating systems include Linux and OS X.

  2. 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.

  3. Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

    NARCIS (Netherlands)

    Paulussen, Aimee D C; Steyls, Anja; Vanoevelen, Jo; Van Tienen, Florence H J; Krapels, Ingrid P C; Claes, Godelieve R F; Chocron, Sonja; Velter, Crool; Tan-Sindhunata, Gita M.; Lundin, Catarina; Valenzuela, Irene; Nagy, Balint; Bache, Iben; Maroun, Lisa Leth; Avela, Kristiina; Brunner, Han G.; Smeets, Hubert J M; Bakkers, Jeroen; Van Den Wijngaard, Arthur

    2016-01-01

    Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and

  4. IL18 Gene Variants Influence the Susceptibility to Chagas Disease.

    Directory of Open Access Journals (Sweden)

    Daniel A Leon Rodriguez

    2016-03-01

    Full Text Available Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC. Interleukin 18 (IL18 encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719, which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595, seropositive asymptomatic (n = 175 and CCC (n = 401, were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77, rs360719 (P = 1.49E-03, OR = 0.76, rs2043055 (P = 2.52E-03, OR = 1.29, and rs1946518 (P = 0.0162, OR = 1.22. However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.

  5. Loss aversion and 5HTT gene variants in adolescent anxiety

    Directory of Open Access Journals (Sweden)

    Monique Ernst

    2014-04-01

    Full Text Available Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR in healthy and clinically anxious adolescents. Findings show that loss aversion (1 does manifest in adolescents, (2 does not differ between healthy and clinically anxious participants, and (3, when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents.

  6. Loss aversion and 5HTT gene variants in adolescent anxiety.

    Science.gov (United States)

    Ernst, Monique; Plate, Rista C; Carlisi, Christina O; Gorodetsky, Elena; Goldman, David; Pine, Daniel S

    2014-04-01

    Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT) gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR) in healthy and clinically anxious adolescents. Findings show that loss aversion (1) does manifest in adolescents, (2) does not differ between healthy and clinically anxious participants, and (3), when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. 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.

  8. A global evolutionary and metabolic analysis of human obesity gene risk variants.

    Science.gov (United States)

    Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

    2017-09-05

    It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

  9. A variant in the fat mass and obesity-associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) do not influence dietary intake

    DEFF Research Database (Denmark)

    Hasselbalch, Ann L; Angquist, Lars; Christiansen, Lene

    2010-01-01

    We investigated the role of the fat mass and obesity associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) in modulating habitual intake of total energy and macronutrients, glycemic index, glycemic load, dietary energy density, and energy from 20 food groups in adults...

  10. Genetic predisposition to ischaemic stroke byRAGEandHMGB1gene variants in Chinese Han population.

    Science.gov (United States)

    Li, You; Zhu, Jing; Chen, Linfa; Hu, Weidong; Wang, Mengxu; Li, Shengnan; Gu, Xuefeng; Tao, Hua; Zhao, Bin; Ma, Guoda; Li, Keshen

    2017-11-21

    Emerging evidence suggests that the multiligand receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 protein (HMGB1) contribute to the pathophysiology of ischaemic stroke (IS). The present study aimed to investigate the association of RAGE and HMGB1 variants with the risk of IS. A total of 1,034 patients and 1,015 age- and sex-matched healthy controls were genotyped to detect five genetic variants of the RAGE gene and four genetic variants of the HMGB1 gene using the Multiplex SNaPshot assay. We found that the rs2070600 variant of RAGE was associated with an increased risk of IS (OR = 1.19, 95% CI: 1.02-1.38, P = 0.043), whereas the rs2249825 variant of HMGB1 was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041). Further stratification by IS subtypes revealed that the presence of the TT genotype of the RAGE rs2070600 variant confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.036). Moreover, patients with the variant T allele of the RAGE rs2070600 variant presented with reduced serum soluble RAGE production. Patients carrying the variant G allele of the HMGB1 rs2249825 variant exhibited significantly lower infarct volumes than those with the major CC genotype. These clues may help in the development of optimal personalized therapeutic approaches for IS patients.

  11. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

    Science.gov (United States)

    Kasahara, Takaoki; Ishiwata, Mizuho; Kakiuchi, Chihiro; Fuke, Satoshi; Iwata, Nakao; Ozaki, Norio; Kunugi, Hiroshi; Minabe, Yoshio; Nakamura, Kazuhiko; Iwata, Yasuhide; Fujii, Kumiko; Kanba, Shigenobu; Ujike, Hiroshi; Kusumi, Ichiro; Kataoka, Muneko; Matoba, Nana; Takata, Atsushi; Iwamoto, Kazuya; Yoshikawa, Takeo; Kato, Tadafumi

    2017-08-01

    Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease. © 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

  12. Identification of variants of the SPINK1 gene and their association with pancreatitis in Miniature Schnauzers.

    Science.gov (United States)

    Bishop, Micah A; Xenoulis, Panagiotis G; Levinski, Melinda D; Suchodolski, Jan S; Steiner, Jörg M

    2010-05-01

    To evaluate the serine protease inhibitor, Kazal type 1 (SPINK1) gene for variants and to determine their possible association with pancreatitis in Miniature Schnauzers. 39 Miniature Schnauzers with pancreatitis, 25 healthy Miniature Schnauzers, and 23 healthy dogs of other breeds. The entire canine SPINK1 gene with its intron-exon boundaries was initially sequenced in 22 Miniature Schnauzers. Then, 2 regions of the gene were sequenced in 65 additional canine DNA samples at the locations of variants identified in the initial sequencing of the entire SPINK1 gene. Analysis of the SPINK1 gene in Miniature Schnauzers revealed 3 closely associated variants in healthy Miniature Schnauzers and Miniature Schnauzers with pancreatitis. These variants consisted of 2 missense mutations in the second exon (N20K and N25T) and a poly T insertion in the third intron that was near the boundary of exon 3 (IVS3+26-27ins(T)33-39,15_61dup11). Pancreatitis was significantly associated with homozygous alleles for these 3 variants in Miniature Schnauzers. In healthy dogs of other breeds, only the 2 exon variants were identified. Variants of the SPINK1 gene may be associated with the development of pancreatitis in Miniature Schnauzers.

  13. Human aldehyde dehydrogenase genes: alternatively spliced transcriptional variants and their suggested nomenclature.

    Science.gov (United States)

    Black, William J; Stagos, Dimitrios; Marchitti, Satori A; Nebert, Daniel W; Tipton, Keith F; Bairoch, Amos; Vasiliou, Vasilis

    2009-11-01

    The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g. Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimer's disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes. Data-mining methods were used to retrieve all human ALDH sequences. Alternatively spliced transcriptional variants were determined based on (i) criteria for sequence integrity and genomic alignment; (ii) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and (iii) if available, empirical evidence of variants from the literature. Alternatively spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. To avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein. In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily.

  14. Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

    DEFF Research Database (Denmark)

    Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed

    2012-01-01

    ) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short...

  15. Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density.

    NARCIS (Netherlands)

    Thorleifsson, G.; Holm, H.; Edvardsson, V.; Walters, G.B.; Styrkarsdottir, U.; Gudbjartsson, D.F.; Sulem, P.; Halldorsson, B.V.; Vegt, F. de; D'Ancona, F.C.H.; Heijer, M. den; Franzson, L.; Christiansen, C.; Alexandersen, P.; Rafnar, T.; Kristjansson, K.; Sigurdsson, G.; Kiemeney, L.A.L.M.; Bodvarsson, M.; Indridason, O.S.; Palsson, R.; Kong, A.; Thorsteinsdottir, U.; Stefansson, K.

    2009-01-01

    Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate

  16. A systematic survey of loss-of-function variants in human protein-coding genes

    NARCIS (Netherlands)

    MacArthur, D.G.; Balasubramanian, S.; Frankish, A.; Huang, N.; Morris, J.; Walter, K.; Jostins, L.; Habegger, L.; Pickrell, J.K.; Montgomery, S.B.; Albers, C.A.; Zhang, Z.D.; Conrad, D.F.; Lunter, G.; Zheng, H.; Ayub, Q.; DePristo, M.A.; Banks, E.; Hu, M.; Handsaker, R.E.; Rosenfeld, J.A.; Fromer, M.; Jin, M.; Mu, X.J.; Khurana, E.; Ye, K.; Kay, M.; Saunders, G.I.; Suner, M.M.; Hunt, T.; Barnes, I.H.; Amid, C.; Carvalho-Silva, D.R.; Bignell, A.H.; Snow, C.; Yngvadottir, B.; Bumpstead, S.; Cooper, D.N.; Xue, Y.; Romero, I.G.; Genomes Project, C.; Wang, J; Li, Y.; Gibbs, R.A.; McCarroll, S.A.; Dermitzakis, E.T.; Pritchard, J.K.; Barrett, J.C.; Harrow, J.; Hurles, M.E.; Gerstein, M.B.; Tyler-Smith, C.

    2012-01-01

    Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to

  17. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

    NARCIS (Netherlands)

    Hendricks, Audrey E.; Bochukova, Elena G.; Marenne, Gaëlle; Keogh, Julia M.; Atanassova, Neli; Bounds, Rebecca; Wheeler, Eleanor; Mistry, Vanisha; Henning, Elana; Körner, Antje; Muddyman, Dawn; McCarthy, Shane; Hinney, Anke; Hebebrand, Johannes; Scott, Robert A.; Langenberg, Claudia; Wareham, Nick J.; Surendran, Praveen; Howson, Joanna M M; Butterworth, Adam S.; Danesh, John; Nordestgaard, Børge G.; Nielsen, Sune F.; Afzal, Shoaib; Papadia, Sofia; Ashford, Sofie; Garg, Sumedha; Millhauser, Glenn L.; Palomino, Rafael I.; Kwasniewska, Alexandra; Tachmazidou, Ioanna; O'Rahilly, Stephen; Zeggini, Eleftheria; Barroso, Inês; Farooqi, I. Sadaf; Benzeval, Michaela; Burton, Jonathan; Buck, Nicholas; Jäckle, Annette; Kumari, Meena; Laurie, Heather; Lynn, Peter; Pudney, Stephen; Rabe, Birgitta; Wolke, Dieter; Overvad, Kim; Tjønneland, Anne; Clavel-Chapelon, Francoise; Kaaks, Rudolf; Boeing, Heiner; Trichopoulou, Antonia; Ferrari, Pietro; Palli, Domenico; Krogha, Vittorio; Panico, Salvatore; Tuminoa, Rosario; Matullo, Giuseppe; Boer, Jolanda Ma; Van Der Schouw, Yvonne; Weiderpass, Elisabete; Quiros, J. Ramon; Sánchez, María José; Navarro, Carmen; Moreno-Iribas, Conchi; Arriola, Larraitz; Melander, Olle; Wennberg, Patrik; Key, Timothy J.; Riboli, Elio; Al-Turki, Saeed; Anderson, Carl A; Anney, Richard; Antony, Dinu; Soler Artigas, María; Ayub, Muhammad; Bala, Senduran; Barrett, Jeffrey C; Beales, Phil; Bentham, Jamie; Bhattacharyaa, Shoumo; Birney, Ewan; Blackwooda, Douglas; Bobrow, Martin; Bolton, Patrick F.; Boustred, Chris; Breen, Gerome; Calissanoa, Mattia; Carss, Keren; Charlton, Ruth; Chatterjee, Krishna; Chen, Lu; Ciampia, Antonio; Cirak, Sebahattin; Clapham, Peter; Clement, Gail; Coates, Guy; Coccaa, Massimiliano; Collier, David A; Cosgrove, Catherine; Coxa, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Danecek, Petr; Day, Ian N M; Day-Williams, Aaron G; Dominiczak, Anna; Down, Thomas; Du, Yuanping; Dunham, Ian; Durbin, Richard; Edkins, Sarah; Ekong, Rosemary; Ellis, Peter; Evansa, David M.; FitzPatrick, David R.; Flicek, Paul; Floyd, James S.; Foley, A. Reghan; Franklin, Christopher S.; Futema, Marta; Gallagher, Louise; Gaunt, Tom R.; Geihs, Matthias; Geschwind, Daniel H.; Greenwood, Celia M.T.; Griffin, Heather; Grozeva, Detelina; Guo, Xiaosen; Guo, Xueqin; Gurling, Hugh; Hart, Deborah J.; Holmans, Peter A; Howie, Bryan; Huang, Jie; Huang, Liren; Hubbard, Tim; Humphries, Steve E.; Hurles, Matthew E.; Hysi, Pirro G.; Iotchkova, Valentina; Jackson, David K.; Jamshidi, Yalda; Joyce, Chris; Karczewski, Konrad J.; Kaye, Jane; Keane, Thomas; Kemp, John P.; Kennedy, Karen; Kent, Alastair; Khawaja, Farrah; Van Kogelenberg, Margriet; Kolb-Kokocinski, Anja; Lachance, Genevieve; Langford, Cordelia; Lawson, Daniel; Lee, Irene; Lek, Monkol; Li, Rui; Li, Yingrui; Liang, Jieqin; Lin, Hong; Liu, Ryan; Lönnqvist, Jouko; Lopes, Luis R.; Lopes, Margarida; MacArthur, Daniel G.; Mangino, Massimo; Marchini, Jonathan; Maslen, John; Mathieson, Iain; McGuffin, Peter; McIntosh, Andrew M.; McKechanie, Andrew G.; McQuillin, Andrew; Memari, Yasin; Metrustry, Sarah; Migone, Nicola; Min, Josine L.; Mitchison, Hannah M; Moayyeri, Alireza; Morris, Andrew D.; Morris, James; Muntoni, Francesco; Northstone, Kate; O'Donovan, Michael C.; Onoufriadis, Alexandros; Oualkacha, Karim; Owen, Michael J; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Payne, Stewart J.; Perry, John R. B.; Pietilainen, Olli; Plagnol, Vincent; Pollitt, Rebecca C.; Porteous, David J.; Povey, Sue; Quail, Michael A.; Quaye, Lydia; Raymond, F. Lucy; Rehnström, Karola; Richards, J Brent; Ridout, Cheryl K.; Ring, Susan M.; Ritchie, Graham R.S.; Roberts, Nicola; Robinson, Rachel L.; Savage, David B.; Scambler, Peter; Schiffels, Stephan; Schmidts, Miriam; Schoenmakers, Nadia; Scott, Richard H.; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shaw, Adam; Shihab, Hashem A.; Shin, So Youn; Skuse, David; Small, Kerrin S; Smee, Carol; Smith, Blair H.; Davey Smith, George; Soranzo, Nicole; Southam, Lorraine; Spasic-Boskovic, Olivera; Spector, Timothy D; St Clair, David; St Pourcain, Beate; Stalker, Jim; Stevens, Elizabeth; Sun, Jianping; Surdulescu, Gabriela L; Suvisaari, Jaana; Syrris, Petros; Taylor, Rohan; Tian, Jing; Timpson, Nicholas J.; Tobin, Martin D; Valdes, Ana M.; Vandersteen, Anthony M.; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walter, Klaudia; Walters, James T.R.; Wang, Guangbiao; Wang, Jun; Wang, Nai-Yu; Ward, Kirsten; Whyte, Tamieka; Williams, Hywel J.; Williamson, Kathleen A.; Wilson, Crispian; Wilson, Scott G.; Wong, Kim; Xu, Changjiang; Yang, Jian; Zhang, Feng; Zhang, Pingbo; Zheng, Hou Feng

    2017-01-01

    Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS,

  18. Mouse ribosomal RNA genes contain multiple differentially regulated variants.

    Directory of Open Access Journals (Sweden)

    Hung Tseng

    2008-03-01

    Full Text Available Previous cytogenetic studies suggest that various rDNA chromosomal loci are not equally active in different cell types. Consistent with this variability, rDNA polymorphism is well documented in human and mouse. However, attempts to identify molecularly rDNA variant types, which are regulated individually (i.e., independent of other rDNA variants and tissue-specifically, have not been successful. We report here the molecular cloning and characterization of seven mouse rDNA variants (v-rDNA. The identification of these v-rDNAs was based on restriction fragment length polymorphisms (RFLPs, which are conserved among individuals and mouse strains. The total copy number of the identified variants is less than 100 and the copy number of each individual variant ranges from 4 to 15. Sequence analysis of the cloned v-rDNA identified variant-specific single nucleotide polymorphisms (SNPs in the transcribed region. These SNPs were used to develop a set of variant-specific PCR assays, which permitted analysis of the v-rDNAs' expression profiles in various tissues. These profiles show that three v-rDNAs are expressed in all tissues (constitutively active, two are expressed in some tissues (selectively active, and two are not expressed (silent. These expression profiles were observed in six individuals from three mouse strains, suggesting the pattern is not randomly determined. Thus, the mouse rDNA array likely consists of genetically distinct variants, and some are regulated tissue-specifically. Our results provide the first molecular evidence for cell-type-specific regulation of a subset of rDNA.

  19. Genetic variant in the IGF2BP2 gene may interact with fetal malnutrition to affect glucose metabolism

    NARCIS (Netherlands)

    van Hoek, Mandy; Langendonk, Janneke G.; de Rooij, Susanne R.; Sijbrands, Eric J. G.; Roseboom, Tessa J.

    2009-01-01

    OBJECTIVE: Fetal malnutrition may predispose to type 2 diabetes through gene programming and developmental changes. Previous studies showed that these effects may be modulated by genetic variation. Genome-wide association studies discovered and replicated a number of type 2 diabetes-associated

  20. Identification of rare and frequent variants of the CASR gene by high-resolution melting

    DEFF Research Database (Denmark)

    Nissen, Peter H.; Christensen, Signe E; Ladefoged, Søren

    2011-01-01

    BACKGROUND: Calcium metabolic disorders like familial hypocalciuric hypercalcemia (FHH) and autosomal dominant familial isolated hypoparathyroidism (FIH) can be caused by rare variants of the calcium sensing receptor gene (CASR). Molecular genetic screening of the CASR is often based on DNA...

  1. Male-and female-specific variants of doublesex gene products have ...

    Indian Academy of Sciences (India)

    specific variants of doublesex gene products have different roles to play towards regulation of Sex combs reduced expression and sex comb morphogenesis in Drosophila. Thangjam Ranjita Devi B V Shyamala. Brief communication Volume 38 ...

  2. Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice

    International Nuclear Information System (INIS)

    Selden, R.F.; Wagner, T.E.; Blethen, S.; Yun, J.S.; Rowe, M.E.; Goodman, H.M.

    1988-01-01

    The nucleotide sequence of the human growth hormone variant gene, one of the five members of the growth hormone gene family, predicts that it encodes a growth hormone-like protein. As a first step in determining whether this gene is functional in humans, the authors have expressed a mouse methallothionein I/human growth hormone variant fusion gene in mouse L cells and in transgenic mice. The growth hormone variant protein expressed in transiently transfected L cells is distinct from growth hormone itself with respect to reactivity with anti-growth hormone monoclonal antibodies, behavior during column chromatography, and isoelectric point. Transgenic mice expressing the growth hormone variant protein are 1.4- to 1.9-fold larger than nontransgenic controls, suggesting that the protein has growth-promoting properties

  3. Analysis of common SHOX gene sequence variants and ∼4.9-kb ...

    Indian Academy of Sciences (India)

    [Solc R., Hirschfeldova K., Kebrdlova V. and Baxova A. 2014 Analysis of common SHOX gene sequence variants and ∼4.9-kb PAR1 deletion in ISS patients. J. Genet. 93, 505–508]. Introduction. Defects of the SHOX gene (short stature homeobox- containing gene), localized in the pseudoautosomal region 1. (PAR1) have ...

  4. Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

    Science.gov (United States)

    Pang, Shirley Yin-Yu; Hsu, Jacob Shujui; Teo, Kay-Cheong; Li, Yan; Kung, Michelle H W; Cheah, Kathryn S E; Chan, Danny; Cheung, Kenneth M C; Li, Miaoxin; Sham, Pak-Chung; Ho, Shu-Leong

    2017-10-01

    Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. MEGA-V: detection of variant gene sets in patient cohorts.

    Science.gov (United States)

    Gambardella, Gennaro; Cereda, Matteo; Benedetti, Lorena; Ciccarelli, Francesca D

    2017-04-15

    : Detecting significant associations between genetic variants and disease may prove particularly challenging when the variants are rare in the population and/or act together with other variants to cause the disease. We have developed a statistical framework named Mutation Enrichment Gene set Analysis of Variants (MEGA-V) that specifically detects the enrichments of genetic alterations within a process in a cohort of interest. By focusing on the mutations of several genes contributing to the same function rather than on those affecting a single gene, MEGA-V increases the power to detect statistically significant associations. MEGA-V is available at https://github.com/ciccalab/MEGA. francesca.ciccarelli@kcl.ac.uk. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  6. Resequencing array for gene variant detection in malignant hyperthermia and butyrylcholinestherase deficiency.

    Science.gov (United States)

    Levano, Soledad; Gonzalez, Asensio; Singer, Martine; Demougin, Philippe; Rüffert, Henrik; Urwyler, Albert; Girard, Thierry

    2017-05-01

    Malignant hyperthermia (MH) and butyrylcholinestherase (BCHE) deficiency are two relevant pharmacogenetic disorders in anesthetic practice linked with sequence variants, the former in the RyR1 and CACNA1S genes, the latter in the BCHE gene. Genotyping for known pathogenic variants in these genes is useful to help identify susceptible individuals, and others may exist but remain unknown, because full-length sequence of these genes is, in general, not investigated. To facilitate this task, we developed a resequencing DNA array, the perioperative patient safety (POPS) array, to be able to screen the entire coding sequences of the RyR1, CACNA1S and BCHE genes. MH-susceptible individuals (n = 121) identified with the in vitro contracture test, the standard diagnostic tool for MH susceptibility, were genotyped with the arrays. Compared with capillary sequencing, call rates with the arrays could achieve 100% at maximal sensitivity, although to reduce false positive rates, sensitivity was adjusted to 0.85, 0.87 and 0.66 for RyR1, CACNA1S and BCHE respectively, with overall base call specificity exceeding 99%. Detection of 29 predetermined RyR1 variants in 44 individuals was successful in 97% of the cases, among them all 16 variants of established diagnostic value. In a trial application of the arrays, 21 MH-susceptible subjects with no known RyR1 or CACNA1S variants were screened, resulting in the discovery of new variants, all confirmed by capillary sequencing. In conclusion, arrays offer an efficient high-throughput alternative for diagnostic genotyping of candidate genes affecting MH susceptibility, BCHE deficiency and other neuromuscular disorders, simultaneously enabling a comprehensive search for rare variants in these genes. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene.

    Science.gov (United States)

    Drost, Mark; Koppejan, Hester; de Wind, Niels

    2013-11-01

    Lynch syndrome (LS) is a common cancer predisposition caused by an inactivating mutation in one of four DNA mismatch repair (MMR) genes. Frequently a variant of uncertain significance (VUS), rather than an obviously pathogenic mutation, is identified in one of these genes. The inability to define pathogenicity of such variants precludes targeted healthcare. Here, we have modified a cell-free assay to test VUS in the MMR gene PMS2 for functional activity. We have analyzed nearly all VUS in PMS2 found thus far and describe loss of MMR activity for five, suggesting the applicability of the assay for diagnosis of LS. © 2013 WILEY PERIODICALS, INC.

  8. ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population

    NARCIS (Netherlands)

    M.N. Niemeijer (Maartje); M.E. van den Berg (Marten); J.W. Deckers (Jaap); A.L.H.J. Aarnoudse (Albert-Jan); A. Hofman (Albert); O.H. Franco (Oscar); A.G. Uitterlinden (André); P.R. Rijnbeek (Peter); M. Eijgelsheim (Mark); B.H.Ch. Stricker (Bruno)

    2015-01-01

    textabstractObjective: The ATP-binding cassette B1 (ABCB1) gene encodes P-glycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. We aimed to investigate the interaction between variants within the ABCB1 gene and digoxin on the risk of sudden cardiac death

  9. Genome-wide identification of structural variants in genes encoding drug targets

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Dahmcke, Christina Mackeprang

    2012-01-01

    The objective of the present study was to identify structural variants of drug target-encoding genes on a genome-wide scale. We also aimed at identifying drugs that are potentially amenable for individualization of treatments based on knowledge about structural variation in the genes encoding...

  10. 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

  11. Determination of variants in the 3'-region of the Tyrosinase gene requires locus specific amplification.

    NARCIS (Netherlands)

    Chaki, M.; Mukhopadhyay, A.; Ray, K.

    2005-01-01

    Mutations in the Tyrosinase gene (TYR, 11q14-q21) cause oculocutaneous albinism type 1 (OCA1). The 3'-region of the TYR shows 98.55% sequence identity with a pseudogene, known as Tyrosinase-Like Gene (TYRL, 11p11.2-cen). A large number of publicly available nucleotide variants of TYR in this region

  12. The promoter for a variant surface glycoprotein gene expression site in Trypanosoma brucei

    NARCIS (Netherlands)

    Zomerdijk, J. C.; Ouellette, M.; ten Asbroek, A. L.; Kieft, R.; Bommer, A. M.; Clayton, C. E.; Borst, P.

    1990-01-01

    The variant-specific surface glycoprotein (VSG) gene 221 of Trypanosoma brucei is transcribed as part of a 60 kb expression site (ES). We have identified the promoter controlling this multigene transcription unit by the use of 221 chromosome-enriched DNA libraries and VSG gene 221 expression site

  13. Genetic variants in hormone-related genes and risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Tess Clendenen

    Full Text Available Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

  14. New unstable variants of green fluorescent protein for studies of transient gene expression in bacteria

    DEFF Research Database (Denmark)

    Andersen, Jens Bo; Sternberg, Claus; Poulsen, Lars K.

    1998-01-01

    Use of the green fluorescent protein (Gfp) from the jellyfish Aequorea victoria ia is a powerful method for nondestructive in situ monitoring, since expression of green fluorescence does not require any substrate addition. To expand the use of Gfp as a reporter protein, new variants have been con...... and Pseudomonas putida. The new Gfp variants should be useful for in situ studies of temporal gene expression....

  15. Common Variants within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage

    Science.gov (United States)

    Anderson, Christopher D.; Biffi, Alessandro; Nalls, Michael A.; Devan, William J.; Schwab, Kristin; Ayres, Alison M.; Valant, Valerie; Ross, Owen A.; Rost, Natalia S.; Saxena, Richa; Viswanathan, Anand; Worrall, Bradford B.; Brott, Thomas G.; Goldstein, Joshua N.; Brown, Devin; Broderick, Joseph P.; Norrving, Bo; Greenberg, Steven M.; Silliman, Scott L.; Hansen, Björn M.; Tirschwell, David L.; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Selim, Magdy; Roquer, Jaume; Montaner, Joan; Singleton, Andrew B.; Kidwell, Chelsea S.; Woo, Daniel; Furie, Karen L.; Meschia, James F.; Rosand, Jonathan

    2013-01-01

    Background and Purpose Prior studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods This association study employed a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis (GSEA) was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing GSEA were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio (OR)=1.17, p=0.008) and Complex I (OR=1.06, p=0.050). Among IS subtypes, small vessel (SV) stroke showed association with OXPHOS (OR=1.16, p=0.007), Complex I (OR=1.13, p=0.027) and Complex IV (OR 1.14, p=0.018). To further explore this SV association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and Complex IV (OR=1.08, p=0.008). Conclusions This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for SV stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. PMID:23362085

  16. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder.

    Science.gov (United States)

    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 vs. 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 variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the "common variant-common disease" hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations ( Table 2 ). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations ( Table 2 ). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in autism

  17. Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome.

    Science.gov (United States)

    Liu, Qing; Thompson, Bryony A; Ward, Robyn L; Hesson, Luke B; Sloane, Mathew A

    2016-05-01

    Lynch syndrome is the most common familial cancer condition that mainly predisposes to tumors of the colon and endometrium. Cancer susceptibility is caused by the autosomal dominant inheritance of a loss-of-function mutation or epimutation in one of the DNA mismatch repair (MMR) genes. Cancer risk assessment is often possible with nonsynonymous coding region mutations, but in many cases patients present with DNA sequence changes within noncoding regions, including the promoters, of MMR genes. The pathogenic role of promoter variants, and hence clinical significance, is unclear and this hinders the clinical management of carriers. In this review, we provide an overview of the classification of MMR gene variants, outline the laboratory assays and online resources that can be used to assess the causality of promoter variants in Lynch syndrome, and highlight some of the practical challenges of demonstrating the pathogenicity of these variants. In conclusion, we propose a guide that could be integrated into the current InSiGHT classification scheme to help determine if a MMR gene promoter variant is pathogenic. © 2016 WILEY PERIODICALS, INC.

  18. Association between neuromedin U gene variants and overweight and obesity

    DEFF Research Database (Denmark)

    Hainerová, Irena; Torekov, Signe S; Ek, Jakob

    2006-01-01

    Neuromedin U (NMU) is an anorexic neuropeptide expressed in the hypothalamus. Mice lacking the NmU gene are hyperphagic and obese, whereas mice overexpressing Nmu are hypophagic and lean.......Neuromedin U (NMU) is an anorexic neuropeptide expressed in the hypothalamus. Mice lacking the NmU gene are hyperphagic and obese, whereas mice overexpressing Nmu are hypophagic and lean....

  19. Association analysis of PRKAG3 gene variants with carcass and ...

    African Journals Online (AJOL)

    Yomi

    2012-01-26

    Jan 26, 2012 ... study could add new evidence that PRKAG3 is an important candidate gene to be used for selection of meat traits in the beef cattle industry. .... detected in four Bos taurus cattle breeds; the bovine. PRKAG3 gene described in that study might be involved in muscle-related genetic diseases or meat quality ...

  20. 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 ...

  1. Haplotype combination of the caprine PC1 gene sequence variants ...

    Indian Academy of Sciences (India)

    Mutations in PC1 gene are related to obesity-related traits which may influence the performance of animals, and therefore it has been the focus of this study. In this study, polymorphisms of the caprine PC1 gene were detected in. 407 individuals from three breeds by PCR-SSCP and DNA sequencing methods. The results ...

  2. Association of apolipoprotein A5 gene variants with metabolic syndrome in Tunisian population.

    Science.gov (United States)

    Kefi, Rym; Hechmi, Meriem; Dallali, Hamza; Elouej, Sahar; Jmel, Haifa; Halima, Yossra Ben; Nagara, Majdi; Chargui, Mariem; Fadhel, Sihem Ben; Romdhane, Safa; Kamoun, Ines; Turki, Zinet; Abid, Abdelmajid; Bahri, Sonia; Bahlous, Afaf; Gomis, Ramon; Baraket, Abdelhamid; Grigorescu, Florin; Normand, Christophe; Jamoussi, Henda; Abdelhak, Sonia

    2017-07-01

    APOA5 has been linked to metabolic syndrome (MetS) or its traits in several populations. In North Africa, only the Moroccan population was investigated. Our aim is to assess the association between APOA5 gene polymorphisms with the susceptibility to MetS and its components in the Tunisian population. A total of 594 participants from the Tunisian population were genotyped for two polymorphisms rs3135506 and rs651821 located in APOA5 gene using KASPar technology. Statistical analyses were performed using R software. The SNP rs651821 increased the risk of MetS under the dominant model (OR=1.91 [1.17-3.12], P=0.008) whereas the variant rs3135506 was not associated with MetS. After stratification of the cohort following the sex, only the variant rs651821 showed a significant association with MetS among the women group. The influence of the geographic origin of the studied population on the genotype distribution of APOA5 variants showed that the variant rs651821 was significantly associated with MetS only for the Northern population. The association analyses of the variants rs651821 and rs3135506 with different quantitative traits of MetS showed a significant association only between the variant rs3135506 and triglycerides levels. This is the first study reporting the association of APOA5 gene variants with MetS in Tunisia. Our study emphasizes the role of APOA5 variants in the regulation of the triglycerides blood levels. Further studies are needed to confirm the clinical relevance of these associations and to better understand the physiopathology of the MetS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. An abundance of rare functional variants in 202 drug target genes sequenced in 14.002 people

    DEFF Research Database (Denmark)

    Nelson, Matthew R.; Wegmann, Daniel; Ehm, Margaret G.

    2012-01-01

    Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases)...

  4. Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity

    DEFF Research Database (Denmark)

    L. Santos, José; De la Cruz, Rolando; Holst, Claus

    2011-01-01

    receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets.......The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3...

  5. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Anthony R Torres

    2016-10-01

    Full Text Available 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 variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the common variant—common disease hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics.Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14bp-indel frequencies are significantly increased by more than 5% over control populations (Table2. The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2. Three activating KIR genes: 3DS1, 2DS1 and 2DS2 have increased frequencies of 15%, 22% and 14% in autism populations, respectively. There is a 6% increase in total activating KIR

  6. Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants

    DEFF Research Database (Denmark)

    Shi, Min; Christensen, Kaare; Weinberg, Clarice R

    2007-01-01

    Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings......, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal...... development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants...

  7. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

    DEFF Research Database (Denmark)

    Hendricks, Audrey E; Bochukova, Elena G; Marenne, Gaëlle

    2017-01-01

    Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS.......1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting...... the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do...

  8. Challenges in assessing pathogenicity based on frequency of variants in mismatch repair genes: an extreme case of a MSH2 variant and a meta-analysis.

    Science.gov (United States)

    Woo, Hye In; Woo, Young Min; Kim, Sollip; Lee, Seung-Tae; Ki, Chang-Seok; Kim, Jong-Won

    2014-08-10

    The clinical interpretation of variants in mismatch repair (MMR) genes associated with Lynch syndrome can be confusing when the functional nature of the variant is not clearly defined. We report an extreme case where a polymorphism in the MSH2 gene which had a low minor allele frequency, was misclassified as a mutation based on low evidential methods in the database and previous publications. We expanded this experience to perform a systematic meta-analysis in order to investigate other variants that have potentially been misclassified. Our results suggested that the interpretation of pathogenicity should be more cautious and emphasized the need for solid validation through multiple analyses including functional analysis for variants in MMR genes. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Association between genetic variants of the clock gene and obesity and sleep duration.

    Science.gov (United States)

    Valladares, Macarena; Obregón, Ana María; Chaput, Jean-Philippe

    2015-12-01

    Obesity is a multifactorial disease caused by the interaction of genetic and environmental factors related to lifestyle aspects. It has been shown that reduced sleep is associated with increased body mass index (BMI). Circadian Locomotor Output Cycles Kaput (CLOCK) gene variants have also been associated with obesity. The objective of this mini-review was to discuss the available literature related to CLOCK gene variants associated with adiposity and sleep duration in humans. In total, 16 articles complied with the terms of the search that reported CLOCK variants associated with sleep duration, energy intake, and BMI. Overall, six CLOCK single nucleotide polymorphisms (SNPs) have been associated with sleep duration, and three variants have been associated with energy intake variables. Overall, the most studied area has been the association of CLOCK gene with obesity; close to eight common variants have been associated with obesity. The most studied CLOCK SNP in different populations is rs1801260, and most of these populations correspond to European populations. Collectively, identifying at risk CLOCK genotypes is a new area of research that may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations.

  10. Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat.

    Directory of Open Access Journals (Sweden)

    Keijiro Mizukami

    Full Text Available Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats.

  11. Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

    Science.gov (United States)

    Mitropoulos, Konstantinos; Merkouri Papadima, Eleni; Xiromerisiou, Georgia; Balasopoulou, Angeliki; Charalampidou, Kyriaki; Galani, Vasiliki; Zafeiri, Krystallia-Vassiliki; Dardiotis, Efthymios; Ralli, Styliani; Deretzi, Georgia; John, Anne; Kydonopoulou, Kyriaki; Papadopoulou, Elpida; di Pardo, Alba; Akcimen, Fulya; Loizedda, Annalisa; Dobričić, Valerija; Novaković, Ivana; Kostić, Vladimir S; Mizzi, Clint; Peters, Brock A; Basak, Nazli; Orrù, Sandro; Kiskinis, Evangelos; Cooper, David N; Gerou, Spyridon; Drmanac, Radoje; Bartsakoulia, Marina; Tsermpini, Evangelia-Eirini; Hadjigeorgiou, Georgios M; Ali, Bassam R; Katsila, Theodora; Patrinos, George P

    2017-12-08

    Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

  12. [Variant fusion transcript in ALL children with E2A-PBX1 fusion gene positive].

    Science.gov (United States)

    Li, Zhi-Gang; Zhao, Wei; Wu, Min-Yuan; Hu, Ya-Mei

    2006-06-01

    The study was aimed to investigate the expression of E2A-PBX1 fusion gene in children with acute lymphoblastic leukemia (ALL). The primers located at different sites of E2A and PBX1 gene were used to screen for the fusion gene in 410 children with ALL, including 362 cases of B cell ALL and 48 cases of T cell ALL. The results showed that 17 children carried the fusion gene. The positive rate was 4.1%. Furthermore, all the positive cases expressed a variant type of fusion transcript. It resulted from different splicing of the 13th exon (159 bp) of E2A gene. Analyses with BLASTn indicated that the variant type of transcript retained the open reading frame. However, the loss of 53 amino acid residues which were located at the 2nd activation domain resulted in the partial deletion of the putative loop-helix (LH) structure as well as the complete deletion of the heptad leucine repeat. It is concluded that all the children with ALL positive for the E2A-PBX1 fusion gene express typical and variant fusion transcripts. The latter resulted from different splicing of the 13th exon (159 bp) of E2A gene. The loss of 53aa would lead to the partial deletion of the putative loop-helix (LH) structure as well as the complete deletion of the heptad leucine repeat.

  13. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis

    Czech Academy of Sciences Publication Activity Database

    Abdelmagid, N.; Bereczky-Veress, B.; Atanur, S.; Musilová, Alena; Zídek, Václav; Saba, L.; Warnecke, A.; Khademi, M.; Studahl, M.; Aurelius, E.; Hjalmarsson, A.; Garcia-Dias, A.; Denis, C. V.; Bergström, T.; Sköldenberg, B.; Kockum, I.; Aitman, T.; Hübner, N.; Olsson, T.; Pravenec, Michal; Diez, M.

    2016-01-01

    Roč. 11, č. 5 (2016), e0155832 E-ISSN 1932-6203 R&D Projects: GA MŠk(CZ) 7E10067; GA MŠk(CZ) LL1204 Institutional support: RVO:67985823 Keywords : Von Willebrand Factor gene * Herpes simplex encephalitis * rat * humans Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.806, year: 2016

  14. Lipoprotein lipase gene variants: Association with acute myocardial ...

    African Journals Online (AJOL)

    Background: Studies showed that lipid metabolism disorders are significant risk factors for myocardial infarction and coronary artery disease (CAD). Therefore, genes involved in lipid and lipoprotein metabolism pathways such as lipoprotein lipase (LPL), are proper candidates for susceptibility to CAD. Aim: To investigate the ...

  15. Haplotype combination of the caprine PC1 gene sequence variants ...

    Indian Academy of Sciences (India)

    Proprotein convertase 1 (PC1) is an endopeptidase involved in proteolytic processing of peptide hormone precursors in granules of the regulated secretory pathway of endocrine cells. Mutations in PC1 gene are related to obesity-related traits which may influence the performance of animals, and therefore it has been the ...

  16. The methylenetetrahydrofolate reductase gene variant (C677T) in ...

    African Journals Online (AJOL)

    This unreeled study aimed to examine the relationship between the genetic polymorphisms C677T in MTHFR gene and mapped this figure with other ethnic populations. The present study examined 70 Saudi females (30 mothers with DS children plus 40 healthy mothers who gave birth only to healthy children) for C677T ...

  17. Association of LXRA gene variants with carcass and meat quality ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-10-20

    Oct 20, 2008 ... 2Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100094, China. Accepted 28 July, 2008. LXRA is an important regulator of genes involved in lipid, fatty acid and glucose metabolism in liver, and adipose tissue as well as in skeletal muscle. In this study, we discovered and ...

  18. Association analysis of PRKAG3 gene variants with carcass and ...

    African Journals Online (AJOL)

    In this study, we detected four single nucleotide polymorphisms (SNPs) at the PRKAG3 gene (DQ082736) in 267 beef cattle. The SNP marker association analysis indicated that the SNP markers T2885C was significantly associated with tenderness trait. Animals with the TT genotype had lower Warner-Bratzler shear force ...

  19. Identification and characterization of the genes encoding the core histones and histone variants of Neurospora crassa.

    OpenAIRE

    Hays, Shan M; Swanson, Johanna; Selker, Eric U

    2002-01-01

    We have identified and characterized the complete complement of genes encoding the core histones of Neurospora crassa. In addition to the previously identified pair of genes that encode histones H3 and H4 (hH3 and hH4-1), we identified a second histone H4 gene (hH4-2), a divergently transcribed pair of genes that encode H2A and H2B (hH2A and hH2B), a homolog of the F/Z family of H2A variants (hH2Az), a homolog of the H3 variant CSE4 from Saccharomyces cerevisiae (hH3v), and a highly diverged ...

  20. An Association Between Epac-1 Gene Variants and Anxiety and Depression in Two Independent Samples

    NARCIS (Netherlands)

    Middeldorp, C.M.; Vink, J.M.; Hettema, J.M.; de Geus, E.J.C.; Kendler, K.; Willemsen, G.; Neale, M.C.; Boomsma, D.I.; Chen, X.

    2010-01-01

    Deficiency in signal transduction might play a role in the development of anxiety and depression, as suggested by a study on the involvement of the PKA-independent Epac pathway. We investigated the association between Epac-1 gene variants, also known as RapGEF-3, and measures of anxiety and

  1. The CYP7A1 gene rs3808607 variant is associated with ...

    African Journals Online (AJOL)

    The CYP7A1 gene rs3808607 variant is associated with susceptibility of tuberculosis in Moroccan population. Mounia Qrafli, Youssef Amar, Jamaleddine Bourkadi, Jouda Ben Amor, Ghali Iraki, Youssef Bakri, Saaîd Amzazi, Ouafae Lahlou, Fouad Seghrouchni, Rajae El Aouad, Khalid Sadki ...

  2. The prevalence of PAI-1 4G/5G gene variant in Serbian population

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available Introduction: Plasminogen activator inhibitor 1 (PAI-1 has a major role in inhibition of firinolysis and normal haemostasis. The presence of the PAI-1 4G/4G genotype leads to increased expression of PAI-1. High blood level of PAI-1 is associated with many diseases such as thrombosis, cerebral insult, myocardial infarction, pregnancy loss, preeclampsia, insulin resistance, type 2 diabetes, breast cancer and asthma. In this study, the prevalence of PAI-1 4G/5G gene variant was determined in healthy subjects from Serbian population. Methods: The study was carried out in a group of 210 healthy subjects (105 women and 105 men. The presence of PAI-1 4G/5G gene variant was detected by PCR-RFLP analysis. Results: The prevalence of PAI-1 4G/4G genotype was 34.76% and it was increased compared to PAI-1 5G/5G genotype (19.05%. The most frequent was PAI-1 4G/5G genotype (46.19%. Allelic frequency for 4G allele was higher (0.58 compared to 5G allele (0.42. Conclusions: The prevalence of PAI-1 4G/5G gene variant in Serbian population is similar to the neighboring populations. Results of this study represent the first data for Serbian population. This study could be useful for further research where the role of PAI-1 4G/5G gene variant will be assessed in the pathogenesis of many diseases.

  3. Haplotypes of bovine FoxO1 gene sequence variants and ...

    Indian Academy of Sciences (India)

    Haplotypes of bovine FoxO1 gene sequence variants and association with growth traits in Qinchuan cattle. YUJIA SUN1, JING XUE1, WENJIAO GUO1, MINGXUN LI1, YONGZHEN HUANG1, XIANYONG LAN1,. CHUZHAO LEI1, CHUNLEI ZHANG2 and HONG CHEN1∗. 1College of Animal Science and Technology, ...

  4. 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.

  5. A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis

    DEFF Research Database (Denmark)

    Mero, Inger-Lise; Lorentzen, Aslaug R; Ban, Maria

    2010-01-01

    A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We gen...

  6. OGG1, MYH and MTH1 gene variants identified in gastric cancer ...

    Indian Academy of Sciences (India)

    OGG1, MYH and MTH1 gene variants identified in gastric cancer patients exhibiting both 8-hydroxy-2 -deoxyguanosine accumulation and low inflammatory cell infiltration in their gastric mucosa. MASANORI GOTO1, KAZUYA SHINMURA1, HIDETAKA YAMADA1, TOSHIHIRO TSUNEYOSHI2 and HARUHIKO SUGIMURA1∗.

  7. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

    DEFF Research Database (Denmark)

    Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.

    2015-01-01

    contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among...... coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC....

  8. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

    Directory of Open Access Journals (Sweden)

    Esther Erdei

    Full Text Available A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR.Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia, or oral squamous cell carcinoma (SCCA were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption.Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70. The transforming growth factor beta-1 (TGFβ-1 -509 C/T polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79. The matrix metalloproteinase gene (MMP-1 variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53 compared to people with ancestral alleles.Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

  9. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

    Science.gov (United States)

    Erdei, Esther; Luo, Li; Sheng, Huiping; Maestas, Erika; White, Kirsten A M; Mackey, Amanda; Dong, Yan; Berwick, Marianne; Morse, Douglas E

    2013-01-01

    A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR). Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia), or oral squamous cell carcinoma (SCCA) were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs) were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption. Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α) -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70). The transforming growth factor beta-1 (TGFβ-1 -509 C/T) polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79). The matrix metalloproteinase gene (MMP-1) variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53) compared to people with ancestral alleles. Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

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

    Science.gov (United States)

    Robak, Laurie A; Jansen, Iris E; van Rooij, Jeroen; Uitterlinden, André G; Kraaij, Robert; Jankovic, Joseph; Heutink, Peter; Shulman, Joshua M

    2017-12-01

    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 sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Angiotensinogen gene variants in a Pakistani hypertensive population of Punjab.

    Science.gov (United States)

    Alvi, Farrakh M; Hasnain, Shahida

    2008-03-01

    The renin-angiotensin-aldosterone system (RAAS) plays a key role in blood pressure (BP) regulation. Among the components of the RAAS, the gene for the angiotensinogen (AGT) has been extensively studied. Several studies in different populations link Threonine instead of methionine at position 235 (M235T) and Methinine instead of threonine at position 174 (T174M) polymorphisms with essential hypertension. We were unable to study these polymorphisms in the Punjab population of Pakistan through routine Restriction Fragment Length Polymorphism (RFLP) method. Considering the importance of this region we decided to further investigate the 300 bp region harbouring these two single nucleotide polymorphisms. Samples were derived from a larger study group. Polymerase chain reaction amplified fragments were subjected to either RFLP or Single Strand Conformation Polymorphism. Single stranded DNA showing mobility shift on denaturing gel were sequenced. Sequencing confirmed the presence of M235T and T174M polymorphisms in the local population. In addition to these polymorphisms one additional base was found at an identical position in two of the samples. We found a substitution of G with C just adjacent to T174M polymorphism in all seven of our samples studied. We report two additional bases and one substitution in the angiotensinogen gene of Punjab population. We also suggest that SsmI can be used for the investigation of T174M polymorphism.

  12. Identification and characterization of two functional variants in the human longevity gene FOXO3

    DEFF Research Database (Denmark)

    Flachsbart, Friederike; Dose, Janina; Gentschew, Liljana

    2017-01-01

    FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs......, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays...

  13. Comprehensive analysis of DNA repair gene variants and risk of meningioma

    DEFF Research Database (Denmark)

    Bethke, L.; Murray, A.; Webb, E.

    2008-01-01

    of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility. METHODS: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA......(trend) = 8.95 x 10(-6); P = .009 after adjusting for multiple testing). CONCLUSIONS: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial...

  14. Gene-based segregation method for identifying rare variants in family-based sequencing studies.

    Science.gov (United States)

    Qiao, Dandi; Lange, Christoph; Laird, Nan M; Won, Sungho; Hersh, Craig P; Morrow, Jarrett; Hobbs, Brian D; Lutz, Sharon M; Ruczinski, Ingo; Beaty, Terri H; Silverman, Edwin K; Cho, Michael H

    2017-05-01

    Whole-exome sequencing using family data has identified rare coding variants in Mendelian diseases or complex diseases with Mendelian subtypes, using filters based on variant novelty, functionality, and segregation with the phenotype within families. However, formal statistical approaches are limited. We propose a gene-based segregation test (GESE) that quantifies the uncertainty of the filtering approach. It is constructed using the probability of segregation events under the null hypothesis of Mendelian transmission. This test takes into account different degrees of relatedness in families, the number of functional rare variants in the gene, and their minor allele frequencies in the corresponding population. In addition, a weighted version of this test allows incorporating additional subject phenotypes to improve statistical power. We show via simulations that the GESE and weighted GESE tests maintain appropriate type I error rate, and have greater power than several commonly used region-based methods. We apply our method to whole-exome sequencing data from 49 extended pedigrees with severe, early-onset chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD study (BEOCOPD) and identify several promising candidate genes. Our proposed methods show great potential for identifying rare coding variants of large effect and high penetrance for family-based sequencing data. The proposed tests are implemented in an R package that is available on CRAN (https://cran.r-project.org/web/packages/GESE/). © 2017 WILEY PERIODICALS, INC.

  15. Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility

    DEFF Research Database (Denmark)

    Ram, Ramesh; Mehta, Munish; Nguyen, Tri Quang

    2016-01-01

    levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4+ and CD8+ T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one......Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility......, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r2 > 0.8) with the reported single...

  16. Liver X Receptor Genes Variants Modulate ALS Phenotype.

    Science.gov (United States)

    Mouzat, Kevin; Molinari, Nicolas; Kantar, Jovana; Polge, Anne; Corcia, Philippe; Couratier, Philippe; Clavelou, Pierre; Juntas-Morales, Raul; Pageot, Nicolas; Lobaccaro, Jean -Marc A; Raoul, Cedric; Lumbroso, Serge; Camu, William

    2018-03-01

    Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.

  17. 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.

  18. 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.

  19. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

    Science.gov (United States)

    Jahanshad, Neda; Rajagopalan, Priya; Hua, Xue; Hibar, Derrek P.; Nir, Talia M.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Medland, Sarah E.; Montgomery, Grant W.; Hansell, Narelle K.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Thompson, Paul M.; Weiner, Michael; Aisen, Paul; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowski, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Liu, Enchi; Green, Robert C.; Montine, Tom; Petersen, Ronald; Aisen, Paul; Gamst, Anthony; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Beckett, Laurel; Harvey, Danielle; Gamst, Anthony; Donohue, Michael; Kornak, John; Jack, Clifford R.; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Jagust, William; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Morris, John; Cairns, Nigel J.; Taylor-Reinwald, Lisa; Trojanowki, J.Q.; Shaw, Les; Lee, Virginia M.Y.; Korecka, Magdalena; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Saykin, Andrew J.; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Khachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Petersen, Ronald; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Mitsis, Effie; Romirowsky, Aliza; deToledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; Kielb, Stephanie; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Coleman, R. Edward; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Lu, Po H.; Bartzokis, George; Silverman, Daniel H.S.; Graff-Radford, Neill R.; Parfitt, Francine; Johnson, Heather; Farlow, Martin R.; Hake, Ann Marie; Matthews, Brandy R.; Herring, Scott; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristina; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan; Belden, Christine; Jacobson, Sandra; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O.; Wolday, Saba; Bwayo, Salome K.; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Longmire, Crystal Flynn; Spicer, Kenneth; Finger, Elizabeth; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Drost, Dick

    2013-01-01

    Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases. PMID:23471985

  20. Genetic Association of HLA Gene Variants with MRI Brain Structure in Alzheimer's Disease.

    Science.gov (United States)

    Wang, Zi-Xuan; Wan, Yu; Tan, Lin; Liu, Jinyuan; Wang, Hui-Fu; Sun, Fu-Rong; Tan, Meng-Shan; Tan, Chen-Chen; Jiang, Teng; Tan, Lan; Yu, Jin-Tai

    2017-07-01

    There is accumulating evidence that the human leukocyte antigen (HLA) gene variants are associated with Alzheimer's disease (AD). However, how they affect AD occurrence is still unknown. In this study, we firstly investigated the association of gene variants in HLA gene variants and brain structures on MRI in a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA on AD pathogenesis. We selected hippocampus, hippocampus CA1 subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). According to the previous association studies of HLA variants and AD, 12 SNPs in HLA were identified in the dataset following quality control measures. In total group analysis, our results showed that TNF-α SNPs at rs2534672 and rs2395488 were significantly positively associated with the volume of the left middle temporal lobe (rs2534672: P = 0.00035, Pc = 0.004; rs2395488: P = 0.0038, Pc = 0.023) at baseline. In the longitudinal study, HFE rs1800562 was remarkably correlated with the lower atrophy rate of right middle temporal lobe (P = 0.0003, Pc = 0.003) and RAGE rs2070600 was associated with the atrophy rate of right hippocampus substructure-CA1 over 2 years (P = 0.003, Pc = 0.035). Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subgroup analysis, as well as the association of rs2534672 with the baseline volume of the left middle temporal lobe in normal cognition (NC) subgroup analysis. Our study provided preliminary evidences that HLA gene variants might participate in the structural alteration of AD associated brain regions, hence modulating the susceptibility of AD.

  1. Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort

    Directory of Open Access Journals (Sweden)

    Stefanie Krüger

    2016-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis for C9orf72. Our aim was to (1 identify potentially disease-causing variants, to (2 assess a proposed model of polygenic inheritance in ALS and to (3 connect ALS with other neurodegenerative entities.We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenic C9orf72 repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such as C9orf72 or SOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediate C9orf72 repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants in GBE1 and SPG7 which might represent differential diagnoses

  2. Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence.

    Science.gov (United States)

    Randesi, Matthew; van den Brink, Wim; Levran, Orna; Blanken, Peter; Butelman, Eduardo R; Yuferov, Vadim; da Rosa, Joel Correa; Ott, Jurg; van Ree, Jan M; Kreek, Mary Jeanne

    2016-11-01

    Heroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence. Genetic information from four subject groups was collected: non-dependent opioid users (NOD) [n=163]; opioid-dependent (OD) patients in methadone maintenance treatment (MMT) [n=143]; opioid-dependent MMT-resistant patients in heroin-assisted treatment (HAT) [n=138]; and healthy controls with no history of opioid use (HC) [n=153]. Eighty-two variants in eight opioid system genes were studied. To establish the role of these genes in (a) non-dependent opioid use, and (b) heroin dependence, the following groups were compared: HC vs. NOD; HC vs. OD (MMT+HAT); and NOD vs. OD (MMT+HAT). Five unique SNPs in four genes showed nominally significant associations with non-dependent opioid use and heroin dependence. The association of the delta opioid receptor (OPRD1) intronic SNP rs2236861 with non-dependent opioid use (HC vs. NOD) remained significant after correction for multiple testing (OR=0.032; p corrected =0.015). This SNP exhibited a significant gene-gene interaction with prepronociceptin (PNOC) SNP rs2722897 (OR=5.24; p corrected =0.041) (HC vs. NOD). This study identifies several new and some previously reported associations of variants with heroin dependence and with non-dependent opioid use, an important and difficult to obtain group not extensively studied previously. Further studies are warranted to confirm and elucidate the potential roles of these variants in the vulnerability to illicit drug use and drug addiction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. The role of tyrosine hydroxylase gene variants in suicide attempt in schizophrenia.

    Science.gov (United States)

    Hu, Jiayi; Chan, Lai Fong; Souza, Renan P; Tampakeras, Maria; Kennedy, James L; Zai, Clement; De Luca, Vincenzo

    2014-01-24

    Evidence has shown that attempted suicide in psychiatric disorders is a complex interplay of genes and environment. Noradrenergic dysfunction due to abnormalities in the tyrosine hydroxylase (TH) gene has been implicated in the pathogenesis of suicidal behavior in mood disorders. However, suicide is a leading cause of mortality in schizophrenia too. Recent evidence suggests that TH gene variants may also increase the risk of suicide attempts in schizophrenia patients, although the interaction with established clinical risk factors is unclear. This study aimed to identify TH gene variants conferring risk for suicide attempt in schizophrenia while accounting for the interaction between this gene and clinical risk factors. We performed analysis on four TH SNPs (rs11564717, rs11042950, rs2070762, rs689) and the common TCAT repeat (UniSTS:240639) for 234 schizophrenia patients (51 suicide attempters and 183 non-attempters). Clinical risk factors and ethnic stratification were included as covariates. Single marker analysis identified the SNP rs11564717 (p=0.042) and the TCAT(6) (p=0.004) as risk variants for suicide attempt. We also identified the haplotype A-A-A-G as a risk factor for suicide attempt (p=0.0025). In conclusion, our findings suggest that TH polymorphisms may contribute to the risk of attempted suicide in schizophrenia even after accounting for established clinical risk factors and ethnic stratification. Further larger scale studies are needed to confirm these findings and to understand the mechanisms underlying the role of TH gene variants in suicide attempt in schizophrenia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.

    Science.gov (United States)

    Rao, Shitao; Leung, Cherry She Ting; Lam, Macro Hb; Wing, Yun Kwok; Waye, Mary Miu Yee; Tsui, Stephen Kwok Wing

    2017-03-01

    To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese. Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest. After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene. This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Selection of Highly Expressed Gene Variants in Escherichia coli Using Translationally Coupled Antibiotic Selection Markers

    DEFF Research Database (Denmark)

    Rennig, Maja; Daley, Daniel O.; Nørholm, Morten H. H.

    2018-01-01

    Strategies to select highly expressed variants of a protein coding sequence are usually based on trial-and-error approaches, which are time-consuming and expensive. We address this problem using translationally coupled antibiotic resistance markers. The system requires that the target gene can...... be fused at the 3'-end with a translational coupling element and an antibiotic resistance gene. Highly expressed target genes can then be selected using a fast and simple whole cell survival assay in the presence of high antibiotic concentrations. Herein we show that the system can be used to select highly...

  6. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

    DEFF Research Database (Denmark)

    Drost, Mark; Lützen, Anne; van Hees, Sandrine

    2013-01-01

    In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloging of residues of MMR genes critical for MMR gene...

  7. Molecular Screening of Keratoconus Susceptibility Sequence Variants in VSX1, TGFBI, DOCK9, STK24, and IPO5 Genes in Polish Patients and Novel TGFBI Variant Identification.

    Science.gov (United States)

    Karolak, Justyna A; Polakowski, Piotr; Szaflik, Jerzy; Szaflik, Jacek P; Gajecka, Marzena

    2016-01-01

    Keratoconus (KTCN) is a degenerative disorder of the eye that results in the conical shape and thinning of the cornea and is a leading cause for corneal transplantations. A number of studies suggest that genetic factors play a role in KTCN etiology. Some candidate gene variants have recently been shown to be associated with KTCN. The purpose of our study was to verify the role of VSX1, TGFBI, DOCK9, IPO5, and STK24 sequence variants in Polish KTCN patients. Forty-two Polish patients with sporadic KTCN and 50 control individuals were enrolled into this study. Both affected and unaffected individuals underwent detailed ophthalmic examination. The mutations screening in the candidate genes was performed by the direct sequencing method. Analysis of VSX1, TGFBI, DOCK9, IPO5, and STK24 genes identified numerous sequence variants. Variants c.-264_-255delGGGGTGGGGT, c.627 + 23G > A, c.809-6_809-5insT, and c.*200G > T in the VSX1 gene, and heterozygous c.1598G > A mutation (Arg533Gln) in exon 12 of TGFBI were detected for the first time in KTCN patients. Two known sequence variants of TGFBI c.1620T > C (Phe540Phe) and c.1678 + 23G > A were observed in KTCN patients and control individuals. The newly reported c.717 + 43A > G substitution in intron 7 of DOCK9 was identified in both KTCN patients and healthy individuals. Our investigation showed that KTCN-related sequence variants of analyzed genes were found in a very small proportion of the studied patients indicating that genes other than VSX1, TGFBI, DOCK9, IPO5, and STK24 are involved in the development and progression of KTCN in Polish patients. Our results support the hypothesis about the genetic heterogeneity of KTCN.

  8. Codon-Optimized Luciola Italica Luciferase Variants for Mammalian Gene Expression in Culture and in Vivo

    Directory of Open Access Journals (Sweden)

    Casey A. Maguire

    2012-01-01

    Full Text Available Luciferases have proven to be useful tools in advancing our understanding of biologic processes. Having a multitude of bioluminescent reporters with different properties is highly desirable. We characterized codon-optimized thermostable green- and red-emitting luciferase variants from the Italian firefly Luciola italica for mammalian gene expression in culture and in vivo. Using lentivirus vectors to deliver and stably express these luciferases in mammalian cells, we showed that both variants displayed similar levels of activity and protein half-lives as well as similar light emission kinetics and higher stability compared to the North American firefly luciferase. Further, we characterized the red-shifted variant for in vivo bioluminescence imaging. Intramuscular injection of tumor cells stably expressing this variant into nude mice yielded a robust luciferase activity. Light emission peaked at 10 minutes post-D-luciferin injection and retained > 60% of signal at 1 hour. Similarly, luciferase activity from intracranially injected glioma cells expressing the red-shifted variant was readily detected and used as a marker to monitor tumor growth over time. Overall, our characterization of these codon-optimized luciferases lays the groundwork for their further use as bioluminescent reporters in mammalian cells.

  9. Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation

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    Asmat Ullah

    2018-01-01

    Full Text Available Abstract Split-hand/split-foot malformation (SHFM, also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1–q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154* in exon 4 of the WNT10B gene in two families (A and B. In the other two families (C and D, a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53 was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/foot malformation.

  10. Reliable and rapid characterization of functional FCN2 gene variants reveals diverse geographical patterns

    Directory of Open Access Journals (Sweden)

    Ojurongbe Olusola

    2012-05-01

    Full Text Available Abstract Background Ficolin-2 coded by FCN2 gene is a soluble serum protein and an innate immune recognition element of the complement system. FCN2 gene polymorphisms reveal distinct geographical patterns and are documented to alter serum ficolin levels and modulate disease susceptibility. Methods We employed a real-time PCR based on Fluorescence Resonance Energy Transfer (FRET method to genotype four functional SNPs including -986 G > A (#rs3124952, -602 G > A (#rs3124953, -4A > G (#rs17514136 and +6424 G > T (#rs7851696 in the ficolin-2 (FCN2 gene. We characterized the FCN2 variants in individuals representing Brazilian (n = 176, Nigerian (n = 180, Vietnamese (n = 172 and European Caucasian ethnicity (n = 165. Results We observed that the genotype distribution of three functional SNP variants (−986 G > A, -602 G > A and -4A > G differ significantly between the populations investigated (p p  Conclusions The observed distribution of the FCN2 functional SNP variants may likely contribute to altered serum ficolin levels and this may depend on the different disease settings in world populations. To conclude, the use of FRET based real-time PCR especially for FCN2 gene will benefit a larger scientific community who extensively depend on rapid, reliable method for FCN2 genotyping.

  11. 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...

  12. Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects.

    Science.gov (United States)

    Seo, Heewon; Kwon, Eun Jin; You, Young-Ah; Park, Yoomi; Min, Byung Joo; Yoo, Kyunghun; Hwang, Han-Sung; Kim, Ju Han; Kim, Young Ju

    2018-01-24

    Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca 2+ -related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.

  13. Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women

    Directory of Open Access Journals (Sweden)

    Do Kyeong Song

    2014-08-01

    Full Text Available BackgroundThe fat mass and obesity-associated (FTO gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS. Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.MethodsWe recruited 432 women with PCOS (24±5 years and 927 healthy women with regular menstrual cycles (27±5 years and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.ResultsLogistic regression revealed that the G/G genotype (rs1421085, 1.6%, the C/C genotype (rs17817449, 1.6%, and the A/A genotype (rs8050136, 1.6% were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05. The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05 and higher free testosterone levels (P=0.053 to 0.063 compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI. When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.ConclusionThe rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

  14. Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

    Science.gov (United States)

    Cheurfa, N; Brenner, G M; Reis, A F; Dubois-Laforgue, D; Roussel, R; Tichet, J; Lantieri, O; Balkau, B; Fumeron, F; Timsit, J; Marre, M; Velho, G

    2011-03-01

    We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

  15. Analysis of Genes Associated with Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's disease.

    Science.gov (United States)

    Amininejad, Leila; Charloteaux, Benoit; Theatre, Emilie; Liefferinckx, Claire; Dmitrieva, Julia; Hayard, Pierre; Muls, Vincianne; Maisin, Jean-Marc; Schapira, Michael; Ghislain, Jean-Michel; Closset, Pierre; Talib, Mehdi; Abramowicz, Marc; Momozawa, Yukihide; Deffontaine, Valerie; Crins, François; Mni, Myriam; Karim, Latifa; Cambisano, Nadine; Ornemese, Sandra; Zucchi, Alessandro; Minsart, Charlotte; Deviere, Jacques; Hugot, Jean-Pierre; De Vos, Martine; Louis, Edouard; Vermeire, Severine; Van Gossum, Andre; Coppieters, Wouter; Twizere, Jean-Claude; Georges, Michel; Franchimont, Denis

    2018-02-28

    A few rare monogenic primary immunodeficiencies (PID) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency or rare variants that increase risk for CD. Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. We reproduced the association of the IL10 locus with CD (P=.007), although none of the significantly associated variants modified the coding sequence of IL10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P=.02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause PID X-linked lymphoproliferative disease type 2 (XLP2), yet none of the carriers of these variants had all the clinical features of XLP2. Identified XIAP variants S123N, R233Q and P257A were associated with an impaired activation of NOD2 signaling following MDP stimulation. In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screens for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. 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.

  17. Comprehensive investigation of cytokine- and immune-related gene variants in HBV-associated hepatocellular carcinoma patients.

    Science.gov (United States)

    Yu, Fengxue; Zhang, Xiaolin; Tian, Suzhai; Geng, Lianxia; Xu, Weili; Ma, Ning; Wang, Mingbang; Jia, Yuan; Liu, Xuechen; Ma, Junji; Quan, Yuan; Zhang, Chaojun; Guo, Lina; An, Wenting; Liu, Dianwu

    2017-12-22

    Host genotype may be closely related to the different outcomes of Hepatitis B virus (HBV) infection. To identify the association of variants and HBV infection, we comprehensively investigated the cytokine- and immune-related gene mutations in patients with HBV associated hepatocellular carcinoma (HBV-HCC). Fifty-three HBV-HCC patients, 53 self-healing cases (SH) with HBV infection history and 53 healthy controls (HCs) were recruited, the whole exon region of 404 genes were sequenced at >900× depth. Comprehensive variants and gene levels were compared between HCC and HC, and HCC and SH. Thirty-nine variants (adjusted P HBV-HCC. Thirty-four variants were from eight human leukocyte antigen (HLA) genes that were previously reported to be associated with HBV-HCC. The novelties of our study are: five variants (rs579876, rs579877, rs368692979, NM_145007:c.*131_*130delTG, NM_139165:exon5:c.623-2->TT) from three genes ( REAT1E , NOD-like receptor (NLR) protein 11 ( NLRP11 ), hydroxy-carboxylic acid receptor 2 ( HCAR2 )) were found strongly associated with HBV-HCC. We found 39 different variants in 11 genes that were significantly related to HBV-HCC. Five of them were new findings. Our data implied that chronic hepatitis B patients who carry these variants are at a high risk of developing HCC. © 2017 The Author(s).

  18. Sexually dimorphic effects of oxytocin receptor gene (OXTR variants on Harm Avoidance

    Directory of Open Access Journals (Sweden)

    Stankova Trayana

    2012-07-01

    Full Text Available Abstract Background Recent research has suggested that oxytocin receptor gene (OXTR variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p ≤ 0.01. Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant. Conclusions Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.

  19. Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

    Directory of Open Access Journals (Sweden)

    Kelsey E. Grinde

    2017-09-01

    Full Text Available To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6 and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures.

  20. Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation.

    Science.gov (United States)

    Fakhouri, Fadi; Fila, Marc; Provôt, François; Delmas, Yahsou; Barbet, Christelle; Châtelet, Valérie; Rafat, Cédric; Cailliez, Mathilde; Hogan, Julien; Servais, Aude; Karras, Alexandre; Makdassi, Raifah; Louillet, Feriell; Coindre, Jean-Philippe; Rondeau, Eric; Loirat, Chantal; Frémeaux-Bacchi, Véronique

    2017-01-06

    The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients. Copyright © 2016 by the American Society of Nephrology.

  1. Interaction between the Gly460Trp alpha-adducin gene variant and diuretics on the risk of myocardial infarction

    NARCIS (Netherlands)

    van Wieren-de Wijer, Diane B M A; Maitland-van der Zee, Anke-Hilse; de Boer, Anthonius; Kroon, Abraham A; de Leeuw, Peter W; Schiffers, Paul; Janssen, Rob G J H; Psaty, Bruce M; van Duijn, Cornelia M; Stricker, Bruno H Ch; Klungel, Olaf H

    INTRODUCTION: The Gly460Trp variant of the alpha-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. OBJECTIVE: The aim of the study was to determine whether the alpha-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on

  2. A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion

    DEFF Research Database (Denmark)

    Jonsson, Anna Elisabet; Isomaa, Bo; Tuomi, Tiinamaija

    2009-01-01

    Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion...... and action and predict future type 2 diabetes in subjects from Sweden and Finland....

  3. Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency

    DEFF Research Database (Denmark)

    Rodrigues, Rute; Artieda, Marta; Tejedor, Diego

    2016-01-01

    BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight...... into the deleterious effect of the mutations is clinically essential. METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG. RESULTS: Of the 33...

  4. Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

    NARCIS (Netherlands)

    Hu, Y.J.; Berndt, S.I.; Gustafsson, S.; Ganna, A.; Hirschhorn, J.; North, K.E.; Ingelsson, E.; Lin, D.Y.; Kiemeney, L.A.L.M.; Vermeulen, S.; et al.,

    2013-01-01

    Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with

  5. The presence of the ail gene in clinical strains of Yersinia enterocolitica isolated from stools in Poland and characteristics of gene variant.

    Science.gov (United States)

    Gierczyński, R; Jagielski, M; Rastawicki, W

    2001-01-01

    The non-American variant of ail gene was found independently of the virulence-associated plasmid pYV in all 152 tested clinical Y. enterocolitica O:3 strains isolated from humans in Poland. Data obtained by sequencing exhibited high genetic stability of the ail gene present in the tested isolates obtained from different regions of the country. The PCR-RFLP technique was sufficient for fast identification and characterization of the ail gene variant present in the tested strains.

  6. Maternal iron metabolism gene variants modify umbilical cord blood lead levels by gene-environment interaction: a birth cohort study.

    Science.gov (United States)

    Karwowski, Mateusz P; Just, Allan C; Bellinger, David C; Jim, Rebecca; Hatley, Earl L; Ettinger, Adrienne S; Hu, Howard; Wright, Robert O

    2014-10-06

    Given the relationship between iron metabolism and lead toxicokinetics, we hypothesized that polymorphisms in iron metabolism genes might modify maternal-fetal lead transfer. The objective of this study was to determine whether maternal and/or infant transferrin (TF) and hemochromatosis (HFE) gene missense variants modify the association between maternal blood lead (MBL) and umbilical cord blood lead (UCBL). We studied 476 mother-infant pairs whose archived blood specimens were genotyped for TF P570S, HFE H63D and HFE C282Y. MBL and UCBL were collected within 12 hours of delivery. Linear regression models were used to examine the association between log-transformed MBL and UCBL, examine for confounding and collinearity, and explore gene-environment interactions. The geometric mean MBL was 0.61 μg/dL (range 0.03, 3.2) and UCBL 0.42 (lead transfer among women with MBL 5 μg/dL. Maternal HFE C282Y gene variant status is associated with greater reductions in placental transfer of lead as MBL increases. The inclusion of gene-environment interaction in risk assessment models may improve efforts to safeguard vulnerable populations.

  7. Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation

    KAUST Repository

    Monies, Dorota

    2017-04-06

    The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern.Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples.We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes.Our results show that, in the era of genomic sequencing and

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

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    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.

  9. The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura

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    Sundholm James

    2004-02-01

    Full Text Available Abstract Background The C677T variant in the methylenetetrahydrofolate reductase (MTHFR gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Migraine, with and without aura (MA and MO, is a prevalent and complex neurovascular disorder that may also be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs. Methods A total of 652 Caucasian migraine cases were investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex pedigrees. Results In the unrelated case-control sample we observed an over-representation of the 677T allele in migraine patients compared to controls, specifically for the MA subtype (40% vs. 33% (χ2 = 5.70, P = 0.017. The Armitage test for trend indicated a significant dosage effect of the risk allele (T for MA (χ2 = 5.72, P = 0.017. This linear trend was also present in the independent family-based sample (χ2 = 4.25, Padjusted = 0.039. Overall, our results indicate that the T/T genotype confers a modest, yet significant, increase in risk for the MA subtype (odds ratio: 2.0 – 2.5. No increased risk for the MO subtype was observed (P > 0.05. Conclusions In Caucasians, the C677T variant in the MTHFR gene influences susceptibility to MA, but not MO. Investigation into the enzyme activity of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted.

  10. Studies of metabolic phenotypic correlates of 15 obesity associated gene variants.

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    Camilla Helene Sandholt

    Full Text Available Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms.15 gene variants in 14 loci including TMEM18 (rs7561317, SH2B1 (rs7498665, KCTD15 (rs29941, NEGR1 (rs2568958, ETV5 (rs7647305, BDNF (rs4923461, rs925946, SEC16B (rs10913469, FAIM2 (rs7138803, GNPDA2 (rs10938397, MTCH2 (rs10838738, BAT2 (rs2260000, NPC1 (rs1805081, MAF (rs1424233, and PTER (rs10508503 were genotyped in 18,014 middle-aged Danes.Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008, whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4.Associations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI.

  11. High prevalence of an anti-hypertriglyceridemic variant of the MLXIPL gene in Central Asia.

    Science.gov (United States)

    Nakayama, Kazuhiro; Yanagisawa, Yoshiko; Ogawa, Ayumi; Ishizuka, Yuumi; Munkhtulga, Lkhagvasuren; Charupoonphol, Phitaya; Supannnatas, Somjit; Kuartei, Stevenson; Chimedregzen, Ulziiburen; Koda, Yoshiro; Ishida, Takafumi; Kagawa, Yasuo; Iwamoto, Sadahiko

    2011-12-01

    MLXIPL is a transcription factor integral to the regulation of glycolysis and lipogenesis in the liver. Common variants of the MLXIPL gene (MLXIPL) are known to influence plasma triglyceride levels in people of European descent. As MLXIPL has a key role in energy storage, genetic variations of the MLXIPL may be relevant to physiological adaptations to nutritional stresses that have occurred during the evolution of modern humans. In the present study, we assessed the phenotypic consequences of the Q241H variant of MLXIPL in populations of Asian and Oceanian origin and also surveyed the prevalence of Q241H variant in populations worldwide. Multiple linear regression models based on 2373 individuals of Asian origin showed that the H allele was significantly associated with decreased concentrations of plasma triglycerides (P=0.0003). Direct genotyping of 1455 individuals from Africa, Asia and Oceania showed that the triglyceride-lowering H allele was found at quite low frequencies (0.00-0.16) in most of the populations examined. The exceptions were some Central Asian populations, including Mongolians, Tibetans and Uyghurs, which exhibited much higher frequencies of the H allele (0.21-0.26). The high prevalence of the H allele in Central Asia implies that the Q241H variant of MLXIPL might have been significant for utilization of carbohydrates and fats in the common ancestors of these populations, who successfully adapted to the environment of Central Asia by relying on nomadic livestock herding.

  12. The spread of alphabetical writing may have favored the latest variant of the ASPM gene.

    Science.gov (United States)

    Frost, Peter

    2008-01-01

    ASPM, a gene that regulates brain growth, has evolved considerably in the primate lineage that leads to humans. It continued to evolve even after the emergence of modern humans, with the latest ASPM variant arising about 6000 years ago somewhere in the Middle East. The new variant then proliferated within and outside this region, reaching higher incidences in the Middle East (37-52%) and in Europe (38-50%) than in East Asia (0-25%). Despite its apparent selective advantage, this variant does not seem to improve cognitive performance, at least not on standard IQ tests. At present, we can only say that it probably assists performance on a task that exhibited the same geographic expansion from a Middle Eastern origin roughly 6000 years ago. The closest match seems to be the invention of alphabetical writing, specifically the task of transcribing speech and copying texts into alphabetical script. Though more easily learned than ideographs, alphabetical characters place higher demands on mental processing, especially under premodern conditions (continuous text with little or no punctuation, real-time stenography, absence of automated assistance for publishing or copying, etc.). This task was largely delegated to scribes of various sorts who enjoyed privileged status and probably superior reproductive success. Such individuals may have served as vectors for spreading the new ASPM variant.

  13. Common and rare variants in the exons and regulatory regions of osteoporosis-related genes improve osteoporotic fracture risk prediction.

    Science.gov (United States)

    Lee, Seung Hun; Kang, Moo Il; Ahn, Seong Hee; Lim, Kyeong-Hye; Lee, Gun Eui; Shin, Eun-Soon; Lee, Jong-Eun; Kim, Beom-Jun; Cho, Eun-Hee; Kim, Sang-Wook; Kim, Tae-Ho; Kim, Hyun-Ju; Yoon, Kun-Ho; Lee, Won Chul; Kim, Ghi Su; Koh, Jung-Min; Kim, Shin-Yoon

    2014-11-01

    Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. This cross-sectional study was conducted in three clinical units in Korea. Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P risk in an osteopenic individual.

  14. ANALYSIS OF POLYMORPHIC VARIANTS OF CYTOKINE GENES IN PATIENTS WITH HIV INFECTION

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    N. A. Sukhalentseva

    2011-01-01

    Full Text Available Abstract. A distribution mode for allelic variants of cytokine genes was evaluated in 184 patients with slow viral infections, including 97 patients with chronic herpetic infection and 87 HIV-infected patients. Using modern methods of immunogenetics, we have found that relative risks of recurrent course and poor outcome of infection are positively associated with AA promoter region genotype and AA promoter genotype of +874 A/T polymorphism in the IFNG gene. Immunogenetic factors associated with protective effect in slow virus infections, include G allele of TNFA gene (G-308A SNP, and T allele/TT genotype of promoter region in  the IFNG gene (+874 A/T SNP. (Med. Immunol., 2011, vol. 13, N 1, pp 79-82

  15. 'A variant of uncertain significance' and the proliferation of human disease gene databases

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    Nelson David R

    2005-03-01

    Full Text Available Abstract The rapid accumulation of mutation data has led to the creation of nearly 300 locus-specific mutation databases. These sites may contain a few dozen to almost 20,000 mutations for a given gene. Many of the mutations are uncharacterised and have no known effects on the gene product, the 'variant of uncertain significance'. Here, the statistics of mutation distribution are examined for six different gene databases: BRCA1 and BRCA2, haemoglobin-beta (HBB, HPRT1, CFTR and TP53. The percentage of all possible point mutations for a protein (the mutation space is calculated for each gene and the question 'How much mutation data is enough?' is raised.

  16. An R1632C variant in the SCN5A gene causing Brugada syndrome.

    Science.gov (United States)

    García-Molina, Esperanza; Sabater-Molina, María; Muñoz, Carmen; Ruiz-Espejo, Francisco; Gimeno, Juan R

    2016-06-01

    Brugada syndrome (BS) is an electrical disease, inherited in an autosomal dominant manner. BS is caused by mutations in up to 13 different genes. SCN5A is the gene most frequently mutated in BS, although this presents an incomplete penetrance. The present case study investigated the SCN5A gene in a family exhibiting BS. Direct sequencing of the SCN5A gene was performed to identify mutations and a familial investigation was performed. A novel variant was identified in the voltage‑sensing domain of the SCN5A protein. This familial investigation revealed one novel asymptomatic carrier in the family. Genetic investigations are useful to classify individuals who require more frequent clinical monitoring and to stratify the risk of developing the disease.

  17. Assessment of association between lipoxygenase genes variants in elderly Greek population and type 2 diabetes mellitus.

    Science.gov (United States)

    Tsekmekidou, Xanthippi A; Kotsa, Kalliopi D; Tsetsos, Fotis S; Didangelos, Triantafyllos P; Georgitsi, Marianthi A; Roumeliotis, Athanasios K; Panagoutsos, Stylianos A; Thodis, Elias D; Theodoridis, Marios T; Papanas, Nikolaos P; Papazoglou, Dimitrios A; Pasadakis, Ploumis S; Eustratios, Maltezos S; Paschou, Peristera I; Yovos, John G

    2018-02-01

    Inflammation plays a pivotal role in the pathogenesis of diabetes and its complications. Arachidonic acid lipoxygenases have been intensively studied in their role in inflammation in metabolic pathways. Thus, we aimed to explore variants of lipoxygenase genes (arachidonate lipoxygenase genes) in a diabetes adult population using a case-control study design. Study population consisted of 1285 elderly participants, 716 of whom had type 2 diabetes mellitus. The control group consisted of non-diabetes individuals with no history of diabetes history and with a glycated haemoglobin <6.5% (<48 mmol/mol)] and fasting plasma glucose levels <126 mg/dL. Blood samples were genotyped on Illumina Infinium PsychArray. Variants of ALOX5, ALOX5AP, ALOX12, ALOX15 were selected. All statistical analyses were undertaken within PLINK and SPSS packages utilising permutation analysis tests. Our findings showed an association of rs9669952 (odds ratio = 0.738, p = 0.013) and rs1132340 (odds ratio = 0.652, p = 0.008) in ALOX5AP and rs11239524 in ALOX5 gene with disease (odds ratio = 0.808, p = 0.038). Rs9315029 which is located near arachidonate ALOX5AP also associated with type 2 diabetes mellitus ( p = 0.025). No variant of ALOX12 and ALOX15 genes associated with disease. These results indicate a potential protective role of ALOX5AP and 5-arachidonate lipoxygenase gene in diabetes pathogenesis, indicating further the importance of the relationship between diabetes and inflammation. Larger population studies are required to replicate our findings.

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

    Directory of Open Access Journals (Sweden)

    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

  19. Analysis of IL12B Gene Variants in Inflammatory Bowel Disease

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    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

  20. Association of recently identified type 2 diabetes gene variants with Gestational Diabetes in Asian Indian population.

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    Kanthimathi, Sekar; Chidambaram, Manickam; Bodhini, Dhanasekaran; Liju, Samuel; Bhavatharini, Aruyerchelvan; Uma, Ram; Anjana, Ranjit Mohan; Mohan, Viswanathan; Radha, Venkatesan

    2017-06-01

    Earlier studies have provided evidence that the gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2DM) share common genetic background. A recent genome wide association study (GWAS) showed a strong association of six novel gene variants with T2DM among south Asians but not with Europeans. The aim of this study was to investigate whether these variants that confer susceptibility to T2DM in Asian Indian population also correlate with GDM in Asian Indian population. In addition to these novel variants, three T2DM associated SNPs that were previously identified by GWAS in Caucasian populations, which also showed association with T2DM in south Indian population in our previous study were also evaluated for their susceptibility to GDM in our population. The study groups comprised unrelated pregnant women with GDM (n = 518) and pregnant women with normal glucose tolerance (NGT) (n = 1220). A total of nine SNPs in or near nine loci, namely AP3S2 (rs2028299), BAZ1B (rs12056034), CDKN2A/B (rs7020996), GRB14 (rs3923113), HHEX (rs7923837), HMG20A (rs7178572), HNF4A (rs4812829), ST6GAL1 (rs16861329) and VPS26A (rs1802295) were genotyped using the MassARRAY system. Among these nine SNPs that previously showed an association with T2DM in Asian Indians, HMG20A (rs7178572) and HNF4A (rs4812829) gene variants showed a significant association with GDM. The risk alleles of rs7178572 in HMG20A and rs4812829 in HNF4A gene conferred 1.24 and 1.28 times higher risk independently and about 1.44 and 1.97 times increased susceptibility to GDM for one and two risk genotypes, respectively. We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population. This is the first report of the association of HMG20A (rs7178572) and HNF4A (rs4812829) variants with GDM.

  1. Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene.

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    Vodo, Dan; Sarig, Ofer; Geller, Shamir; Ben-Asher, Edna; Olender, Tsviya; Bochner, Ron; Goldberg, Ilan; Nosgorodsky, Judith; Alkelai, Anna; Tatarskyy, Pavel; Peled, Alon; Baum, Sharon; Barzilai, Aviv; Ibrahim, Saleh M; Zillikens, Detlef; Lancet, Doron; Sprecher, Eli

    2016-05-01

    Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.

  2. NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients.

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    Jüngst, Christoph; Stadlbauer, Vanessa; Reichert, Matthias C; Zimmer, Vincent; Weber, Susanne N; Ofner-Ziegenfuß, Lisa; Voigtländer, Torsten; Spindelböck, Walter; Fickert, Peter; Kirchner, Gabriele I; Lammert, Frank; Lankisch, Tim O; Krawczyk, Marcin

    2017-08-01

    Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn's disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.

  3. Variants of CD36 gene and their association with CD36 protein expression in platelets

    Science.gov (United States)

    Xu, Xianguo; Liu, Ying; Hong, Xiaozhen; Chen, Shu; Ma, Kairong; Lan, Xiaofei; Ying, Yanling; He, Ji; Zhu, Faming; Lv, Hangjun

    2014-01-01

    Background The relationship between CD36 expression level in platelets and polymorphism of the CD36 gene still needs to be explored. Here, we investigated polymorphisms of the CD36 gene and CD36 expression level in platelets in the Chinese Han population. Materials and methods A total of 477 samples were sequenced for exons 2 to 14 of the CD36 gene using a polymerase chain reaction sequence-based typing method. In 192 of these individuals the expression levels of CD36 antigen were analysed by flow cytometry. The genotype-phenotype relationship in platelets was analysed. Results A total of 22 variants of the CD36 gene were identified, of which five variants (111 A>T, 681 C>A, 1172–1183 del12b, 1236 delT and 1395 A>C) were novel variations, and nine were also found in single nucleotide polymorphism database (dbSNP) but had not been confirmed in individuals with CD36 deficiency. Two variants (329–332 delAC and 1228–1239 del12bp) in the coding region are the most frequent mutations in the Chinese population. Type II CD36 deficiency was identified in seven of 192 individuals, giving a frequency of 3.6%. Individuals with CD36 variations or wild-type genotypes both showed CD36 antigen negative, low-level and high-level expression patterns in platelets. The frequency of the nt-132 A>C polymorphism in the 5′-UTR is relatively high in the Chinese population (0.3516): the expression of CD36 was lower in individuals with nt-132 A>C than in those with the wild-type genotype. Discussion The distribution of CD36 gene variants in the Chinese population is different from that previously reported. The levels of expression of CD36 antigen in platelets are not determined directly by the genotypes of the CD36 coding region. This suggests that the molecular basis of type II CD36 deficiency may be derived from combined effects of coding region and potential cis-regulatory elements in the 5′-UTR of the CD36 gene. PMID:24960640

  4. Rare variants in axonogenesis genes connect three families with sound-color synesthesia.

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    Tilot, Amanda K; Kucera, Katerina S; Vino, Arianna; Asher, Julian E; Baron-Cohen, Simon; Fisher, Simon E

    2018-03-20

    Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound-color (auditory-visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes- COL4A1 , ITGA2 , MYO10 , ROBO3 , SLC9A6 , and SLIT2 -associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences. Copyright © 2018 the Author(s). Published by PNAS.

  5. Characterization of human FHL2 transcript variants and gene expression regulation in hepatocellular carcinoma.

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    Ng, Chor-Fung; Zhou, Wayne Jun-Wei; Ng, Patrick Kwok-Shing; Li, Man-Shan; Ng, Yuen-Keng; Lai, Paul Bo-San; Tsui, Stephen Kwok-Wing

    2011-07-15

    The four-and-a-half LIM protein 2 (FHL2) was originally identified to be expressed abundantly in the heart, as well as in a wide range of tissues demonstrated in various studies. The human FHL2 gene expresses different transcripts which are known to differ only in the 5'UTR region. However, little is known about the functional role of the different variants and the mechanism of gene regulation. In the present study, we characterized the different alternative spliced transcripts of FHL2 by in silico analysis and RT-PCR analysis. A novel transcript variant was identified. The FHL2 gene produces transcripts by different 5' exons, which may be responsible for tissue-specific regulation. To study the mechanism of FHL2 gene regulation, the potential promoter region was investigated. We have identified a functional promoter region upstream of the transcription start site. Deletion mutation analysis of 5' flanking region showed that the fragment from -138 to +292 bp have positive regulatory effect. We identified the binding sites of Pax-5/ZF5 in this region and found that Pax-5 and ZF5 expression in HCC samples had a significant positive correlation with FHL2 expression, suggesting a possible role for these transcription factors in the regulation of FHL2 expression. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Networks of neuronal genes affected by common and rare variants in autism spectrum disorders.

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    Eyal Ben-David

    Full Text Available Autism spectrum disorders (ASD are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS, we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.

  7. Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing

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    Clare Brookes

    2015-05-01

    Full Text Available Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible.

  8. Neurexin gene family variants as risk factors for autism spectrum disorder.

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    Wang, Jia; Gong, Jianhua; Li, Li; Chen, Yanlin; Liu, Lingfei; Gu, HuaiTing; Luo, Xiu; Hou, Fang; Zhang, Jiajia; Song, Ranran

    2018-01-01

    Increasing evidence suggests that abnormal synaptic function leads to neuronal developmental disorders and is an important component of the etiology of autism spectrum disorder (ASD). Neurexins are presynaptic cell-adhesion molecules that affect the function of synapses and mediate the conduction of nerve signals. Thus, neurexins are attractive candidate genes for autism. Since gene families have greater power to reveal genetic association than single genes, we designed this case-control study to investigate six genetic variants in three neurexin genes (NRXN1, NRXN2, and NRXN3) in a Chinese population including 529 ASD patients and 1,923 healthy controls. We found that two SNPs were significantly associated with ASD after false discovery rate (FDR) adjustment for multiple comparisons. The NRXN2 rs12273892 polymorphism T allele and AT genotype were significantly associated with increased risk of ASD (respectively: OR = 1.328, 95% CI = 1.133-1.557, P Autism Res 2018, 11: 37-43. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is highly heritable, and studies have found a number of candidate genes that might contribute to ASD. Neurexins are presynaptic cell-adhesion molecules that affect the function of synapses and mediate the conduction of nerve signals, and they play an important role in normal brain development and become candidate genes for autism. The purpose of our study is to explore the association between variants of the neurexins gene family and ASD in a Chinese population through a case-control study. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  9. Variants in host viral replication cycle genes are associated with heterosexual HIV-1 acquisition in Africans.

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    Bigham, Abigail W; Mackelprang, Romel D; Celum, Connie; De Bruyn, Guy; Beima-Sofie, Kristin; John-Stewart, Grace; Ronald, Allan; Mugo, Nelly R; Buckingham, Kati; Bamshad, Michael J; Mullins, James I; McElrath, M J; Lingappa, Jairam R

    2014-06-01

    We evaluated genetic variants in 51 candidate genes encoding proteins that interact with HIV-1 during the virus life cycle for association with HIV-1 outcomes in an African cohort. Using a nested case-control study within a cohort of heterosexual HIV-1-serodiscordant couples, we genotyped 475 haplotype-tagging single-nucleotide polymorphisms (tagSNPs) and 18 SNPs previously associated with HIV-1 transmission and/or progression (candidate SNPs) in 51 host genes. We used logistic and Cox proportional hazard regression with adjustment for sex, age, and population stratification to detect SNP associations with HIV-1 acquisition, plasma HIV-1 set point, and a composite measure of HIV-1 disease progression. Significant thresholds for tagSNP, but not candidate SNP, associations were subjected to Bonferroni correction for multiple testing. We evaluated 491 HIV-1-infected and 335 HIV-1-uninfected individuals for 493 SNPs, 459 of which passed quality control filters. Candidate SNP PPIA rs8177826 and tagSNP SMARCB1 rs6003904 were significantly associated with HIV-1 acquisition risk (odds ratio = 0.14, P = 0.03, and odds ratio = 2.11, Pcorr = 0.01, respectively). Furthermore, the TT genotype for CCR5 rs1799988 was associated with a mean 0.2 log10 copies per milliliter lower plasma HIV-1 RNA set point (P = 0.04). We also identified significant associations with HIV-1 disease progression for variants in FUT2 and MBL2. Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with HIV-1 outcomes in this African cohort.

  10. Nonrandom Distribution of miRNAs Genes and Single Nucleotide Variants in Keratoconus Loci.

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    Dorota M Nowak

    Full Text Available Despite numerous studies, the causes of both development and progression of keratoconus remain elusive. Previous studies of this disorder focused mainly on one or two genetic factors only. However, in the analysis of such complex diseases all potential factors should be taken into consideration. The purpose of this study was a comprehensive analysis of known keratoconus loci to uncover genetic factors involved in this disease causation in the general population, which could be omitted in the original studies. In this investigation genomic data available in various databases and experimental own data were assessed. The lists of single nucleotide variants and miRNA genes localized in reported keratoconus loci were obtained from Ensembl and miRBase, respectively. The potential impact of nonsynonymous amino acid substitutions on protein structure and function was assessed with PolyPhen-2 and SIFT. For selected protein genes the ranking was made to choose those most promising for keratoconus development. Ranking results were based on topological features in the protein-protein interaction network. High specificity for the populations in which the causative sequence variants have been identified was found. In addition, the possibility of links between previously analyzed keratoconus loci was confirmed including miRNA-gene interactions. Identified number of genes associated with oxidative stress and inflammatory agents corroborated the hypothesis of their effect on the disease etiology. Distribution of the numerous sequences variants within both exons and mature miRNA which forces you to search for a broader look at the determinants of keratoconus. Our findings highlight the complexity of the keratoconus genetics.

  11. Nonrandom Distribution of miRNAs Genes and Single Nucleotide Variants in Keratoconus Loci.

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    Nowak, Dorota M; Gajecka, Marzena

    2015-01-01

    Despite numerous studies, the causes of both development and progression of keratoconus remain elusive. Previous studies of this disorder focused mainly on one or two genetic factors only. However, in the analysis of such complex diseases all potential factors should be taken into consideration. The purpose of this study was a comprehensive analysis of known keratoconus loci to uncover genetic factors involved in this disease causation in the general population, which could be omitted in the original studies. In this investigation genomic data available in various databases and experimental own data were assessed. The lists of single nucleotide variants and miRNA genes localized in reported keratoconus loci were obtained from Ensembl and miRBase, respectively. The potential impact of nonsynonymous amino acid substitutions on protein structure and function was assessed with PolyPhen-2 and SIFT. For selected protein genes the ranking was made to choose those most promising for keratoconus development. Ranking results were based on topological features in the protein-protein interaction network. High specificity for the populations in which the causative sequence variants have been identified was found. In addition, the possibility of links between previously analyzed keratoconus loci was confirmed including miRNA-gene interactions. Identified number of genes associated with oxidative stress and inflammatory agents corroborated the hypothesis of their effect on the disease etiology. Distribution of the numerous sequences variants within both exons and mature miRNA which forces you to search for a broader look at the determinants of keratoconus. Our findings highlight the complexity of the keratoconus genetics.

  12. Multifactor-dimensionality reduction reveals interaction of important gene variants involved in allergy.

    Science.gov (United States)

    de Guia, R M; Echavez, M D J; Gaw, E L C; Gomez, M R R; Lopez, K A J; Mendoza, R C M; Rapsing, J M C; Retreta, D P; Tubog, C M B; Ventolero, M H; Yao, C L; Ramos, J D A

    2015-06-01

    Elevated IgE levels in the atopic triad of asthma, allergic rhinitis and atopic dermatitis is a multifactorial condition whose genetic component involves interaction of several gene loci. One hundred and two matched pairs of allergic and nonallergic individuals were phenotyped for total serum IgE level using enzyme-linked immunosorbent assay (ELISA). Atopic status was defined by serum IgE concentration ≥100 IU mL(-1) . SNPs genotyped include the IL4 -590C>T (rs2243250), FCER1B E237G (rs569108), CD14 -159C>T (rs2569190), IL4RA Q551R (rs1801275) and ADRB2 R16G (rs1042713). Gene-gene interaction was analysed using multifactor-dimensionality reduction (MDR). Significant association between atopic allergy and the IL4 -590C>T polymorphism was confirmed in three genetic models. Interaction among the 5 gene variants was validated by MDR. The five-locus model was chosen as the best to describe the interaction of the SNPs within the context of atopy. The strongest interaction was between IL4 -590C>T and IL4RA Q551R and between FCER1B E237G and ADRB2 R16G. The IL4 variant also interacts synergistically with the FCER1B and ADRB2 coding variants. CD14 -159C>T, in general, interacts antagonistically with the rest of the SNPs. In conclusion, a five-locus interaction exists among IL4 -590C>T, FCER1B E237G, CD14 -159C>T, IL4RA Q551R and ADRB2 R16G in Filipino cases of atopic allergy. © 2015 John Wiley & Sons Ltd.

  13. Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk

    Science.gov (United States)

    Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chen, Zhihua; Chen, Y. Ann; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Jim, Heather; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Lotte; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vierkant, Robert A.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Kelemen, Linda E.; Berchuck, Andrew; Schildkraut, Joellen M.; Ramus, Susan J.; Goode, Ellen L.; Monteiro, Alvaro N.A.; Gayther, Simon A.; Narod, Steven A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2016-01-01

    Introduction Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population. Methods We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant. Results In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. Conclusion These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC. PMID:26399219

  14. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    LENUS (Irish Health Repository)

    Pangilinan, Faith

    2012-08-02

    AbstractBackgroundNeural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate\\/B12 pathway genes contribute to NTD risk.MethodsA tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate\\/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.ResultsNearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.ConclusionsTo our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the

  15. Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays

    DEFF Research Database (Denmark)

    Heinen, Christopher D; Juel Rasmussen, Lene

    2012-01-01

    ABSTRACT: With the discovery that the hereditary cancer susceptibility disease Lynch syndrome (LS) is caused by deleterious germline mutations in the DNA mismatch repair (MMR) genes nearly 20 years ago, genetic testing can now be used to diagnose this disorder in patients. A definitive diagnosis...... of LS can direct how clinicians manage the disease as well as prevent future cancers for the patient and their families. A challenge emerges, however, when a germline missense variant is identified in a MMR gene in a suspected LS patient. The significance of a single amino acid change in these large...... some of these assays along with the challenges of using such assays to determine the functional consequences of MMR VUS which, in turn, can provide valuable insight into their clinical significance. With increased gene sequencing in patients, the number of identified VUS has expanded dramatically...

  16. Risk of ovarian cancer and inherited variants in relapse-associated genes.

    Directory of Open Access Journals (Sweden)

    Abraham Peedicayil

    2010-01-01

    Full Text Available We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk.Women with and without invasive ovarian cancer (749 cases, 1,041 controls were genotyped at 136 single nucleotide polymorphisms (SNPs within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog was associated with risk of serous cancer (p = 0.03; haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog were associated with risk of invasive disease (p = 0.03. MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03. SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05, and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91.Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.

  17. Molecular characterization of a genetic variant of the steroid hormone-binding globulin gene in heterozygous subjects

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, D.O.; Catterall, J.F. [Population Council, New York, NY (United States); Carino, C. [Instituto National de la Nutricion, Mexico City, MX (United States)] [and others

    1995-04-01

    Steroid hormone-binding globulin in human serum displays different isoelectric focusing (IEF) patterns among individuals, suggesting genetic variation in the gene for this extracellular steroid carrier protein. Analysis of allele frequencies and family studies suggested the existence of two codominant alleles of the gene. Subsequent determination of the molecular basis of a variant of the gene was carried out using DNA from homozygous individuals from a single Belgian family. It was of interest to characterize other variant individuals to determine whether all variants identified by IEF phenotyping were caused by the same mutation or whether other mutations occurred in the gene in different populations. Previous studies identified Mexican subjects who were heterozygous for the variant IEF phenotype. Denaturing gradient gel electrophoresis was used to localize the mutation in these subjects and to purify the variant allele for DNA sequence analysis. The results show that the mutation in this population is identical to that identified in the Belgian family, and no other mutations were detected in the gene. These data represent the first analysis of steroid hormone-binding globulin gene variation in heterozygous subjects and further support the conclusion of biallelism of the gene worldwide. 11 refs., 2 figs., 1 tab.

  18. Surfactant proteins gene variants in premature newborn infants with severe respiratory distress syndrome.

    Science.gov (United States)

    Somaschini, Marco; Presi, Silvia; Ferrari, Maurizio; Vergani, Barbara; Carrera, Paola

    2017-12-19

    Genetic surfactant dysfunction causes respiratory failure in term and near-term newborn infants, but little is known of such condition in prematures. We evaluated genetic surfactant dysfunction in premature newborn infants with severe RDS. A total of 68 preterm newborn infants with gestational age ≤32 weeks affected by unusually severe RDS were analysed for mutations in SFTPB, SFTPC and ABCA3. Therapies included oxygen supplementation, nasal CPAP, different modalities of ventilatory support, administration of exogenous surfactant, inhaled nitric oxide and steroids. Molecular analyses were performed on genomic DNA extracted from peripheral blood and Sanger sequencing of whole gene coding regions and intron junctions. In one case histology and electron microscopy on lung tissue was performed. Heterozygous previously described rare or novel variants in surfactant proteins genes ABCA3, SFTPB and SFTPC were identified in 24 newborn infants. In total, 11 infants died at age of 2 to 6 months. Ultrastructural analysis of lung tissue of one infant showed features suggesting ABCA3 dysfunction. Rare or novel genetic variants in genes encoding surfactant proteins were identified in a large proportion (35%) of premature newborn infants with particularly severe RDS. We speculate that interaction of developmental immaturity of surfactant production in association with abnormalities of surfactant metabolism of genetic origin may have a synergic worsening phenotypic effect.

  19. Genes y variantes polimórficas asociadas a la enfermedad cardiovascular

    Directory of Open Access Journals (Sweden)

    Eliana C. Portilla

    2014-09-01

    Full Text Available La aterosclerosis se considera como la principal causante de enfermedades cardiovasculares. Es una enfermedad multifactorial, caracterizada por procesos inflamatorios y la internalización continua de moléculas lipídicas al interior del vaso. Los estudios de genes candidato han proporcionado conocimiento acerca de la fisiopatología de esta enfermedad y han permitido la postulación de algunos polimorfismos como responsables de la susceptibilidad genética en diversas poblaciones. En particular, estos polimorfismos que modulan ciertas vías moleculares tales como el estrés oxidativo, el metabolismo lipídico y la trombogénesis se asocian con el desarrollo de las enfermedades cardiovasculares. Se han conducido varios estudios para identificar nuevas variantes asociadas con la enfermedad que han permitido el descubrimiento de nuevas vías de la enfermedad. Aunque el hallazgo de nuevos genes asociados a la enfermedad cardiovascular a través de enfoques como el escaneo global del genoma ha contribuido al entendimiento del desarrollo de esta condición, el conocimiento aún es limitado y poco concluyente. El objetivo de esta revisión es identificar los genes y las variantes polimórficas asociadas a la enfermedad cardiovascular, de acuerdo con los diferentes enfoques de análisis de asociación genética.

  20. 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.

  1. Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

    Science.gov (United States)

    Thomson, Cynthia J; Rajala, Amelia K; Carlson, Scott R; Rupert, Jim L

    2014-01-01

    Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

  2. A novel GBE1 gene variant in a child with glycogen storage disease type IV.

    Science.gov (United States)

    Said, Samar M; Murphree, Marine I; Mounajjed, Taofic; El-Youssef, Mounif; Zhang, Lizhi

    2016-08-01

    Glycogen storage disease type IV is an autosomal recessive disorder of carbohydrates caused by deficiency of amylo-1-4-glycanoglycosyltransferase, which leads to accumulation of amylopectin-like polysaccharides in tissues including liver, heart and neuromuscular system. More than 40 different mutations in the glycogen branching enzyme gene (GBE1) have been described. In this study, we report a 2-year-old boy who presented with developmental delay and muscle weakness. He subsequently was diagnosed with glycogen storage disease type IV based on a liver biopsy histology and electron microscopy. Glycogen branching enzyme activity was in the low range. Genetic analysis demonstrated a novel heterozygous variant (c.760A>G; p.Thr254Ala) in exon 6 of the GBE1 gene, which is believed to be pathogenic. This variant was inherited from the patient's mother who was asymptomatic with normal glycogen branching enzyme activity. Whole-exome sequencing failed to reveal additional variations in the GBE1 gene. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Rare variants in axonogenesis genes connect three families with sound–color synesthesia

    Science.gov (United States)

    Kucera, Katerina S.; Vino, Arianna; Asher, Julian E.; Baron-Cohen, Simon

    2018-01-01

    Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences. PMID:29507195

  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. Variants of the serotonin transporter gene and NEO-PI-R Neuroticism

    Science.gov (United States)

    Terracciano, Antonio; Balaci, Lenuta; Thayer, Jason; Scally, Matthew; Kokinos, Sarah; Ferrucci, Luigi; Tanaka, Toshiko; Zonderman, Alan B; Sanna, Serena; Olla, Nazario; Zuncheddu, Maria Antonietta; Naitza, Silvia; Busonero, Fabio; Uda, Manuela; Schlessinger, David; Abecasis, Goncalo; Costa, Paul T.

    2009-01-01

    The polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) is by far the most studied variant hypothesized to influence Neuroticism-related personality traits. The results of previous studies have been mixed and appear moderated by the personality questionnaire used. Studies that used the TCI to assess Harm Avoidance or the EPQ to assess Neuroticism have found no association with the 5-HTTLPR. However, studies that used the NEO-PI-R or related instruments (NEO-PI, NEO-FFI) to measure Neuroticism have found some evidence of association. This study examines the association of variants in the serotonin transporter gene in a sample from a genetically isolated population within Sardinia (Italy) that is several times larger than previous samples that used the NEO-PI-R (N=3,913). The association was also tested in a sample (N=548) from the Baltimore Longitudinal Study of Aging (BLSA), in which repeated NEO-PI-R assessments were obtained. In the SardiNIA sample, we found no significant association of the 5-HTTLPR genotypes with Neuroticism or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability). In the BLSA sample, we found lower scores on Neuroticism traits for the heterozygous group, which is inconsistent with previous studies. We also examined 8 SNPs in the SardiNIA (N=3,972) and 9 SNPs in the BLSA (N=1,182) that map within or near the serotonin transporter gene (SLC6A4), and found no association. Along with other large studies that used different phenotypic measures and found no association, this study substantially increases the evidence against a link between 5-HTT variants and Neuroticism-related traits. PMID:19199283

  6. Estrogen receptor gene variants are associated with anxiety disorders in older women.

    Science.gov (United States)

    Ryan, Joanne; Scali, Jacqueline; Carrière, Isabelle; Scarabin, Pierre-Yves; Ritchie, Karen; Ancelin, Marie-Laure

    2011-11-01

    Estrogen is thought to play a key role in anxiety, but it remains unknown whether genetic variants in the estrogen receptors (ERs) can influence the risk of anxiety. This study investigated whether ESR1 and ESR2 gene variants were associated with specific anxiety disorders in postmenopausal women and evaluated the potential modifying effect of hormone treatment (HT) on these associations. One thousand and ninety-two community-dwelling women aged 65 years and older were recruited as part of the ESPRIT Study in Montpellier, France. Anxiety was assessed using the Mini-International Neuropsychiatry Interview (MINI), according to DSM-IV criteria. Two ESR1 and three ESR2 polymorphisms were genotyped. The most common anxiety disorders were phobia (14.2%) and generalised anxiety disorder (GAD, 8%). The A allele of ESR2 rs1256049 was associated with an increased risk of GAD [OR: 2.06, 95% CI: 1.09-3.87], while both ESR1 polymorphisms were specifically associated with phobia. The C allele of ESR1 rs2234693 decreased the risk of phobia by 42% [95% CI: 0.41-0.83], and this remained significant even after Bonferroni correction. The G allele of ESR1 rs9340799 was associated with a 31% decreased phobia risk [95% CI: 0.49-0.96]. There was also evidence of a significant gene-environment interaction, where only women who were currently using HT had a reduced risk of phobia with these ESR1 gene variants. This study confirms earlier findings of an association between ESR1 and global anxiety in older women, however these associations varied depending on the anxiety syndrome and the use of HT. The results also suggest that the ESR2 may contribute to the genetic vulnerability to GAD, but these findings require further confirmation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. A Genetic Variant in the Distal Enhancer Region of the Human Renin Gene Affects Renin Expression.

    Directory of Open Access Journals (Sweden)

    Yasukazu Makino

    Full Text Available The high heritability of plasma renin activity was confirmed in recent investigations. A variation located near the strong enhancer of the human renin gene (REN, C-5312T, has been shown to have different transcription activity levels depending on its allele: the 5312T allele shows transcription levels that are 45% greater than those of the 5312C allele. The purpose of this study was to confirm the hypothesis that variations in the enhancer region of the REN gene are involved in regulating renal expression of renin.Sixty-four subjects with biopsy-proven renal diseases were included in this study (male/female: 35/29, age 41.9 ± 20.9 years, SBP/DBP 123.1 ± 23.7/73.4 ± 14.8 mmHg, s-Cr 0.93 ± 0.63 mg/dl. A genetic variant of REN, C-5312T, was assayed by PCR-RFLP and the TaqMan method. Total RNAs from a small part of the renal cortex were reverse-transcribed and amplified for REN and GAPDH with a real-time PCR system.Logarithmically transformed expression values of the relative ratio of REN to GAPDH (10-3 were as follows (mean ± SE: CC (26 cases, 0.016 ± 0.005; CT (33 cases, 0.047 ± 0.021 (p = 0.41 vs. CC; TT (5 cases, 0.198 ± 0.194 (p = 0.011 vs. CC, p < 0.031 vs. CT. Thus, significant differences in REN expression were observed among the genetic variants.The results suggest that variants in the enhancer region of the human renin gene have an effect on the expression levels of renin in renal tissue; this observation is in good accordance with the results of the transcriptional assay.

  8. Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China.

    Science.gov (United States)

    Liu, Ning; Huang, Qiuying; Li, Qingge; Zhao, Dehua; Li, Xiaole; Cui, Lixia; Bai, Ying; Feng, Yin; Kong, Xiangdong

    2017-10-05

    Phenylketonuria (PKU), which primarily results from a deficiency of phenylalanine hydroxylase (PAH), is one of the most common inherited inborn errors of metabolism that impairs postnatal cognitive development. The incidence of various PAH variations differs by race and ethnicity. The aim of the present study was to characterize the PAH gene variants of a Han population from Northern China. In total, 655 PKU patients and their families were recruited for this study; each proband was diagnosed both clinically and biochemically with phenylketonuria. Subjects were sequentially screened for single-base variants and exon deletions or duplications within PAH via direct Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). A spectrum of 174 distinct PAH variants was identified: 152 previously documented variants and 22 novel variants. While single-base variants were distributed throughout the 13 exons, they were particularly concentrated in exons 7 (33.3%), 11 (14.2%), 6 (13.2%), 12 (11.0%), 3 (10.4%), and 5 (4.4%). The predominant variant was p.Arg243Gln (17.7%), followed by Ex6-96A > G (8.3%), p.Val399 = (6.4%), p.Arg53His (4.7%), p.Tyr356* (4.7%), p.Arg241Cys (4.6%), p.Arg413Pro (4.6%), p.Arg111* (4.4%), and c.442-1G > A (3.4%). Notably, two patients were also identified as carrying de novo variants. The composition of PAH gene variants in this Han population from Northern China was distinct from those of other ethnic groups. As such, the construction of a PAH gene variant database for Northern China is necessary to lay a foundation for genetic-based diagnoses, prenatal diagnoses, and population screening.

  9. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

    Science.gov (United States)

    Brandom, Barbara W; Bina, Saiid; Wong, Cynthia A; Wallace, Tarina; Visoiu, Mihaela; Isackson, Paul J; Vladutiu, Georgirene D; Sambuughin, Nyamkhishig; Muldoon, Sheila M

    2013-05-01

    Mutations in the ryanodine receptor type 1 gene (RYR1) that encodes the skeletal muscle-specific intracellular calcium (Ca(2+)) release channel are a cause of malignant hyperthermia (MH). In this study, we examined RYR1 mutations in a large number of North American MH-susceptible (MHS) subjects without prior genetic diagnosis. RYR1 was examined in 120 unrelated MHS subjects from the United States in a tiered manner. The α-1 subunit of the dihydropyridine receptor gene (CACNA1S) was screened for 4 variants in subjects in whom no abnormality was found in ≥ 100 exons of RYR1. Ten known causative MH mutations were found in 26 subjects. Variants of uncertain significance in RYR1 were found in 36 subjects, 16 of which are novel. Novel variants in both RYR1 and CACNA1S were found in the 1 subject who died of MH. Two RYR1 variants were found in 4 subjects. Variants of uncertain significance were found outside and inside the hotspots of RYR1. Maximal contractures in the caffeine-halothane contracture test were greater in those who had a known MH mutation or variant of uncertain significance in RYR1 than in those who did not. The identification of novel RYR1 variants and previously observed RYR1 variants of uncertain significance in independent MHS families is necessary for demonstrating the significance of these variants for MH susceptibility and supports the need for functional studies of these variants. Continued reporting of the clinical phenotypes of MH is necessary for interpretation of genetic findings, especially because the pathogenicity of most of these genetic variants associated with MHS remains to be elucidated.

  10. Genomic organization, transcript variants and comparative analysis of the human nucleoporin 155 (NUP155) gene

    DEFF Research Database (Denmark)

    Zhang, Xiuqing; Yang, Huanming; Yu, Jun

    2002-01-01

    are approximately 80 and 8 kb in length, respectively. The human gene is ubiquitously expressed in many tissues analyzed and has two major transcript variants, resulted from an alternative usage of the 5' cryptic or consensus splice donor in intron 1 and two polyadenylation signals. We have also cloned DNA...... complementary to RNAs of the Nup155 orthologs from Fugu and mouse. Comparative analysis of the Nup155 orthologs in many species, including H. sapiens, Mus musculus, Rattus norvegicus, F. rubripes, Arabidopsis thaliana, Drosophila melanogaster, and Saccharomyces cerevisiae, has revealed two paralogs in S...

  11. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    Directory of Open Access Journals (Sweden)

    Pangilinan Faith

    2012-08-01

    Full Text Available Abstract Background Neural tube defects (NTDs are common birth defects (~1 in 1000 pregnancies in the US and Europe that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T and MTHFD1 rs2236225 (R653Q have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. Methods A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents, including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. Results Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury and included the known NTD risk factor MTHFD1 R653Q (rs2236225. The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele. Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. Conclusions To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive

  12. Genotyping of CCR5 gene, CCR2b and SDF1 variants related to HIV-1 infection in Gabonese subjects.

    Science.gov (United States)

    Mombo, Landry Erik; Bisseye, Cyrille; Mickala, Patrick; Ossari, Simon; Makuwa, Maria

    2015-01-01

    Given the magnitude of the HIV epidemic infection, many viral and human factors were analyzed, and the most decisive was the variant CCR5-Δ32. The presence of a low HIV prevalence (1.8%) in Gabon in the 1990s, compared to neighboring countries, represents a paradox that led us to search for viral and human genetic variants in this country. In this study, only variants of coreceptors and chemokines were investigated. Variants of the coding region of the CCR5 gene were analyzed by denaturing gradient gel electrophoresis, and then variants of SDF1 and CCR2b were determined by polymerase chain reaction-restriction fragment length polymorphism. Four rare variants of the CCR5 coreceptor were found, while CCR5-Δ32 and CCR5m303 variants were not found. No association with CCR2b-V64I (17%) and SDF1-3'A (2%) variants was determined in relation to HIV-1 infection in Gabonese patients. The paradox of HIV seroprevalence in Gabon, which ended in the 2000s, was not caused by human genetic variants but rather by environmental factors. © 2015 S. Karger AG, Basel.

  13. Prothrombotic gene variants as risk factors of acute myocardial infarction in young women

    Directory of Open Access Journals (Sweden)

    Tomaiuolo Rossella

    2012-11-01

    Full Text Available Abstract Background Acute myocardial infarction (AMI in young women represent an extreme phenotype associated with a higher mortality compared with similarly aged men. Prothrombotic gene variants could play a role as risk factors for AMI at young age. Methods We studied Factor V Leiden, FII G20210A, MTHFR C677T and beta-fibrinogen -455G>A variants by real-time PCR in 955 young AMI (362 females and in 698 AMI (245 females patients. The data were compared to those obtained in 909 unrelated subjects (458 females from the general population of the same geographical area (southern Italy. Results In young AMI females, the allelic frequency of either FV Leiden and of FII G20210A was significantly higher versus the general population (O.R.: 3.67 for FV Leiden and O.R.: 3.84 for FII G20210A; p Discussion and conclusion Our data confirm that young AMI in females is a peculiar phenotype with specific risk factors as the increased plasma procoagulant activity of FV and FII. On the contrary, the homozygous state for the 677T MTHFR variant may cause increased levels of homocysteine and/or an altered folate status and thus an increased risk for AMI, particularly in males. The knowledge of such risk factors (that may be easily identified by molecular analysis may help to improve prevention strategies for acute coronary diseases in specific risk-group subjects.

  14. Antioxidant response genes sequence variants and BPD susceptibility in VLBW infants.

    Science.gov (United States)

    Sampath, Venkatesh; Garland, Jeffery S; Helbling, Daniel; Dimmock, David; Mulrooney, Neil P; Simpson, Pippa M; Murray, Jeffrey C; Dagle, John M

    2015-03-01

    Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very-low-birth-weight (VLBW) infants. Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. In our cohort (n = 659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD, while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts.

  15. Anti-Oxidant Response Genes sequence variants and BPD susceptibility in VLBW infants

    Science.gov (United States)

    Sampath, Venkatesh; Garland, Jeffery S.; Helbling, Daniel; Dimmock, David; Mulrooney, Neil P.; Simpson, Pippa M.; Murray, Jeffrey C.; Dagle, John M.

    2015-01-01

    Background Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing anti-oxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very low birth weight (VLBW) infants. Methods Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1 and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data was analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. Results In our cohort (n=659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. Conclusions Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts. PMID:25518008

  16. Nucleolin is required for DNA methylation state and the expression of rRNA gene variants in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Frédéric Pontvianne

    2010-11-01

    Full Text Available In eukaryotes, 45S rRNA genes are arranged in tandem arrays in copy numbers ranging from several hundred to several thousand in plants. Although it is clear that not all copies are transcribed under normal growth conditions, the molecular basis controlling the expression of specific sets of rRNA genes remains unclear. Here, we report four major rRNA gene variants in Arabidopsis thaliana. Interestingly, while transcription of one of these rRNA variants is induced, the others are either repressed or remain unaltered in A. thaliana plants with a disrupted nucleolin-like protein gene (Atnuc-L1. Remarkably, the most highly represented rRNA gene variant, which is inactive in WT plants, is reactivated in Atnuc-L1 mutants. We show that accumulated pre-rRNAs originate from RNA Pol I transcription and are processed accurately. Moreover, we show that disruption of the AtNUC-L1 gene induces loss of symmetrical DNA methylation without affecting histone epigenetic marks at rRNA genes. Collectively, these data reveal a novel mechanism for rRNA gene transcriptional regulation in which the nucleolin protein plays a major role in controlling active and repressed rRNA gene variants in Arabidopsis.

  17. A novel homozygous variant in the SMOC1 gene underlying Waardenburg anophthalmia syndrome.

    Science.gov (United States)

    Ullah, Asmat; Umair, Muhammad; Ahmad, Farooq; Muhammad, Dost; Basit, Sulman; Ahmad, Wasim

    2017-01-01

    Waardenburg anophthalmia syndrome (WAS), also known as ophthalmo-acromelic syndrome or anophthalmia-syndactyly, is a rare congenital disorder that segregates in an autosomal recessive pattern. Clinical features of the syndrome include malformation of the eyes and the skeleton. Mostly, WAS is caused by mutations in the SMOC-1 gene. The present report describes a large consanguineous family of Pakistani origin segregating Waardenburg anophthalmia syndrome in an autosomal recessive pattern. Genotyping followed by Sanger sequencing was performed to search for a candidate gene. SNP genotyping using AffymetrixGeneChip Human Mapping 250K Nsp array established a single homozygous region among affected members on chromosome 14q23.1-q24.3 harboring the SMOC1 gene. Sequencing of the gene revealed a novel homozygous missense mutation (c.812G>A; p.Cys271Tyr) in the family. This is the first report of Waardenburg anophthalmia syndrome caused by a SMOC1 variant in a Pakistani population. The mutation identified in the present investigation extends the body of evidence implicating the gene SMOC-1 in causing WAS.

  18. Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome.

    Science.gov (United States)

    Di Napoli, Agnese; Warrier, Varun; Baron-Cohen, Simon; Chakrabarti, Bhismadev

    2015-01-01

    Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.

  19. 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...... aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males......, 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...

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

    Science.gov (United States)

    Hasholt, Lis; Ballegaard, Martin; Bundgaard, Henning; Christiansen, Michael; Law, Ian; Lund, Allan M; Norremolle, Anne; Krogh Rasmussen, Ase; Ravn, Kirstine; Tumer, Zeynep; Wibrand, Flemming; Feldt-Rasmussen, Ulla

    2017-12-01

    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 aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males, 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.

  1. Identification of twenty-nine novel germline unclassified variants of BRCA1 and BRCA2 genes in 1400 Italian individuals.

    Science.gov (United States)

    Santonocito, Concetta; Scapaticci, Margherita; Guarino, Donatella; Bartolini, Andrea; Minucci, Angelo; Concolino, Paola; Scambia, Giovanni; Paris, Ida; Capoluongo, Ettore

    2017-12-01

    Breast and/or ovarian cancers are complex multifactorial diseases caused by interaction of both genetic and non-genetic factors and characterized by predisposition to inheritance. BRCA1 and BRCA2 genes are the most clinically involved with these kinds of cancer and the spectrum of variants affecting these genes is very wide. In fact, point variants, large or small insertions/deletions, genomic rearrangements can be found in these patients, although a large number of variants with uncertain biological and clinical significance continues to be identified. Next-generation sequencing (NGS) technology is actually the most powerful tool for the discovering of causative mutations and novel disease genes, moreover it allows to make a rapid diagnosis of genetic variants giving fast, inexpensive and detailed genetic information. In this study, we report the screening of BRCA1 and BRCA2 genes on 1400 consecutive Caucasian patients with breast and/or ovarian cancer history or family risk, attending the oncogenetic ambulatory at the Foundation Policlinico Agostino Gemelli in Rome. We describe twenty-nine novel BRCA1 and BRCA2 variants detected in Italian individuals suffering from hereditary breast and ovarian cancer syndrome (HBOC). Data regarding novel variants can provide useful information not only at epidemiological but also at clinical level, allowing for the better managing of breast and ovarian cancer patients and their family members. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

    DEFF Research Database (Denmark)

    Druley, Todd E; Wang, Lihua; Lin, Shiow J

    2016-01-01

    : We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually...... from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation...

  3. Circadian gene variants and susceptibility to type 2 diabetes: a pilot study.

    Directory of Open Access Journals (Sweden)

    M Ann Kelly

    Full Text Available BACKGROUND: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. METHODOLOGY/PRINCIPAL FINDINGS: The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732 and without (N = 1780 type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium and white European cohorts (DIAGRAM+ using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 × 10(-5, while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003. Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively. CONCLUSIONS/SIGNIFICANCE: None of the selected circadian gene variants was associated with type

  4. Locus-Specific Databases and Recommendations to Strengthen Their Contribution to the Classification of Variants in Cancer Susceptibility Genes

    NARCIS (Netherlands)

    Greenblatt, Marc S.; Brody, Lawrence C.; Foulkes, William D.; Genuardi, Maurizio; Hofstra, Robert M. W.; Olivier, Magali; Plon, Sharon E.; Sijmons, Rolf H.; Sinilnikova, Olga; Spurdle, Amanda B.

    2008-01-01

    Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play

  5. 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

  6. MTHFR , prothrombin and Factor V gene variants in Turkish patients with coronary artery stenosis

    Directory of Open Access Journals (Sweden)

    Müge Caner

    2008-01-01

    Full Text Available Many epidemiological studies have reported an association between hemostatic factors and risk of both coronary and peripheral artery diseases. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP analysis, we investigated the association between coronary artery disease and polymorphisms in the methylenetetrahydrofolate reductase ( MTHFR C677T and A1298C, prothrombin (G20210A, and factor V (A4070G genes. We screened these gene variants in 174 subjects who had undergone coronary angiography - 115 patients with patent coronary artery disease (grade 3 vessel disease, i.e. , significant coronary stenosis, and 59 healthy controls with grade 0 vessel disease. The analysis of our data did not show any statistically significant association between coronary artery disease (CAD and the investigated polymorphisms.

  7. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

    Science.gov (United States)

    Smith, Douglas R; Stanley, Christine M; Foss, Theodore; Boles, Richard G; McKernan, Kevin

    2017-01-01

    Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  8. Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy.

    Science.gov (United States)

    Gianni, Davide; Li, Airong; Tesco, Giuseppina; McKay, Kenneth M; Moore, John; Raygor, Kunal; Rota, Marcello; Gwathmey, Judith K; Dec, G William; Aretz, Thomas; Leri, Annarosa; Semigran, Marc J; Anversa, Piero; Macgillivray, Thomas E; Tanzi, Rudolph E; del Monte, Federica

    2010-03-16

    Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.

  9. Extensive libraries of gene truncation variants generated by in vitro transposition

    Science.gov (United States)

    Morelli, Aleardo; Cabezas, Yari; Mills, Lauren J.

    2017-01-01

    Abstract The detailed analysis of the impact of deletions on proteins or nucleic acids can reveal important functional regions and lead to variants with improved macromolecular properties. We present a method to generate large libraries of mutants with deletions of varying length that are randomly distributed throughout a given gene. This technique facilitates the identification of crucial sequence regions in nucleic acids or proteins. The approach utilizes in vitro transposition to generate 5΄ and 3΄ fragment sub-libraries of a given gene, which are then randomly recombined to yield a final library comprising both terminal and internal deletions. The method is easy to implement and can generate libraries in three to four days. We used this approach to produce a library of >9000 random deletion mutants of an artificial RNA ligase enzyme representing 32% of all possible deletions. The quality of the library was assessed by next-generation sequencing and detailed bioinformatics analysis. Finally, we subjected this library to in vitro selection and obtained fully functional variants with deletions of up to 18 amino acids of the parental enzyme that had been 95 amino acids in length. PMID:28130425

  10. Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.

    Science.gov (United States)

    Brandler, William M; Morris, Andrew P; Evans, David M; Scerri, Thomas S; Kemp, John P; Timpson, Nicholas J; St Pourcain, Beate; Smith, George Davey; Ring, Susan M; Stein, John; Monaco, Anthony P; Talcott, Joel B; Fisher, Simon E; Webber, Caleb; Paracchini, Silvia

    2013-01-01

    Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.

  11. RNA Analysis as a Tool to Determine Clinically Relevant Gene Fusions and Splice Variants.

    Science.gov (United States)

    Teixidó, Cristina; Giménez-Capitán, Ana; Molina-Vila, Miguel Ángel; Peg, Vicente; Karachaliou, Niki; Rodríguez-Capote, Alejandra; Castellví, Josep; Rosell, Rafael

    2018-04-01

    - Technologic advances have contributed to the increasing relevance of RNA analysis in clinical oncology practice. The different genetic aberrations that can be screened with RNA include gene fusions and splice variants. Validated methods of identifying these alterations include fluorescence in situ hybridization, immunohistochemistry, reverse transcription-polymerase chain reaction, and next-generation sequencing, which can provide physicians valuable information on disease and treatment of cancer patients. - To discuss the standard techniques available and new approaches for the identification of gene fusions and splice variants in cancer, focusing on RNA analysis and how analytic methods have evolved in both tissue and liquid biopsies. - This is a narrative review based on PubMed searches and the authors' own experiences. - Reliable RNA-based testing in tissue and liquid biopsies can inform the diagnostic process and guide physicians toward the best treatment options. Next-generation sequencing methodologies permit simultaneous assessment of molecular alterations and increase the number of treatment options available for cancer patients.

  12. Spread of a new parasitic B chromosome variant is facilitated by high gene flow.

    Directory of Open Access Journals (Sweden)

    María Inmaculada Manrique-Poyato

    Full Text Available The B24 chromosome variant emerged several decades ago in a Spanish population of the grasshopper Eyprepocnemis plorans and is currently reaching adjacent populations. Here we report, for the first time, how a parasitic B chromosome (a strictly vertically transmitted parasite expands its geographical range aided by high gene flow in the host species. For six years we analyzed B frequency in several populations to the east and west of the original population and found extensive spatial variation, but only a slight temporal trend. The highest B24 frequency was found in its original population (Torrox and it decreased closer to both the eastern and the western populations. The analysis of Inter Simple Sequence Repeat (ISSR markers showed the existence of a low but significant degree of population subdivision, as well as significant isolation by distance (IBD. Pairwise Nem estimates suggested the existence of high gene flow between the four populations located in the Torrox area, with higher values towards the east. No significant barriers to gene flow were found among these four populations, and we conclude that high gene flow is facilitating B24 diffusion both eastward and westward, with minor role for B24 drive due to the arrival of drive suppressor genes which are also frequent in the donor population.

  13. Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals.

    Science.gov (United States)

    Hagemeier, Jesper; Ramanathan, Murali; Schweser, Ferdinand; Dwyer, Michael G; Lin, Fuchun; Bergsland, Niels; Weinstock-Guttman, Bianca; Zivadinov, Robert

    2018-01-01

    Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE : rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p men, but only when they had a wild-type allele (p brain iron in healthy and disease states may be influenced by genetic factors.

  14. Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging.

    Science.gov (United States)

    Poon, Audrey H; Houseman, E Andres; Ryan, Louise; Sparrow, David; Vokonas, Pantel S; Litonjua, Augusto A

    2014-07-01

    A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men. We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time. One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time. Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes.

    Science.gov (United States)

    Raza, M Hashim; Domingues, Carlos E F; Webster, Ronald; Sainz, Eduardo; Paris, Emily; Rahn, Rachel; Gutierrez, Joanne; Chow, Ho Ming; Mundorff, Jennifer; Kang, Chang-Soo; Riaz, Naveeda; Basra, Muhammad A R; Khan, Shaheen; Riazuddin, Sheikh; Moretti-Ferreira, Danilo; Braun, Allen; Drayna, Dennis

    2016-04-01

    Homozygous mutations in GNPTAB and GNPTG are classically associated with mucolipidosis II (ML II) alpha/beta and mucolipidosis III (ML III) alpha/beta/gamma, which are rare lysosomal storage disorders characterized by multiple pathologies. Recently, variants in GNPTAB, GNPTG, and the functionally related NAGPA gene have been associated with non-syndromic persistent stuttering. In a worldwide sample of 1013 unrelated individuals with non-syndromic persistent stuttering we found 164 individuals who carried a rare non-synonymous coding variant in one of these three genes. We compared the frequency of these variants with those in population-matched controls and genomic databases, and their location with those reported in mucolipidosis. Stuttering subjects displayed an excess of non-synonymous coding variants compared to controls and individuals in the 1000 Genomes and Exome Sequencing Project databases. We identified a total of 81 different variants in our stuttering cases. Virtually all of these were missense substitutions, only one of which has been previously reported in mucolipidosis, a disease frequently associated with complete loss-of-function mutations. We hypothesize that rare non-synonymous coding variants in GNPTAB, GNPTG, and NAGPA may account for as much as 16% of persistent stuttering cases, and that variants in GNPTAB and GNPTG are at different sites and may in general, cause less severe effects on protein function than those in ML II alpha/beta and ML III alpha/beta/gamma.

  16. Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity

    OpenAIRE

    Froehlich Tanja K.; Amstutz Ursula; Aebi Stefan; Joerger Markus; Largiader Carlo R.

    2015-01-01

    We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early onset fluoropyrimidine (FP) toxicity in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129 5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP based chemotherapy. Associations of DPYD variants and haplotypes with hematologic gastrointestinal infectious and...

  17. Association of ICAM-1 and HMGA1 Gene Variants with Retinopathy in Type 2 Diabetes Mellitus Among Chinese Individuals.

    Science.gov (United States)

    Lv, Zhiping; Li, Ying; Wu, Yongzhong; Qu, Yi

    2016-08-01

    To evaluate the association of intercellular cell-adhesion molecule 1 (ICAM-1) and high-mobility group A1 (HMGA1) gene variants with diabetic retinopathy (DR) in a Chinese type 2 diabetes mellitus (T2DM) cohort. A total of 792 patients with T2DM were enrolled and categorized into two groups: (1) the DR group consisted of 448 patients, which was further subclassified into the proliferative DR (PDR) group with 220 patients and the nonproliferative DR (NPDR) group with 228 patients; (2) the diabetes without retinopathy (DNR) group comprised 344 patients who had no signs of DR. The single-nucleotide polymorphism (SNP) rs5498 in ICAM-1 gene and IVS5-13insC variant in HMGA1 gene were genotyped. No evident association was found in the allele frequencies between SNP rs5498 in ICAM-1 gene and DR patients; the combined p values for the additive, dominant, and recessive models in genotype were greater than 0.05. No significant association was identified between the IVS5-13insC variant in HMGA1 gene and DR individuals. Our results revealed that SNP rs5498 in ICAM-1 gene and IVS5-13insC variant in HMGA1 gene were not associated with the susceptibility of DR in the Chinese T2DM cohort.

  18. KCNQ1 Gene Variants in Large Asymptomatic Populations: Considerations for Genomic Screening of Military Cohorts.

    Science.gov (United States)

    Kruszka, Paul; Weiss, Karin; Hadley, Donald W

    2017-03-01

    The advances in genomic technology of large populations make the potential for genomic screening of military cohorts and recruits feasible, affording the potential to identify at-risk individuals before occurrence of potentially life-threatening events. Exploring sudden cardiac death, known to cause significant morbidity and mortality in young military service members, we focused on the most common gene associated with long QT syndrome (LQTS), KCNQ1. Using the publicly available database Exome Aggregation Consortium as a surrogate for a military population, variants in KCNQ1 were filtered on the basis of population prevalence, classification as a disease mutation in the Human Gene Mutation database, and classification as pathogenic or likely pathogenic in the ClinVar database. Variant prevalence and penetrance estimates were derived using reports from the medical literature. We showed that in a population of over 60,000 individuals, at least 97 (0.2%) individuals would harbor a potentially pathogenic mutation in KCNQ1, which is more prevalent than expected on the basis of current medical literature (p = 0.0004). KCNQ1 variant penetrance was estimated to be only 9% to 17%. Identifying the importance of large genomic studies, our study demonstrates that 46% of pathogenic mutations in KCNQ1 had a population frequency of less than 1:50,000. Screening a large database with genomic screening for a condition that is relevant to active duty service members results in the identification of many individuals with potentially pathogenic mutations in the KCNQ1 gene, which has profound implications for screening military or other adult cohorts in terms of over diagnosis, overtreatment, and increased medical resource usage. This study of KCNQ1 provides a platform for consideration of other genes that cause sudden cardiac death as well as other medically actionable hereditary disorders for which genomic screening is available. We review the potential benefits of genomic screening

  19. Normalization of oligonucleotide arrays based on the least-variant set of genes

    Science.gov (United States)

    Calza, Stefano; Valentini, Davide; Pawitan, Yudi

    2008-01-01

    Background It is well known that the normalization step of microarray data makes a difference in the downstream analysis. All normalization methods rely on certain assumptions, so differences in results can be traced to different sensitivities to violation of the assumptions. Illustrating the lack of robustness, in a striking spike-in experiment all existing normalization methods fail because of an imbalance between up- and down-regulated genes. This means it is still important to develop a normalization method that is robust against violation of the standard assumptions Results We develop a new algorithm based on identification of the least-variant set (LVS) of genes across the arrays. The array-to-array variation is evaluated in the robust linear model fit of pre-normalized probe-level data. The genes are then used as a reference set for a non-linear normalization. The method is applicable to any existing expression summaries, such as MAS5 or RMA. Conclusion We show that LVS normalization outperforms other normalization methods when the standard assumptions are not satisfied. In the complex spike-in study, LVS performs similarly to the ideal (in practice unknown) housekeeping-gene normalization. An R package called lvs is available in . PMID:18318917

  20. Genetic variants in glucose-6-phosphate isomerase gene as prognosis predictors in hepatocellular carcinoma.

    Science.gov (United States)

    Lyu, Zhuomin; Chen, Yibing; Guo, Xu; Zhou, Feng; Yan, Zhaoyong; Xing, Jinliang; An, Jiaze; Zhang, Hongxin

    2016-12-01

    Metabolic reprogramming is an important hallmark of cancer cells, including the alterations of activity and expression of enzymes in glucose metabolism. Previous studies have demonstrated the critical role of glucise-6-phosphate isomerase (GPI) in cancer initiation, metastasis and progression. However, the significance of single nucleotide polymorphisms (SNPs) in GPI gene has not been investigated in hepatocellular carcinoma (HCC). In this study, a total of 3 functional SNPs in GPI gene were genotyped in 492 HCC patients with surgical treatment. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the analysis of overall survival (OS) and recurrence-free survival (RFS). The homozygous variant genotypes of rs7248411 in mRNA splice sites of GPI gene were significantly associated with an increased risk of death in the multivariate analysis (Hazard ratio [HR], 2.07; 95% confidence interval [95% CI]: 1.16-3.68 in a recessive model). In stratified analysis, the association remained significant in patients with high α-fetal protein (AFP) level (HR=2.37, 95% CI 1.25-4.49). Moreover, we identified the interaction between rs7248411 and AFP level in predicting the prognosis of HCC patients (P for interaction<0.001). Our data suggest that GPI gene polymorphism may serve as potential biomarkers to predict the OS of HCC. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway.

    Science.gov (United States)

    Paré-Brunet, Laia; Glubb, Dylan; Evans, Patrick; Berenguer-Llergo, Antoni; Etheridge, Amy S; Skol, Andrew D; Di Rienzo, Anna; Duan, Shiwei; Gamazon, Eric R; Innocenti, Federico

    2014-02-01

    Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis-eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis-eQTLs provided mechanistic evidence for two genome-wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role. © 2013 WILEY PERIODICALS, INC.

  2. Association analysis of genetic variants in the myosin IXB gene in acute pancreatitis.

    Directory of Open Access Journals (Sweden)

    Rian M Nijmeijer

    Full Text Available INTRODUCTION: Impairment of the mucosal barrier plays an important role in the pathophysiology of acute pancreatitis. The myosin IXB (MYO9B gene and the two tight-junction adaptor genes, PARD3 and MAGI2, have been linked to gastrointestinal permeability. Common variants of these genes are associated with celiac disease and inflammatory bowel disease, two other conditions in which intestinal permeability plays a role. We investigated genetic variation in MYO9B, PARD3 and MAGI2 for association with acute pancreatitis. METHODS: Five single nucleotide polymorphisms (SNPs in MYO9B, two SNPs in PARD3, and three SNPs in MAGI2 were studied in a Dutch cohort of 387 patients with acute pancreatitis and over 800 controls, and in a German cohort of 235 patients and 250 controls. RESULTS: Association to MYO9B and PARD3 was observed in the Dutch cohort, but only one SNP in MYO9B and one in MAGI2 showed association in the German cohort (p < 0.05. Joint analysis of the combined cohorts showed that, after correcting for multiple testing, only two SNPs in MYO9B remained associated (rs7259292, p = 0.0031, odds ratio (OR 1.94, 95% confidence interval (95% CI 1.35-2.78; rs1545620, p = 0.0006, OR 1.33, 95% CI 1.16-1.53. SNP rs1545620 is a non-synonymous SNP previously suspected to impact on ulcerative colitis. None of the SNPs showed association to disease severity or etiology. CONCLUSION: Variants in MYO9B may be involved in acute pancreatitis, but we found no evidence for involvement of PARD3 or MAGI2.

  3. Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances.

    Science.gov (United States)

    Kao, A C C; Rojnic Kuzman, M; Tiwari, A K; Zivkovic, M V; Chowdhury, N I; Medved, V; Kekin, I; Zai, C C; Lieberman, J A; Meltzer, H Y; Bozina, T; Bozina, N; Kennedy, J L; Sertic, J; Müller, D J

    2014-07-01

    Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. 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

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

    Science.gov (United States)

    Leon Rodriguez, Daniel A; Acosta-Herrera, Marialbert; 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.

  6. 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

    2016-01-01

    Background & Aims Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed ≤5 y of age, 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. Methods 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 (ages 3 weeks 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 post-processing and variant calling. Following functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency 1 Mbp of coding sequence, were selected from the whole exome data. Our analysis revealed 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. Conclusions 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 identification of previously unidentified IBD-associated variants. PMID:26193622

  7. SAH Gene Variants Revisited in the European Project on Genes in Hypertension

    Czech Academy of Sciences Publication Activity Database

    Tikhonoff, V.; Staessen, J.A.; Kuznetsova, T.; Thijs, L.; Hasenkamp, S.; Stolarz, K.; Seidlerová, J.; Filipovský, J.; Nikitin, Y.; Peleška, Jan; Kawecka-Jaszcz, K.; Casiglia, E.; Brand-Herrmann, S.M.; Brand, E.

    2008-01-01

    Roč. 26, č. 2 (2008), s. 244-250 ISSN 0263-6352 Institutional research plan: CEZ:AV0Z10300504 Keywords : body mass index * hypertension * population study * SAH gene * serum lipids Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 5.132, year: 2008

  8. Association of IL8 and IL10 gene allelic variants with ischemic stroke risk and prognosis

    Directory of Open Access Journals (Sweden)

    Kucherenko A. M.

    2014-05-01

    Full Text Available Aim. Evaluating a role of IL8 gene –781 C/T, and IL10 gene –592C/A polymorphisms as genetic markers of ischemic stroke risk. Methods. A case group consisted of 183 patients with ischemic stroke, which were treated in the Brain Vascular Pathology unit of SI «Institute of Gerontology of NAMS of Ukraine». A control group included 88 healthy individuals older than 65 years without any history of ischemic stroke. Genotyping was performed using PCR followed by restriction fragment length polymorphism analysis. Results. Significantly (P < 0,05 higher frequency of IL8 –781T allele carriers in the case group (81,6 % comparing to the control (70,1% was revealed. –781T allele carriers have nearly 2-fold increased ischemic stroke development risk (OR = 1.886; 95 % CI: 1.041–3.417. Significantly (P < 0,05 higher frequency of IL10 gene –592C allele carriers was observed in the patients with ischemic stroke (98,2% comparing to the control (90,7 %. The ischemic stroke development risk in such individuals is 5-fold increased (OR = 5.71; 95 % CI: 1.48–22.11. It was revealed that –592C allele homozygotes with ischemic stroke have more than 2-fold higher improvement (according to the Rankin scale chances during the first fortnight of treatment (OR = 2,76; 95 % CI: 1,26–6,07. Conclusions. On the basis of the obtained significant differences, IL8 gene –781T and IL10 gene –592C variants may be considered the factors of ischemic stroke hereditary susceptibility. Besides, IL10 gene –592CC genotype is a genetic marker of the patients state positive dynamics during first two weeks of treatment.

  9. FEATURES OF THE CLINICAL SIGNIFICANCE OF POLYMORPHIC VARIANTS OF ENOS AND AGTR2 GENES IN PATIENTS WITH CAD

    Directory of Open Access Journals (Sweden)

    A. L. Khokhlov

    2016-01-01

    Full Text Available Coronary heart disease (CHD is a major cause of mortality. Morphological substrate of CHD in most cases is atherosclerosis, which is based on structural genes polymorphism eNOS and AGTR2. The aim of the study was to study the prevalence of eNOS and AGTR2 genes in patients with coronary artery disease and the association of these genes with coronary heart disease. The study involved 187 patients aged 36 to 86 years (62,2±11,2 with different forms of CHD: stable and unstable angina, myocardial infarction and 45 people without CHD. Determination of gene polymorphisms was performed by real-time PCR analyzer of nucleic acids IQ 5 Bio-Rad. Statistical analysis was performed using Statistica 10.0. The study revealed a significant difference between the incidence of homozygous AA allelic variant gene AGTR2 group of patients with myocardial infarction and the comparison group; polymorphic variant AA AGTR2 gene is associated with earlier onset of coronary artery disease; It found that carriers of the polymorphic variant gene GA AGTR2 beginning statistically CHD occurred significantly later than in carriers of alleles GG and AA; age CHD debut TT allele carriers of the eNOS gene is associated with an earlier onset of the disease and statistically significantly different from the age of first CHD in carriers of alleles of polymorphic variants of GG and GT; revealed a positive correlation between the polymorphic allele AGTR2 gene with the presence of arterial hypertension in patients with coronary artery disease; It determined that the T allele carriers of the polymorphic gene eNOS is associated more early onset of hypertension, found the association of the polymorphic allele gene AGTR2 the need to use higher doses of ACE inhibitor — perindopril.

  10. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    International Nuclear Information System (INIS)

    Trubicka, Joanna; Byrski, Tomasz; Gronwald, Jacek; Złowocka, Elżbieta; Kładny, Józef; Banaszkiewicz, Zbigniew; Wiśniowski, Rafał; Kowalska, Elżbieta; Lubinski, Jan; Scott, Rodney J; Grabowska-Kłujszo, Ewa; Suchy, Janina; Masojć, Bartłomiej; Serrano-Fernandez, Pablo; Kurzawski, Grzegorz; Cybulski, Cezary; Górski, Bohdan; Huzarski, Tomasz

    2010-01-01

    CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations

  11. Novel Streptococcus infantarius subsp. infantarius variants harboring lactose metabolism genes homologous to Streptococcus thermophilus.

    Science.gov (United States)

    Jans, Christoph; Gerber, Andrea; Bugnard, Joséphine; Njage, Patrick Murigu Kamau; Lacroix, Christophe; Meile, Leo

    2012-08-01

    Streptococcus infantarius subsp. infantarius belongs to the Streptococcus bovis/Streptococcus equinus complex (SBSEC) commonly associated with human and animal infections. We elucidated the lactose metabolism of S. infantarius subsp. infantarius predominant in African fermented milk products. S. infantarius subsp. infantarius isolates (n = 192) were identified in 88% of spontaneously fermented camel milk suusac samples (n = 24) from Kenya and Somalia at log₁₀ 8.2-8.5 CFU mL⁻¹. African S. infantarius isolates excreted stoichiometric amounts of galactose when grown on lactose, exhibiting a metabolism similar to Streptococcus thermophilus and distinct from their type strain. African S. infantarius subsp. infantarius CJ18 harbors a regular gal operon with 99.7-100% sequence identity to S. infantarius subsp. infantarius ATCC BAA-102(T) and a gal-lac operon with 91.7-97.6% sequence identity to S. thermophilus, absent in all sequenced SBSEC strains analyzed. The expression and functionality of lacZ was demonstrated in a β-galactosidase assay. The gal-lac operon was identified in 100% of investigated S. infantarius isolates (n = 46) from suusac samples and confirmed in Malian fermented cow milk isolates. The African S. infantarius variant potentially evolved through horizontal gene transfer of an S. thermophilus-homologous lactose pathway. Safety assessments are needed to identify any putative health risks of this novel S. infantarius variant. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. A Common Variant in the SETD7 Gene Predicts Serum Lycopene Concentrations

    Directory of Open Access Journals (Sweden)

    Christopher R. D’Adamo

    2016-02-01

    Full Text Available Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10−9. Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841 in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.

  13. Inflammatory gene variants in the Tsimane, an indigenous Bolivian population with a high infectious load.

    Science.gov (United States)

    Vasunilashorn, Sarinnapha; Finch, Caleb E; Crimmins, Eileen M; Vikman, Suvi A; Stieglitz, Jonathan; Gurven, Michael; Kaplan, Hillard; Allayee, Hooman

    2011-01-01

    The Tsimane of lowland Bolivia are an indigenous forager-farmer population living under conditions resembling pre-industrial European populations, with high infectious morbidity, high infection and inflammation, and shortened life expectancy. Analysis of 917 persons ages 5 to 60+ showed that allele frequencies of 9 SNPs examined in the apolipoprotein E (apoE), C-reactive protein (CRP), and interleukin-6 (IL-6) genes differed from some European, African, and north Asian-derived populations. The apoE2 allele was absent, whereas four SNPs related to CRP and IL-6 were monomorphic: CRP (rs1800947, rs3093061, and rs3093062) and IL-6 (rs1800795). No significant differences in apoE, CRP, and IL-6 variants across age were found CRP levels were higher in carriers of two CRP proinflammatory SNPs, whereas they were lower in carriers of apoE4. Taken together the evidence for (1) different allele frequencies between the Tsimane and other populations and (2) the correlations of CRP and apoE alleles with blood CRP may suggest that these variants are under selection in response to a high infection environment.

  14. Fusion gene and splice variant analyses in liquid biopsies of lung cancer patients.

    Science.gov (United States)

    Aguado, Cristina; Giménez-Capitán, Ana; Karachaliou, Niki; Pérez-Rosado, Ana; Viteri, Santiago; Morales-Espinosa, Daniela; Rosell, Rafael

    2016-10-01

    Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance. In contrast, a blood extraction is safe, can be performed at many time points during the course disease and encourages appropriate therapy modifications, potentially improving the patient's clinical outcome and quality of life. Fusion of the tyrosine kinase genes anaplastic lymphoma kinase ( ALK ), C-ROS oncogen 1 ( ROS 1 ), rearranged during transfection ( RET ) and neurotrophic tyrosine kinase 1 ( NTRK1 ) occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors. In addition, a MET splicing variant of exon 14, has been reported in 2-4% of lung adenocarcinoma and recent studies suggests that targeted therapies inhibiting MET signaling would be beneficial for patients with this alteration. In this review, we will summarize the new techniques recently developed to detect ALK , RET , ROS and NTRK1 fusions and MET exon 14 splicing variant in liquid biopsy using plasma, serum, circulating tumor cells (CTCs), platelets and exosomes as starting material.

  15. Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia

    International Nuclear Information System (INIS)

    Mosor, Maria; Ziółkowska-Suchanek, Iwona; Nowicka, Karina; Dzikiewicz-Krawczyk, Agnieszka; Januszkiewicz–Lewandowska, Danuta; Nowak, Jerzy

    2013-01-01

    The MRE11, RAD50, and NBN genes encode proteins of the MRE11-RAD50-NBN (MRN) complex involved in cellular response to DNA damage and the maintenance of genome stability. In our previous study we showed that the germline p.I171V mutation in NBN may be considered as a risk factor in the development of childhood acute lymphoblastic leukemia (ALL) and some specific haplotypes of that gene may be associated with childhood leukemia. These findings raise important questions about the role of mutations in others genes of the MRN complex in childhood leukemia. The aim of this study was to answer the question whether MRE11 and RAD50 alterations may be associated with childhood ALL or AML. We estimated the frequency of constitutional mutations and polymorphisms in selected regions of MRE11, RAD50, and NBN in the group of 220 children diagnosed with childhood leukemias and controls (n=504/2200). The analysis was performed by specific amplification of region of interest by PCR and followed by multi-temperature single-strand conformation polymorphism (PCR-MSSCP) technique. We performed two molecular tests to examine any potential function of the detected the c.551+19G>A SNP in RAD50 gene. To our knowledge, this is the first analysis of the MRE11, RAD50 and NBN genes in childhood leukemia. The frequency of either the AA genotype or A allele of RAD50-rs17166050 were significantly different in controls compared to leukemia group (ALL+AML) (p<0.0019 and p<0.0019, respectively). The cDNA analysis of AA or GA genotypes carriers has not revealed evidence of splicing abnormality of RAD50 pre-mRNA. We measured the allelic-specific expression of G and A alleles at c.551+19G>A and the statistically significant overexpression of the G allele has been observed. Additionally we confirmed the higher incidence of the p.I171V mutation in the leukemia group (7/220) than among controls (12/2400) (p<0.0001). The formerly reported sequence variants in the RAD50 and MRE11 gene may not constitute a

  16. Common Variants in the TBX5 Gene Associated with Atrial Fibrillation in a Chinese Han Population.

    Science.gov (United States)

    Zhang, Rongfeng; Tian, Xiaochen; Gao, Lianjun; Li, Huihua; Yin, Xiaomeng; Dong, Yingxue; Yang, Yanzong; Xia, Yunlong

    2016-01-01

    PR interval variations have recently been associated with an increased risk of long-term atrial fibrillation (AF), heart block and all-cause mortality. Genome-wide association studies have linked the PR interval with several common variants in the TBX5 gene. Several variants in the TBX5 gene, including rs7312625 and rs883079, have been associated with AF. The purpose of this study was to determine the association of single-nucleotide polymorphisms (SNPs) in the TBX5 gene, rs7312625 and rs883079, with AF in Chinese Han patients. In this case-control association study, large cohorts of AF patients (n = 1132) and controls (n = 1206) were recruited from different hospitals. The genotyping was performed using a Rotor-Gene TM 6000 high-resolution melt system. Rs7312625, rs3825214 and rs883079 were analyzed. We found that SNP 3825214 was significantly associated with AF (P-obs = 0.002, odds ratio [OR] = 0.82), and lone AF (P-obs = 6.77x10-5, odds ratio [OR] = 0.71). SNP rs7312625 was significantly associated with lone AF (P-obs = 0.015, odds ratio [OR] = 1.27), although its association with AF was not significant. No significant association of SNP rs883079 with AF or lone AF was observed. Thus, we analyzed the interaction among these three loci. We demonstrated significant interaction among rs3825214, rs7312625 and rs883079. Four-locus risk alleles showed the highest odds ratio in combined rs3825214 and rs7312625 (P-obsSix-locus risk alleles showed the highest odds ratio in combined rs3825214, rs7312625 and rs 883079(P-obs<0.0001, odds ratio [OR] = 2.35). Significance was established with the trend test (P<0.0001). For the first time, we report the strong association of SNP rs3825214 in the TBX5 gene with AF and lone AF in a Chinese Han population. Rs7312625 was significantly associated with lone AF, and snp-snp interaction increased the risk of atrial fibrillation. Our data might provide new insights into understanding AF pathogenesis and designing novel genetic

  17. Common Variants in the TBX5 Gene Associated with Atrial Fibrillation in a Chinese Han Population.

    Directory of Open Access Journals (Sweden)

    Rongfeng Zhang

    Full Text Available PR interval variations have recently been associated with an increased risk of long-term atrial fibrillation (AF, heart block and all-cause mortality. Genome-wide association studies have linked the PR interval with several common variants in the TBX5 gene. Several variants in the TBX5 gene, including rs7312625 and rs883079, have been associated with AF. The purpose of this study was to determine the association of single-nucleotide polymorphisms (SNPs in the TBX5 gene, rs7312625 and rs883079, with AF in Chinese Han patients.In this case-control association study, large cohorts of AF patients (n = 1132 and controls (n = 1206 were recruited from different hospitals. The genotyping was performed using a Rotor-Gene TM 6000 high-resolution melt system. Rs7312625, rs3825214 and rs883079 were analyzed. We found that SNP 3825214 was significantly associated with AF (P-obs = 0.002, odds ratio [OR] = 0.82, and lone AF (P-obs = 6.77x10-5, odds ratio [OR] = 0.71. SNP rs7312625 was significantly associated with lone AF (P-obs = 0.015, odds ratio [OR] = 1.27, although its association with AF was not significant. No significant association of SNP rs883079 with AF or lone AF was observed. Thus, we analyzed the interaction among these three loci. We demonstrated significant interaction among rs3825214, rs7312625 and rs883079. Four-locus risk alleles showed the highest odds ratio in combined rs3825214 and rs7312625 (P-obs<0.0001, odds ratio [OR] = 2.21. Six-locus risk alleles showed the highest odds ratio in combined rs3825214, rs7312625 and rs 883079(P-obs<0.0001, odds ratio [OR] = 2.35. Significance was established with the trend test (P<0.0001.For the first time, we report the strong association of SNP rs3825214 in the TBX5 gene with AF and lone AF in a Chinese Han population. Rs7312625 was significantly associated with lone AF, and snp-snp interaction increased the risk of atrial fibrillation. Our data might provide new insights into understanding AF

  18. Reporter system for the detection of in vivo gene conversion: changing colors from blue to green using GFP variants.

    Science.gov (United States)

    Sommer, Jeffrey R; Alderson, Jon; Laible, Goetz; Petters, Robert M

    2006-06-01

    We have devised a system for the study of in vivo gene correction based on the detection of color variants of the green fluorescent protein (GFP) from the jellyfish Aequorea victoria. The intensity and spectra of the fluorescence emitted by the blue (BFP) and red-shifted (EGFP) variants of GFP differ from each other. We modified one nucleotide from an EGFP expression vector that we predicted would yield a blue variant (TAC-CAC, Tyr(66)-His(66)). Cells that were either transiently or stably transfected with the reporter system were used to test the functionality and feasibility of the detection of in vivo gene correction. A thio-protected single-stranded oligonucleotide designed to convert the genotype of the blue variant to that of the EGFP variant by the correction of a single base pair was delivered to the reporter cells using a variety of methodologies and strategies.Conversion events were easily observed using fluorescent microscopy because of the enhanced emission intensity and different spectra of the EGFP variant.

  19. Spinocerebellar variant of adrenoleukodystrophy with a novel ABCD1 gene mutation.

    Science.gov (United States)

    Li, Jie-Yuan; Hsu, Chia-Chi; Tsai, Chi-Ren

    2010-03-15

    X-linked adrenoleukodystrophy (X-ALD) shows a wide range of phenotypic expression, and clinical presentation as adult-onset spinocerebellar ataxia has been rarely reported. Here, we report a Taiwanese family with X-ALD. The proband, a 37-year-old man presented with dysarthria, cerebellar ataxia and mild spastic paraparesis, and had atrophy of cerebellum and upper cervical cord on MRI. One of his nephews, a 9-year-old boy had a classic childhood cerebral ALD phenotype. This family harbors a novel deletion of 1 base pair in exon 8 at nucleotide position 2245 (2245delA) in the ABCD1 gene. This is the first report of the 2245delA mutation presenting with a spinocerebellar variant of X-ALD.

  20. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Kozyrev, Sergey V; Abelson, Anna-Karin; Wojcik, Jerome

    2008-01-01

    -cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta2), encoding a protein...... without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1...

  1. Genetic Variants in the FADS Gene: Implications for Dietary Recommendations for Fatty Acid Intake.

    Science.gov (United States)

    Mathias, Rasika A; Pani, Vrindarani; Chilton, Floyd H

    2014-06-01

    Unequivocally, genetic variants within the fatty acid desaturase ( FADS ) cluster are determinants of long chain polyunsaturated fatty acid (LC-PUFA) levels in circulation, cells and tissues. A recent series of papers have addressed these associations in the context of ancestry; evidence clearly supports that the associations are robust to ethnicity. However ∼80% of African Americans carry two copies of the alleles associated with increased levels of arachidonic acid, compared to only ∼45% of European Americans raising important questions of whether gene-PUFA interactions induced by a modern western diet are differentially driving the risk of diseases of inflammation in diverse populations, and are these interactions leading to health disparities. We highlight an important aspect thus far missing in the debate regarding dietary recommendations; we content that current evidence from genetics strongly suggest that an individual's, or at the very least the population from which an individual is sampled, genetic architecture must be factored into dietary recommendations currently in place.

  2. A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis.

    Science.gov (United States)

    Mero, Inger-Lise; Lorentzen, Aslaug R; Ban, Maria; Smestad, Cathrine; Celius, Elisabeth G; Aarseth, Jan H; Myhr, Kjell-Morten; Link, Jenny; Hillert, Jan; Olsson, Tomas; Kockum, Ingrid; Masterman, Thomas; Oturai, Annette Bang; Søndergaard, Helle Bach; Sellebjerg, Finn; Saarela, Janna; Kemppinen, Anu; Elovaara, Irina; Spurkland, Anne; Dudbridge, Frank; Lie, Benedicte A; Harbo, Hanne F

    2010-04-01

    A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 x 10(-4), odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 x 10(-9), OR 0.77) was shown.

  3. Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis

    Directory of Open Access Journals (Sweden)

    Jun Ueda

    2017-01-01

    Full Text Available Cellular differentiation is associated with dynamic chromatin remodeling in establishing a cell-type-specific epigenomic landscape. Here, we find that mouse testis-specific and replication-dependent histone H3 variant H3t is essential for very early stages of spermatogenesis. H3t gene deficiency leads to azoospermia because of the loss of haploid germ cells. When differentiating spermatogonia emerge in normal spermatogenesis, H3t appears and replaces the canonical H3 proteins. Structural and biochemical analyses reveal that H3t-containing nucleosomes are more flexible than the canonical nucleosomes. Thus, by incorporating H3t into the genome during spermatogonial differentiation, male germ cells are able to enter meiosis and beyond.

  4. Social environment influences performance in a cognitive task in natural variants of the foraging gene.

    Science.gov (United States)

    Kohn, Nancy R; Reaume, Christopher J; Moreno, Celine; Burns, James G; Sokolowski, Marla B; Mery, Frederic

    2013-01-01

    In Drosophila melanogaster, natural genetic variation in the foraging gene affects the foraging behaviour of larval and adult flies, larval reward learning, adult visual learning, and adult aversive training tasks. Sitters (for(s)) are more sedentary and aggregate within food patches whereas rovers (for(R)) have greater movement within and between food patches, suggesting that these natural variants are likely to experience different social environments. We hypothesized that social context would differentially influence rover and sitter behaviour in a cognitive task. We measured adult rover and sitter performance in a classical olfactory training test in groups and alone. All flies were reared in groups, but fly training and testing were done alone and in groups. Sitters trained and tested in a group had significantly higher learning performances compared to sitters trained and tested alone. Rovers performed similarly when trained and tested alone and in a group. In other words, rovers learning ability is independent of group training and testing. This suggests that sitters may be more sensitive to the social context than rovers. These differences in learning performance can be altered by pharmacological manipulations of PKG activity levels, the foraging (for) gene's gene product. Learning and memory is also affected by the type of social interaction (being in a group of the same strain or in a group of a different strain) in rovers, but not in sitters. These results suggest that for mediates social learning and memory in D. melanogaster.

  5. Associating disease-related genetic variants in intergenic regions to the genes they impact

    Directory of Open Access Journals (Sweden)

    Geoff Macintyre

    2014-10-01

    Full Text Available We present a method to assist in interpretation of the functional impact of intergenic disease-associated SNPs that is not limited to search strategies proximal to the SNP. The method builds on two sources of external knowledge: the growing understanding of three-dimensional spatial relationships in the genome, and the substantial repository of information about relationships among genetic variants, genes, and diseases captured in the published biomedical literature. We integrate chromatin conformation capture data (HiC with literature support to rank putative target genes of intergenic disease-associated SNPs. We demonstrate that this hybrid method outperforms a genomic distance baseline on a small test set of expression quantitative trait loci, as well as either method individually. In addition, we show the potential for this method to uncover relationships between intergenic SNPs and target genes across chromosomes. With more extensive chromatin conformation capture data becoming readily available, this method provides a way forward towards functional interpretation of SNPs in the context of the three dimensional structure of the genome in the nucleus.

  6. Gene variants of the phosphatidylcholine synthesis pathway do not contribute to RDS in the Chinese population.

    Science.gov (United States)

    Chen, Yu-Jun; Meyer, Julia; Wambach, Jennifer A; DePass, Kelcey; Wegner, Daniel J; Fan, Xin; Zhang, Qun-Yuan; Hillary, Heins; Cole, F Sessions; Hamvas, Aaron

    2018-02-01

    To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort. We used bloodspots from 2010 that were obtained from the Guangxi Neonatal Screening Center in Nannning China and included the Han (n = 443) and Zhuang (n = 313) ethnic groups. We sequenced the exons of cholinephosphate cytidylyltransferase (PCYT1B) lysophospholipid acyltransferase 1 (LPCAT1), and cholinephosphotransferase (CHPT1) genes, and analyzed both rare and common exonic variants. We obtained five mutations (G199D, A299V, G434C, Y490C, L312S) with eight alleles in the three candidate genes. The collapsed minor allele frequency for candidate genes was not significantly different between the Han and Zhuang populations (0.0045 vs. 0.0064, respectively, P = 0.725). The combined Han and Zhuang pool collapsed carrier frequency of rare mutation allele was found to be 1.06%, which is much higher than previously reported for the Missouri population (0.1%). Further, we detected six exonic common variants (three in LPCAT1 and three in CHPT1), with three non-synonymous variants (F162S, F341L, M427K) among them. Two of the non-synonymous exonic variants (F341L, M427K) were not found in CHB; F341L was also not previously reported in exome sequencing project. The population-based frequency of mutations in the phosphatidylcholine synthesis pathway-associated genes PCYT1B LPCAT1, CHPT1 is low in southern Chinese newborns and there is no evidence of contribution to population-based disease burden of respiratory distress syndrome. As a population-based study of rare mutations and common variants, this work is valuable in directing future research.

  7. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

    International Nuclear Information System (INIS)

    Nan, Hongmei; Qureshi, Abrar A; Hunter, David J; Han, Jiali

    2009-01-01

    The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the FGFR2 gene has been identified in a number of cancer sites. Overexpression of the FGFR4 protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the FGFR2 and FGFR4 genes and development of various cancers. We evaluated the associations of four genetic variants in the FGFR2 gene highly related to breast cancer risk and the three common tag-SNPs in the FGFR4 gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer. Given the power of this study, we did not detect any contribution of genetic variants in the FGFR2 or FGFR4 genes to inherited predisposition to skin cancer among Caucasian women

  8. Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility

    Directory of Open Access Journals (Sweden)

    Gianfrancesco Fernando

    2010-06-01

    Full Text Available Abstract Background Glutamate is the principal excitatory neurotransmitter in the central nervous system which acts by the activation of either ionotropic (AMPA, NMDA and kainate receptors or G-protein coupled metabotropic receptors. Glutamate is widely accepted to play a major role in the path physiology of migraine as implicated by data from animal and human studies. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could be, therefore, considered as potential candidates for causing/predisposing to migraine when mutated. Methods The association of polymorphic variants of GRIA1-GRIA4 genes which encode for the four subunits (GluR1-GluR4 of the alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA receptor for glutamate was tested in migraineurs with and without aura (MA and MO and healthy controls. Results Two variants in the regulative regions of GRIA1 (rs2195450 and GRIA3 (rs3761555 genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively, but not associated with MO, suggesting their role in cortical spreading depression. Whereas the rs548294 variant in GRIA1 gene showed association primarily with MO phenotype, supporting the hypothesis that MA and MO phenotypes could be genetically related. These variants modify binding sites for transcription factors altering the expression of GRIA1 and GRIA3 genes in different conditions. Conclusions This study represents the first genetic evidence of a link between glutamate receptors and migraine.

  9. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

    Directory of Open Access Journals (Sweden)

    Qureshi Abrar A

    2009-06-01

    Full Text Available Abstract Background The human fibroblast growth factor (FGF and its receptor (FGFR play an important role in tumorigenesis. Deregulation of the FGFR2 gene has been identified in a number of cancer sites. Overexpression of the FGFR4 protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the FGFR2 and FGFR4 genes and development of various cancers. Methods We evaluated the associations of four genetic variants in the FGFR2 gene highly related to breast cancer risk and the three common tag-SNPs in the FGFR4 gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS among 218 melanoma cases, 285 squamous cell carcinoma (SCC cases, 300 basal cell carcinoma (BCC cases, and 870 controls. Results We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer. Conclusion Given the power of this study, we did not detect any contribution of genetic variants in the FGFR2 or FGFR4 genes to inherited predisposition to skin cancer among Caucasian women.

  10. Association of genetic variants in tachykinins pathway genes with colorectal cancer risk.

    Science.gov (United States)

    Yu, Yunxian; Pan, Yifeng; Jin, Mingjuan; Zhang, Mingwu; Zhang, Shanchun; Li, Qilong; Jiang, Xia; Liu, Hui; Guo, Jing; Liu, He; Chen, Kun

    2012-11-01

    This study aims to explore the associations of polymorphisms in tachykinin, precursor 1 (TAC1), tachykinin receptor 1 (TACR1), and tachykinin receptor 2 (TACR2) genes and their interactions with the risk of colorectal cancer (CRC) among Chinese population. A population-based case-control study which included 394 cases and 393 cancer-free controls was carried out. A total of 19 tagSNPs in the three genes were chosen based on HapMap and NCBI datasets and genotyped by SNPshot assay. Multiple logistic regression models were applied to evaluate the associations of SNPs with CRC after adjustment for potential covariates. Furthermore, generalized multifactor dimensionality reduction (GMDR) method was used to test the interactive effect among three genes on CRC. Compared with those carrying rs3755457 CC/CT or rs12477554 TT/CT genotype, individuals carrying homozygous variants had higher risk of colorectal cancer (adjusted OR = 1.80, 95 % CI = 1.03-3.13, P = 0.039 for rs3755457; adjusted OR = 1.73, 95 % CI = 1.07-2.79, P = 0.024 for rs12477554). As for rs10198644, GG genotype was associated with a 1.72-fold (95 % CI = 0.37-0.88) decreased risk when compared with the common CC genotype. Moreover, the GMDR analysis indicated that the best interactive model included five polymorphisms: rs2072100 (TAC1), rs10198644 (TACR1), rs2193409 (TACR1), rs3771810 (TACR1), and rs4644560 (TACR2). Our study suggests that tachykinins pathway genes may participate in the development of CRC and the potential interactions among the three genes on CRC may exist, which has to be confirmed in future larger studies.

  11. Evaluation of common variants in 16 genes involved in the regulation of neurotransmitter release in ADHD.

    Science.gov (United States)

    Sánchez-Mora, Cristina; Cormand, Bru; Ramos-Quiroga, Josep Antoni; Hervás, Amaia; Bosch, Rosa; Palomar, Glòria; Nogueira, Mariana; Gómez-Barros, Núria; Richarte, Vanesa; Corrales, Montse; Garcia-Martinez, Iris; Corominas, Roser; Guijarro, Silvina; Bigorra, Aitana; Bayés, Mònica; Casas, Miguel; Ribasés, Marta

    2013-06-01

    Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappropriate difficulties to sustain attention, control impulses and modulate activity level. Although ADHD is one of the most prevalent childhood psychiatric disorders, it also persists into adulthood in around 30-50% of the cases. Based on the effect of psychostimulants used in the pharmacological treatment of ADHD, dysfunctions in neuroplasticity mechanisms and synapses have been postulated to be involved in the pathophysiology of ADHD. With this background, we evaluated, both in childhood and adulthood ADHD, the role of several genes involved in the control of neurotransmitter release through synaptic vesicle docking, fusion and recycling processes by means of a population-based association study. We analyzed single nucleotide polymorphisms across 16 genes in a clinical sample of 950 ADHD patients (506 adults and 444 children) and 905 controls. Single and multiple-marker analyses identified several significant associations after correcting for multiple testing with a false discovery rate (FDR) of 15%: (i) the SYT2 gene was strongly associated with both adulthood and childhood ADHD (p=0.001, OR=1.49 (1.18-1.89) and p=0.007, OR=1.37 (1.09-1.72), respectively) and (ii) STX1A was found associated with ADHD only in adults (p=0.0041; OR=1.28 (1.08-1.51)). These data provide preliminary evidence for the involvement of genes that participate in the control of neurotransmitter release in the genetic predisposition to ADHD through a gene-system association study. Further follow-up studies in larger cohorts and deep-sequencing of the associated genomic regions are required to identify sequence variants directly involved in ADHD. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  12. Determination of disease phenotypes and pathogenic variants from exome sequence data in the CAGI 4 gene panel challenge.

    Science.gov (United States)

    Kundu, Kunal; Pal, Lipika R; Yin, Yizhou; Moult, John

    2017-09-01

    The use of gene panel sequence for diagnostic and prognostic testing is now widespread, but there are so far few objective tests of methods to interpret these data. We describe the design and implementation of a gene panel sequencing data analysis pipeline (VarP) and its assessment in a CAGI4 community experiment. The method was applied to clinical gene panel sequencing data of 106 patients, with the goal of determining which of 14 disease classes each patient has and the corresponding causative variant(s). The disease class was correctly identified for 36 cases, including 10 where the original clinical pipeline did not find causative variants. For a further seven cases, we found strong evidence of an alternative disease to that tested. Many of the potentially causative variants are missense, with no previous association with disease, and these proved the hardest to correctly assign pathogenicity or otherwise. Post analysis showed that three-dimensional structure data could have helped for up to half of these cases. Over-reliance on HGMD annotation led to a number of incorrect disease assignments. We used a largely ad hoc method to assign probabilities of pathogenicity for each variant, and there is much work still to be done in this area. © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  13. Studying gene and gene-environment effects of uncommon and common variants on continuous traits: a marker-set approach using gene-trait similarity regression.

    Science.gov (United States)

    Tzeng, Jung-Ying; Zhang, Daowen; Pongpanich, Monnat; Smith, Chris; McCarthy, Mark I; Sale, Michèle M; Worrall, Bradford B; Hsu, Fang-Chi; Thomas, Duncan C; Sullivan, Patrick F

    2011-08-12

    Genomic association analyses of complex traits demand statistical tools that are capable of detecting small effects of common and rare variants and modeling complex interaction effects and yet are computationally feasible. In this work, we introduce a similarity-based regression method for assessing the main genetic and interaction effects of a group of markers on quantitative traits. The method uses genetic similarity to aggregate information from multiple polymorphic sites and integrates adaptive weights that depend on allele frequencies to accomodate common and uncommon variants. Collapsing information at the similarity level instead of the genotype level avoids canceling signals that have the opposite etiological effects and is applicable to any class of genetic variants without the need for dichotomizing the allele types. To assess gene-trait associations, we regress trait similarities for pairs of unrelated individuals on their genetic similarities and assess association by using a score test whose limiting distribution is derived in this work. The proposed regression framework allows for covariates, has the capacity to model both main and interaction effects, can be applied to a mixture of different polymorphism types, and is computationally efficient. These features make it an ideal tool for evaluating associations between phenotype and marker sets defined by linkage disequilibrium (LD) blocks, genes, or pathways in whole-genome analysis. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  14. Gene expression, single nucleotide variant and fusion transcript discovery in archival material from breast tumors.

    Directory of Open Access Journals (Sweden)

    Nadine Norton

    Full Text Available Advantages of RNA-Seq over array based platforms are quantitative gene expression and discovery of expressed single nucleotide variants (eSNVs and fusion transcripts from a single platform, but the sensitivity for each of these characteristics is unknown. We measured gene expression in a set of manually degraded RNAs, nine pairs of matched fresh-frozen, and FFPE RNA isolated from breast tumor with the hybridization based, NanoString nCounter (226 gene panel and with whole transcriptome RNA-Seq using RiboZeroGold ScriptSeq V2 library preparation kits. We performed correlation analyses of gene expression between samples and across platforms. We then specifically assessed whole transcriptome expression of lincRNA and discovery of eSNVs and fusion transcripts in the FFPE RNA-Seq data. For gene expression in the manually degraded samples, we observed Pearson correlations of >0.94 and >0.80 with NanoString and ScriptSeq protocols, respectively. Gene expression data for matched fresh-frozen and FFPE samples yielded mean Pearson correlations of 0.874 and 0.783 for NanoString (226 genes and ScriptSeq whole transcriptome protocols respectively, p<2x10(-16. Specifically for lincRNAs, we observed superb Pearson correlation (0.988 between matched fresh-frozen and FFPE pairs. FFPE samples across NanoString and RNA-Seq platforms gave a mean Pearson correlation of 0.838. In FFPE libraries, we detected 53.4% of high confidence SNVs and 24% of high confidence fusion transcripts. Sensitivity of fusion transcript detection was not overcome by an increase in depth of sequencing up to 3-fold (increase from ~56 to ~159 million reads. Both NanoString and ScriptSeq RNA-Seq technologies yield reliable gene expression data for degraded and FFPE material. The high degree of correlation between NanoString and RNA-Seq platforms suggests discovery based whole transcriptome studies from FFPE material will produce reliable expression data. The RiboZeroGold ScriptSeq protocol

  15. Assessment of polymorphic variants in the melanocortin-1 receptor gene with cutaneous pigmentation using an evolutionary approach.

    Science.gov (United States)

    Kanetsky, Peter A; Ge, Fan; Najarian, Derek; Swoyer, Jennifer; Panossian, Saarene; Schuchter, Lynn; Holmes, Robin; Guerry, DuPont; Rebbeck, Timothy R

    2004-05-01

    The melanocortin-1 receptor gene (MC1R) encodes a membrane-bound receptor protein that is central to melanin synthesis. The coding region of MC1R is highly polymorphic and associations of variants with pigmentation phenotypes and risk for cutaneous neoplasms have been reported. We sought to determine the distribution and frequency of MC1R variants and their relationship to pigmentation characteristics in 179 Caucasian controls from the United States. One hundred thirty-five (75.4%) subjects carried one or more variants, and we determined that carriage of the previously designated "red hair color" (RHC) alleles, R151C, R160W, and D294H was strongly associated with fair pigmentation phenotypes including light hair and eye color, tendency to burn, decreased tendency to tan, and freckling. We used SIFT software to define MC1R protein positions that were predicted intolerant to amino acid substitutions; detected variants that corresponded to intolerant substitutions were D84E, R142H, R151C, I155T, R160W, and D294H. Carriage of one or more of these putative functionally important variants or the frameshift variant ins86A was significantly associated with fair pigmentation phenotypes. Analyses limited to carriage of ins86A and the three non-RHC alleles identified by SIFT were attenuated and no longer reached statistical significance. This is the first study to describe MC1R variants among control subjects from the U.S. Our results indicate that the frequency of variants is similar to that previously observed among non-U.S. Caucasians. Risk variants defined by either the published literature or by evolutionary criteria are strongly and significantly associated with all fair pigmentation phenotypes that were measured.

  16. Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

    Directory of Open Access Journals (Sweden)

    Marijn C Visschedijk

    Full Text Available Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC. However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls. In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

  17. Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

    Science.gov (United States)

    Visschedijk, Marijn C; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J; Pierik, Marieke; Spekhorst, Lieke M; Imhann, Floris; van der Meulen-de Jong, Andrea E; van der Woude, C Janneke; van Bodegraven, Adriaan A; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A; Franke, Andre; van Diemen, Cleo C; Weersma, Rinse K

    2016-01-01

    Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

  18. Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction.

    Science.gov (United States)

    Sullivan, D; Pinsonneault, J K; Papp, A C; Zhu, H; Lemeshow, S; Mash, D C; Sadee, W

    2013-01-22

    Epistatic gene-gene interactions could contribute to the heritability of complex multigenic disorders, but few examples have been reported. Here, we focus on the role of aberrant dopaminergic signaling, involving the dopamine transporter DAT, a cocaine target, and the dopamine D2 receptor, which physically interacts with DAT. Splicing polymorphism rs2283265 of DRD2, encoding D2 receptors, were shown to confer risk of cocaine overdose/death (odds ratio ∼3) in subjects and controls from the Miami Dade County Brain Bank.(1) Risk of cocaine-related death attributable to the minor allele of rs2283265 was significantly enhanced to OR=7.5 (P=0.0008) in homozygous carriers of the main 6-repeat allele of DAT rs3836790, a regulatory VNTR in intron8 lacking significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P=0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3'-UTR, occurred in nearly one-third of the cocaine abusers but was absent in African American controls, apparently conferring strong risk. These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication.

  19. Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast

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    Hudler Petra

    2009-10-01

    Full Text Available Abstract Background Loss of DNA mismatch repair (MMR in humans, mainly due to mutations in the hMLH1 gene, is linked to hereditary nonpolyposis colorectal cancer (HNPCC. Because not all MLH1 alterations result in loss of MMR function, accurate characterization of variants and their classification in terms of their effect on MMR function is essential for reliable genetic testing and effective treatment. To date, in vivo assays for functional characterization of MLH1 mutations performed in various model systems have used episomal expression of the modified MMR genes. We describe here a novel approach to determine accurately the functional significance of hMLH1 mutations in vivo, based on co-expression of human MLH1 and PMS2 in yeast cells. Methods Yeast MLH1 and PMS1 genes, whose protein products form the MutLα complex, were replaced by human orthologs directly on yeast chromosomes by homologous recombination, and the resulting MMR activity was tested. Results The yeast strain co-expressing hMLH1 and hPMS2 exhibited the same mutation rate as the wild-type. Eight cancer-related MLH1 variants were introduced, using the same approach, into the prepared yeast model, and their effect on MMR function was determined. Five variants (A92P, S93G, I219V, K618R and K618T were classified as non-pathogenic, whereas variants T117M, Y646C and R659Q were characterized as pathogenic. Conclusion Results of our in vivo yeast-based approach correlate well with clinical data in five out of seven hMLH1 variants and the described model was thus shown to be useful for functional characterization of MLH1 variants in cancer patients found throughout the entire coding region of the gene.

  20. Clinically Significant Unclassified Variants inBRCA1andBRCA2genes among Korean Breast Cancer Patients.

    Science.gov (United States)

    Yoon, Kyong-Ah; Park, Boyoung; Lee, Byung Il; Yang, Moon Jung; Kong, Sun-Young; Lee, Eun Sook

    2017-07-01

    Unclassified variants (UVs) of BRCA1 and BRCA2 genes are not defined as pathogenic for breast cancer, and their clinical significance currently remains undefined. Therefore, this study was conducted to identify potentially pathogenic UVs by comparing their prevalence between breast cancer patients and controls. A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. Genetic variants of BRCA genes that were categorized as unclassified according to the Breast Cancer Information Core database were selected based on allelic frequency, after which candidate variants were genotyped in 421 healthy controls. We also examined family members of the study participants. Finally, the effects of amino acid substitutions on protein structure and function were predicted in silico . Genetic tests revealed 33 UVs in BRCA1 and 47 in BRCA2 . Among 15 candidates genotyped in healthy controls, c.5339T>C in BRCA1 and c.6029T>G, c.7522G>A in BRCA2 were not detected. Moreover, the c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. This nonsynonymous variant (Leu1780Pro) in the BRCA1 C-terminal domain was predicted to have an effect on BRCA1 protein structure/function. This study showed that comparison of genotype frequency between cases and controls could help identify UVs of BRCA genes that are potentially pathogenic. Moreover, ourfindings suggest that c.5339T>C in BRCA1 might be a pathogenic variant for patients and their families.

  1. Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A.

    Science.gov (United States)

    Nguyen, G N; George, L A; Siner, J I; Davidson, R J; Zander, C B; Zheng, X L; Arruda, V R; Camire, R M; Sabatino, D E

    2017-01-01

    Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a

  2. Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

    DEFF Research Database (Denmark)

    Paulussen, Aimee D C; Steyls, Anja; Vanoevelen, Jo

    2016-01-01

    male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression...

  3. Calling genotypes from public RNA-sequencing data enables identification of genetic variants that affect gene-expression levels

    NARCIS (Netherlands)

    Deelen, Patrick; Zhernakova, Daria V.; de Haan, Mark; van der Sijde, Marijke; Bonder, Marc Jan; Karjalainen, Juha; van der Velde, K. Joeri; Abbott, Kristin M.; Fu, Jingyuan; Wijmenga, Cisca; Sinke, Richard J.; Swertz, Morris A.; Franke, Lude

    2015-01-01

    Background: RNA-sequencing (RNA-seq) is a powerful technique for the identification of genetic variants that affect gene-expression levels, either through expression quantitative trait locus (eQTL) mapping or through allele-specific expression (ASE) analysis. Given increasing numbers of RNA-seq

  4. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A)

    NARCIS (Netherlands)

    Longstreth, W. T.; Rosendaal, F. R.; Siscovick, D. S.; Vos, H. L.; Schwartz, S. M.; Psaty, B. M.; Raghunathan, T. E.; Koepsell, T. D.; Reitsma, P. H.

    1998-01-01

    Factor V Leiden and a prothrombin gene variant, G20210A, are mutations associated with a thrombotic risk. The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age. We conducted a case-control study in western Washington state. Case

  5. COMT Val[superscript 108/158] Met Gene Variant, Birth Weight, and Conduct Disorder in Children with ADHD

    Science.gov (United States)

    Sengupta, Sarojini M.; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Amor, Leila Ben; Bellingham, Johanne; de Guzman, Rosherrie; Polotskaia, Anna; Stepanian, Marina Ter; Thakur, Geeta; Joober, Ridha

    2006-01-01

    Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. Method: Children (n = 191)…

  6. 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....

  7. Induced pluripotent stem cells derived from a patient with autosomal dominant familial neurohypophyseal diabetes insipidus caused by a variant in the AVP gene

    DEFF Research Database (Denmark)

    Toustrup, Lise Bols; Zhou, Yan; Kvistgaard, Helene

    2017-01-01

    Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by variants in the arginine vasopressin (AVP) gene. Here we report the generation of induced pluripotent stem cells (iPSCs) from a 42-year-old man carrying an adFNDI causing variant in exon 1 of the AVP gene using...

  8. Detection of copy number variants reveals association of cilia genes with neural tube defects.

    Directory of Open Access Journals (Sweden)

    Xiaoli Chen

    Full Text Available BACKGROUND: Neural tube defects (NTDs are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs. METHODS: The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined. RESULTS: Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV. Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05. Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87. Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05, corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01. Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways. CONCLUSIONS: Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.

  9. Common genetic variants in Wnt signaling pathway genes as potential prognostic biomarkers for colorectal cancer.

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    Wen-Chien Ting

    Full Text Available Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs in adenomatous polyposis coli (APC/β-catenin (CTNNB1 genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank P = 0.001. After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.

  10. A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism.

    Science.gov (United States)

    Pillar, Nir; Pleniceanu, Oren; Fang, Mingyan; Ziv, Limor; Lahav, Einat; Botchan, Shay; Cheng, Le; Dekel, Benjamin; Shomron, Noam

    2017-07-01

    Isolated familial hypoparathyroidism is an extremely rare disorder, which to date has been linked to several loci including mutations in CASR, GCM2, and PTH, as well as a rare condition defined as X-linked recessive hypoparathyroidism, previously associated with a 1.5 Mb region on Xq26-q27. Here, we report a patient with hypocalcemia-induced seizures leading to the diagnosis of primary hypoparathyroidism. Mutations in CASR, GCM2, and PTH were ruled out, while whole exome sequencing of the family suggested FHL1, located on chromosome Xq26, as the most likely causative gene variant (FHL1, exon 4, c.C283T, p.R95W). Since FHL1 has not been linked to calcium regulation before, we provide evidence for its functional role in hypoparathyroidism by: (i) bioinformatics analysis coupling its action to known modulators of PTH function; (ii) observing strong expression of fhl1b in Corpuscles of Stannius, gland-like aggregates in zebrafish that function in calcium regulation similar to mammalian PTH; and (iii) implicating fhl1b and FHL1 as regulators of calcium homeostasis in zebrafish and human cells, respectively. Altogether, our data suggest that FHL1 is a novel regulator of calcium homeostasis and implicate it as the causative gene for X-linked recessive hypoparathyroidism.

  11. Molecular analysis of DNA polymerase eta gene in Japanese patients diagnosed as xeroderma pigmentosum variant type.

    Science.gov (United States)

    Tanioka, Miki; Masaki, Taro; Ono, Ryusuke; Nagano, Tohru; Otoshi-Honda, Eriko; Matsumura, Yasuhiro; Takigawa, Masahiro; Inui, Hiroki; Miyachi, Yoshiki; Moriwaki, Shinichi; Nishigori, Chikako

    2007-07-01

    POLH mutations were identified in 16 Japanese patients, who were diagnosed, both clinically and at a cellular level, as being of the xeroderma pigmentosum variant type (XPV). While all the patients developed skin cancer with an average onset of the cancer at 45 years, in non-XP Japanese the onset was at over 70 years. All the cell strains from the patients were normal or slightly hypersensitive to UV and most of these showed enhanced UV sensitivity when the post-UV colony formation was performed in the presence of caffeine. Immunoprecipitation analysis with two kinds of anti-POLH protein antibodies revealed that cells from 13 patients did not show the 83 kDa POLH band and that cells from one patient had a faint 83 kDa band. All of these 14 cell strains, without a POLH band or with a weak POLH band, had mutations in the POLH gene. The IP analysis of the POLH protein revealed a very useful method for screening the patients suspected of XPV. Seven mutations in the POLH gene including three novel mutations were identified. Among the mutations detected, 11 alleles out of 28 (39%) were G490T mutations.

  12. 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

  13. Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant.

    Science.gov (United States)

    Gupta, Saumya; Radhakrishnan, Aparna; Nitin, Rachana; Raharja-Liu, Pandu; Lin, Gen; Steinmetz, Lars M; Gagneur, Julien; Sinha, Himanshu

    2016-08-09

    Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae During mitosis, the common TAO3 allele interacts with CBK1-a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2-a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait. Copyright © 2016 Gupta et al.

  14. Gene-Gene Interplay and Gene-Diet Interactions Involving the MTNR1B rs10830963 Variant with Body Weight Loss.

    Science.gov (United States)

    Goni, Leticia; Cuervo, Marta; Milagro, Fermin I; Martínez, J Alfredo

    2014-01-01

    Investigation of the genetic makeup may facilitate the implementation of more personalized nutritional interventions. The aims were to examine whether the rs10830963 MTNR1B polymorphism affects weight loss in response to a hypocaloric diet and to find potential gene-gene interplays and gene-diet interactions. 167 subjects enrolled in a personalized nutritional intervention for weight loss (3-6 weeks) were examined for anthropometric measurements, dietary habits and physical activity at baseline and at the first follow-up visit. Three polymorphisms, which have previously been associated with body weight regulation, rs10830963 (MTNR1B), rs9939609 (FTO) and rs17782313 (MC4R), were analyzed using the Luminex® 100/200™ System. After adjusting for covariates, females with the rs10830963 CG/GG genotype showed lower weight loss than those with the CC genotype. In the total population, carriers of variant alleles of both FTO and MC4R showed a significant association with MTNR1B and weight loss outcome. Moreover, among women, higher total protein and animal protein intakes were associated with a lower weight loss in G allele carriers of the MTNR1B variant. Our data evidenced that rs10830963 MTNR1B polymorphism could be associated with individual differences in weight loss induced by a hypocaloric diet. This association was influenced by FTO and MC4R loci and modified by baseline protein intake. © 2015 S. Karger AG, Basel.

  15. -116A and K BCHE gene variants associated with obesity and hypertriglyceridemia in adolescents from Southern Brazil.

    Science.gov (United States)

    Chaves, Thaís Jannuzzi; Leite, Neiva; Milano, Gerusa Eisfeld; Milano, Gisele Eisfeld; Souza, Ricardo Lehtonen Rodrigues; Chautard-Freire-Maia, Eleidi Alice; Furtado-Alle, Lupe

    2013-03-25

    Butyrylcholinesterase (BChE) has been associated to body mass index (BMI), weight, cholesterol and triglyceride levels. -116A (rs1126680) and K (A539T, 1615A, rs1803274) BCHE gene variants had previously been associated to BChE activity, weight and BMI variance in adults. The present study examined -116A and K variants, BChE activity, anthropometric and biochemical variables associated with obesity in adolescents (120 obese and 150 non-obese from Curitiba, Brazil). Both -116A and K variants were found with significantly lower frequencies (pobese adolescents when compared with non-obese adolescents and with the general population. Mean BChE activity (KU/L) was significantly higher in obese adolescents when compared with non-obese adolescents and with the general population. Analyzing only the obese adolescents, it was found that carriers of the -116A variant showed lower BChE activity and higher triglyceride levels than homozygotes for the usual allele. Indeed, obese carriers of the -116A variant had triglyceride levels considered high according to reference values for serum triglycerides in Brazilian adolescents. These results show: (1) a protective effect of -116A and K variants on juvenile obesity risk, suggesting a role for the BCHE gene on juvenile onset obesity different from that observed on adult onset obesity and (2) an association of the -116A variant with hypertriglyceridemia in obese adolescents probably because of its effect on lowering BChE activity and consequently diminishing the enzyme capability of maintaining homeostasis on lipid metabolism during the metabolic stress caused by obesity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Screening for coding variants in FTO and SH2B1 genes in Chinese patients with obesity.

    Directory of Open Access Journals (Sweden)

    Zhaojing Zheng

    Full Text Available To investigate potential functional variants in FTO and SH2B1 genes among Chinese children with obesity.Sanger sequencing of PCR products of all FTO and SH2B1 exons and their flanking regions were performed in 338 Chinese Han children with obesity and 221 age- and sex-matched lean controls.A total of seven and five rare non-synonymous variants were identified in FTO and SH2B1, respectively. The overall frequencies of FTO and SH2B1 rare non-synonymous variants were similar in obese and lean children (2.37% and 0.90% vs. 1.81% and 1.36%, P>0.05. However, four out of the seven variants in FTO were novel and all were unique to obese children (p>0.05. None of the novel variants was consistently being predicted to be deleterious. Four out of five variants in SH2B1 were novel and one was unique to obese children (p>0.05. One variant (L293R that was consistently being predicted as deleterious in SH2B1 gene was unique to lean control. While rare missense mutations were more frequently detected in girls from obesity as well as lean control than boys, the difference was not statistically significant. In addition, it's shown that the prevalence of rare missense mutations of FTO as well as SH2B1 was similar across different ethnic groups.The rare missense mutations of FTO and SH2B1 did not confer risks of obesity in Chinese Han children in our cohort.

  17. Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy.

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    Dara G Torgerson

    Full Text Available Severe infection with respiratory syncytial virus (RSV during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20 at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively, and NOS1 in African Americans (p = 2.3x10-11. One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888, which was also nominally associated with asthma (p = 0.027 and active asthma (p = 0.013 among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.

  18. Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume.

    Science.gov (United States)

    Saxena, R; Bjonnes, A C; Georgopoulos, N A; Koika, V; Panidis, D; Welt, C K

    2015-07-01

    menopausal age and PCOS. The project was supported by award number R01HD065029 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, award number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. C.K.W. is a consultant for Takeda Pharmaceuticals. NCT00166569. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Molecular Evolution of the VP1 Gene in Human Norovirus GII.4 Variants in 1974–2015

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    Takumi Motoya

    2017-12-01

    Full Text Available Human norovirus (HuNoV is a leading cause of viral gastroenteritis worldwide, of which GII.4 is the most predominant genotype. Unlike other genotypes, GII.4 has created various variants that escaped from previously acquired immunity of the host and caused repeated epidemics. However, the molecular evolutionary differences among all GII.4 variants, including recently discovered strains, have not been elucidated. Thus, we conducted a series of bioinformatic analyses using numerous, globally collected, full-length GII.4 major capsid (VP1 gene sequences (466 strains to compare the evolutionary patterns among GII.4 variants. The time-scaled phylogenetic tree constructed using the Bayesian Markov chain Monte Carlo (MCMC method showed that the common ancestor of the GII.4 VP1 gene diverged from GII.20 in 1840. The GII.4 genotype emerged in 1932, and then formed seven clusters including 14 known variants after 1980. The evolutionary rate of GII.4 strains was estimated to be 7.68 × 10−3 substitutions/site/year. The evolutionary rates probably differed among variants as well as domains [protruding 1 (P1, shell, and P2 domains]. The Osaka 2007 variant strains probably contained more nucleotide substitutions than any other variant. Few conformational epitopes were located in the shell and P1 domains, although most were contained in the P2 domain, which, as previously established, is associated with attachment to host factors and antigenicity. We found that positive selection sites for the whole GII.4 genotype existed in the shell and P1 domains, while Den Haag 2006b, New Orleans 2009, and Sydney 2012 variants were under positive selection in the P2 domain. Amino acid substitutions overlapped with putative epitopes or were located around the epitopes in the P2 domain. The effective population sizes of the present strains increased stepwise for Den Haag 2006b, New Orleans 2009, and Sydney 2012 variants. These results suggest that HuNoV GII.4 rapidly

  20. Exome sequencing reveals novel rare variants in the ryanodine receptor and calcium channel genes in malignant hyperthermia families.

    Science.gov (United States)

    Kim, Jerry H; Jarvik, Gail P; Browning, Brian L; Rajagopalan, Ramakrishnan; Gordon, Adam S; Rieder, Mark J; Robertson, Peggy D; Nickerson, Deborah A; Fisher, Nickla A; Hopkins, Philip M

    2013-11-01

    About half of malignant hyperthermia (MH) cases are associated with skeletal muscle ryanodine receptor 1 (RYR1) and calcium channel, voltage-dependent, L type, α1S subunit (CACNA1S) gene mutations, leaving many with an unknown cause. The authors chose to apply a sequencing approach to uncover causal variants in unknown cases. Sequencing the exome, the protein-coding region of the genome, has power at low sample sizes and identified the cause of over a dozen Mendelian disorders. The authors considered four families with multiple MH cases lacking mutations in RYR1 and CACNA1S by Sanger sequencing of complementary DNA. Exome sequencing in two affecteds per family, chosen for maximum genetic distance, were compared. Variants were ranked by allele frequency, protein change, and measures of conservation among mammals to assess likelihood of causation. Finally, putative pathogenic mutations were genotyped in other family members to verify cosegregation with MH. Exome sequencing revealed one rare RYR1 nonsynonymous variant in each of three families (Asp1056His, Val2627Met, Val4234Leu), and one CACNA1S variant (Thr1009Lys) in the fourth family. These were not seen in variant databases or in our control population sample of 5,379 exomes. Follow-up sequencing in other family members verified cosegregation of alleles with MH. The authors found that using both exome sequencing and allele frequency data from large sequencing efforts may aid genetic diagnosis of MH. In a sample selected by the authors, this technique was more sensitive for variant detection in known genes than Sanger sequencing of complementary DNA, and allows for the possibility of novel gene discovery.

  1. Estrogen and progesterone-related gene variants and colorectal cancer risk in women

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    Gunter Marc J

    2011-05-01

    Full Text Available Abstract Background Observational studies and randomized trials have suggested that estrogens and/or progesterone may lower the risk for colorectal cancer. Inherited variation in the sex-hormone genes may be one mechanism by which sex hormones affect colorectal cancer, although data are limited. Method We conducted a comprehensive evaluation of single nucleotide polymorphisms (SNPs in genes encoding 3 hormone receptors (ESR1, ESR2, PGR and 5 hormone synthesizers (CYP19A1 and CYP17A1, HSD17B1, HSD17B2, HSD17B4 among 427 women with incident colorectal cancer and 871 matched controls who were Caucasians of European ancestry from 93676 postmenopausal women enrolled in the Women's Health Initiative Observational cohort. A total of 242 haplotype-tagging and functional SNPs in the 8 genes were included for analysis. Unconditional logistic regression with adjustment for age and hysterectomy status was used to estimate odds ratios (ORs and 95% confidence intervals (CIs. Results We observed a weak association between the CYP17A1 rs17724534 SNP and colorectal cancer risk (OR per risk allele (A = 1.39, 95% CI = 1.09-1.78, corrected p-value = 0.07. In addition, a suggestive interaction between rs17724534 and rs10883782 in 2 discrete LD blocks of CYP17A1 was observed in relation to colorectal cancer (empirical p value = 0.04. Moreover, one haplotype block of CYP19A1 was associated with colorectal cancer (corrected global p value = 0.02, which likely reflected the association with the tagging SNP, rs1902584, in the block. Conclusion Our findings offer some support for a suggestive association of CYP17A1 and CYP19A1 variants with colorectal cancer risk.

  2. Inherited variants in regulatory T cell genes and outcome of ovarian cancer.

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    Ellen L Goode

    Full Text Available Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL and sequence-based tagging single nucleotide polymorphisms (tagSNPs for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p=2.7×10(-5, LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p=4.5×10(-4, and rs3753348, p=9.0×10(-4, respectively, and CD80 (endometrioid, rs13071247, p=8.0×10(-4. Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p=0.006. An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p=8.1×10(-4 among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.

  3. Novel sequence variants of viral hexon and fibre genes in two dogs with canine adenovirus type 1-associated disease.

    Science.gov (United States)

    Balboni, A; Dondi, F; Agnoli, C; Verin, R; Gruarin, M; Morini, M; Battilani, M

    2017-05-01

    There is little information on sequence variation of canine adenovirus type 1 (CAdV-1), the aetiological agent of infectious canine hepatitis (ICH). This study reports hexon and fibre gene sequence variants of CAdV-1 in a dog with systemic ICH and a dog with the ocular form of the disease ('blue eye') in Northern Italy in 2013. One of the sequence variants matched a CAdV-1 fox sequence previously detected in Italy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

    DEFF Research Database (Denmark)

    Helgason, Agnar; Pálsson, Snaebjörn; Thorleifsson, Gudmar

    2007-01-01

    diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East...... Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy...

  5. Two splice variants of the bovine lactoferrin gene identified in Staphylococcus aureus isolated from mastitis in dairy cattle.

    Science.gov (United States)

    Huang, J M; Wang, Z Y; Ju, Z H; Wang, C F; Li, Q L; Sun, T; Hou, Q L; Hang, S Q; Hou, M H; Zhong, J F

    2011-12-21

    Bovine lactoferrin (bLF) is a member of the transferrin family; it plays an important role in the innate immune response. We identified novel splice variants of the bLF gene in mastitis-infected and healthy cows. Reverse transcription-polymerase chain reaction (RT-PCR) and clone sequencing analysis were used to screen the splice variants of the bLF gene in the mammary gland, spleen and liver tissues. One main transcript corresponding to the bLF reference sequence was found in three tissues in both healthy and mastitis-infected cows. Quantitative real-time PCR analysis showed that the expression levels of the LF gene's main transcript were not significantly different in tissues from healthy versus mastitis-infected cows. However, the new splice variant, LF-AS2, which has the exon-skipping alternative splicing pattern, was only identified in mammary glands infected with Staphylococcus aureus. Sequencing analysis showed that the new splice variant was 251 bp in length, including exon 1, part of exon 2, part of exon 16, and exon 17. We conclude that bLF may play a role in resistance to mastitis through alternative splicing mechanisms.

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

    Science.gov (United States)

    Ho, Chi-Chun; Tai, Shuk-Mui; Lee, Edmond Chi-Nam; Mak, Timothy Shin-Heng; Liu, Timothy Kam-Tim; Tang, Victor Wai-Lun; Poon, Wing-Tat

    2017-01-01

    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. PMID:28379183

  7. 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.

  8. The effect of BCMO1 gene variants on macular pigment optical density in young healthy Caucasians

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    Zachary eKyle-Little

    2014-12-01

    Full Text Available Background: Serum lutein (L and zeaxanthin (Z positively correlate with macular pigment optical density (MPOD, hence the latter is a valuable indirect tool for measuring L and Z content in the macula. L and Z have been attributed antioxidant capacity and protection from certain retinal diseases but their uptake within the eye is thought to depend on genetic, age and environmental factors. In particular gene variants within beta-carotene monooxygenase (BCMO1 are thought to modulate MPOD in the macula.Objectives: To determine the effect of BCMO1 single nucleotide polymorphisms (SNPs rs11645428, rs6420424 and rs6464851 on macular pigment optical density (MPOD in a cohort of young healthy participants of Caucasian origin with normal ocular health.Design: In this cohort study, MPOD was assessed in 46 healthy participants (22 male and 24 female with a mean age of 24 ± 4.0 years (range 19-33. The three SNPs, rs11645428, rs6420424, rs6564851 that have established associations with MPOD were determined using MassEXTEND (hME Sequenom assay. One-way analysis of variance (ANOVA was performed on groups segregated into homozygous and heterozygous BCMO1 genotypes. Correlations between body mass index (BMI, iris colour, gender, central retinal thickness (CRT, diet and MPOD were investigated.Results: MPOD did not significantly vary with BCMO1 rs11645428 (F2,41 = 0.700, p = 0.503, rs6420424 (F2,41 = 0.210, p = 0.801 nor rs6464851 homozygous or heterozygous genotypes (F2,41 = 0,13, p = 0.88, in this young healthy cohort. The combination of these three SNPs into triple genotypes based on plasma conversion efficiency did not affect MPOD (F2,41 = 0.07, p = 0.9. There was a significant negative correlation with MPOD and central retinal thickness (r = - 0.39, p = 0.01 but no significant correlation between BMI, iris colour, gender and MPOD. Conclusion: Our results indicate that macular pigment deposition within the central retina is not dependent on BCMO1 gene variant

  9. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors

    DEFF Research Database (Denmark)

    Husemoen, Lise Lotte; Fenger, Mogens; Friedrich, Nele

    2008-01-01

    BACKGROUND: Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure-disease associations in epidemiologic studies of health effects of alcohol drinking......-MCV), and lipids]. ADH and ALDH gene variants were determined by standard techniques. Data were analyzed by regression analyses adjusted for relevant confounders. RESULTS: Self-reported alcohol drinking was significantly associated with increasing levels of ALAT, E-MCV, high-density lipoprotein cholesterol...... interactions between any of the gene variants and alcohol consumption in relation to the various outcomes. CONCLUSIONS: In this Caucasian population sample, we found evidence to support that genetic variation in ethanol metabolism may influence drinking habits, but no statistically significant gene...

  10. High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.

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    Raymond J Kelleher

    Full Text Available Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.

  11. Novel variants of major drug-metabolising enzyme genes in diverse African populations and their predicted functional effects

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    Matimba Alice

    2009-01-01

    Full Text Available Abstract Pharmacogenetics enables personalised therapy based on genetic profiling and is increasingly applied in drug discovery. Medicines are developed and used together with pharmacodiagnostic tools to achieve desired drug efficacy and safety margins. Genetic polymorphism of drug-metabolising enzymes such as cytochrome P450s (CYPs and N-acetyltransferases (NATs has been widely studied in Caucasian and Asian populations, yet studies on African variants have been less extensive. The aim of the present study was to search for novel variants of CYP2C9, CYP2C19, CYP2D6 and NAT2 genes in Africans, with a particular focus on their prevalence in different populations, their relevance to enzyme functionality and their potential for personalised therapy. Blood samples from various ethnic groups were obtained from the AiBST Biobank of African Populations. The nine exons and exon-intron junctions of the CYP genes and exon 2 of NAT2 were analysed by direct DNA sequencing. Computational tools were used for the identification, haplotype analysis and prediction of functional effects of novel single nucleotide polymorphisms (SNPs. Novel SNPs were discovered in all four genes, grouped to existing haplotypes or assigned new allele names, if possible. The functional effects of non-synonymous SNPs were predicted and known African-specific variants were confirmed, but no significant differences were found in the frequencies of SNPs between African ethnicities. The low prevalence of our novel variants and most known functional alleles is consistent with the generally high level of diversity in gene loci of African populations. This indicates that profiles of rare variants reflecting interindividual variability might become the most relevant pharmacodiagnostic tools explaining Africans' diversity in drug response.

  12. Features of progression of chronic hepatitis C in children with different variants of polymorphism of the gene IL-28B

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    Berezenko V.S.

    2016-03-01

    Full Text Available Purpose. To study the features of the progression of chronic hepatitis C in children with different variants of polymorphism of the gene IL-28B. Materials and methods. The study involved 57 children aged 3–18 years with CHC. All patients were involved in clinical, laboratory and instrumental examination. The stage of fibrosis was assessed morphologicallyon a scale METAVIR, by the calculation method — Fibro Test, on APRI index, and by the concentration of hyaluronic acid (HA, transforming growth factor TGF- β1 in serum usingIFA. The SNP genotypes of rs8099917 and rs12979860 lociin IL-28B were determinedby the method of the polymer chain reaction (PCR. A statistical analysis of the data was conducted. Resume. Most of the patients were children with chronic hepatitis C who had genotype CT at rs12979860 locus of the gene IL-28B (54% and the TT geno-type at rs8099917 locus (60%. It was found that fibrogenesis in the liver of patients with chronic hepatitis C depends on the polymorphism of the gene IL-28B. Unfavorable genotypevariants for the development of liver fibrosis are: TT (rs12979860, CT (rs12979860 and TG/GG (rs8099917. Variants CC (rs12979860 and TT (rs8099917 have a beneficial effect on the course of chronic hepatitis C, including patients with a lower stage of fibrosis. To determine the risk of progression of chronic hepatitis C it may be sufficient to determine the polymorphism of rs12979860locusin the gene IL-28B. Conclusions.The polymorphism variants CC (rs12979860 and TT (rs8099917of the gene IL-28Bare more favorable (lower severity of fibrosis in the progression of chronic hepatitis C in children. Variant TT (rs12979860 in the polymorphism of the gene IL-28B is associated with the progression of hepatitis — faster development of liver fibrosis.

  13. Association of Transforming Growth Factor Alpha and Methylenetetrahydrofolate reductase gene variants with nonsyndromic cleft lip and palate in the Indian population

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    Asavari L Desai

    2014-01-01

    Full Text Available Objectives: The aim was to evaluate the relationship of the K-primer variant of the transforming growth factor-alpha (TGF-α gene and C677T variant of the methylenetetrahydrofolate reductase (MTHFR gene with nonsyndromic cleft lip and palate (CL/P in the Indian population. Setting and Sample Population: The study group consisted of DNA samples of 25 subjects with nonsyndromic CL with or without cleft palate and 25 unrelated controls, already existing in the Department of Orthodontics, D.A.P.M.R.V. Dental College, Bengaluru, Karnataka, India. Materials and Methods: The DNA samples were divided into two categories: Group A which included the 25 subjects with nonsyndromic CL/P; and Group B, which consisted of the 25 unrelated controls. The polymerase chain reaction (PCR test was done for amplification of the region of interest from the DNA samples. Restriction digestion was then performed on the amplified product using the restriction enzyme HinfI, separately for each of the variants. The digested PCR products were separated into channels on a 1.5% agarose gel containing ethidium bromide in an electrophoretic chamber. A U.V. transilluminator was used to see the specific bands of base pairs of the digested PCR products. Results: In Group A, the TGF-α gene variant was present in 16 subjects (P = 0.001 and MTHFR gene variant was present in 8 subjects (P = 0.185. A combination of both gene variants were present in seven subjects, which was an interesting finding. In Group B, four subjects tested positive for the TGF-α and MTHFR gene variants. Conclusions: The TGF-α gene variant and a combination of TGF-α + MTHFR gene variants significantly contribute to the development of nonsyndromic CL/P and can be considered as genetic markers for Indian population. The MTHFR gene variant, though a minor risk factor, cannot be considered as a genetic marker.

  14. Expression of P. falciparum var Genes Involves Exchange of the Histone Variant H2A.Z at the Promoter

    Science.gov (United States)

    Petter, Michaela; Lee, Chin Chin; Byrne, Timothy J.; Boysen, Katja E.; Volz, Jennifer; Ralph, Stuart A.; Cowman, Alan F.; Brown, Graham V.; Duffy, Michael F.

    2011-01-01

    Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are

  15. Changes in global gene expression profiles induced by HPV 16 E6 oncoprotein variants in cervical carcinoma C33-A cells

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    Zacapala-Gómez, Ana Elvira, E-mail: zak_ana@yahoo.com.mx [Laboratorio de Biomedicina Molecular, Unidad Académica de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Gro., México (Mexico); Del Moral-Hernández, Oscar, E-mail: odelmoralh@gmail.com [Laboratorio de Biomedicina Molecular, Unidad Académica de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Gro., México (Mexico); Villegas-Sepúlveda, Nicolás, E-mail: nvillega@cinvestav.mx [Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D.F., México (Mexico); Hidalgo-Miranda, Alfredo, E-mail: ahidalgo@inmegen.gob.mx [Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica (INMEGEN), México, D.F., México (Mexico); Romero-Córdoba, Sandra Lorena, E-mail: sromero_cordoba@hotmail.com [Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica (INMEGEN), México, D.F., México (Mexico); and others

    2016-01-15

    We analyzed the effects of the expression of HPV 16 E6 oncoprotein variants (AA-a, AA-c, E-A176/G350, E-C188/G350, E-G350), and the E-Prototype in global gene expression profiles in an in vitro model. E6 gene was cloned into an expression vector fused to GFP and was transfected in C33-A cells. Affymetrix GeneChip Human Transcriptome Array 2.0 platform was used to analyze the expression of over 245,000 coding transcripts. We found that HPV16 E6 variants altered the expression of 387 different genes in comparison with E-Prototype. The altered genes are involved in cellular processes related to the development of cervical carcinoma, such as adhesion, angiogenesis, apoptosis, differentiation, cell cycle, proliferation, transcription and protein translation. Our results show that polymorphic changes in HPV16 E6 natural variants are sufficient to alter the overall gene expression profile in C33-A cells, explaining in part the observed differences in oncogenic potential of HPV16 variants. - Highlights: • Amino acid changes in HPV16 E6 variants modulate the transciption of specific genes. • This is the first comparison of global gene expression profile of HPV 16 E6 variants. • Each HPV 16 E6 variant appears to have its own molecular signature.

  16. Changes in global gene expression profiles induced by HPV 16 E6 oncoprotein variants in cervical carcinoma C33-A cells

    International Nuclear Information System (INIS)

    Zacapala-Gómez, Ana Elvira; Del Moral-Hernández, Oscar; Villegas-Sepúlveda, Nicolás; Hidalgo-Miranda, Alfredo; Romero-Córdoba, Sandra Lorena

    2016-01-01

    We analyzed the effects of the expression of HPV 16 E6 oncoprotein variants (AA-a, AA-c, E-A176/G350, E-C188/G350, E-G350), and the E-Prototype in global gene expression profiles in an in vitro model. E6 gene was cloned into an expression vector fused to GFP and was transfected in C33-A cells. Affymetrix GeneChip Human Transcriptome Array 2.0 platform was used to analyze the expression of over 245,000 coding transcripts. We found that HPV16 E6 variants altered the expression of 387 different genes in comparison with E-Prototype. The altered genes are involved in cellular processes related to the development of cervical carcinoma, such as adhesion, angiogenesis, apoptosis, differentiation, cell cycle, proliferation, transcription and protein translation. Our results show that polymorphic changes in HPV16 E6 natural variants are sufficient to alter the overall gene expression profile in C33-A cells, explaining in part the observed differences in oncogenic potential of HPV16 variants. - Highlights: • Amino acid changes in HPV16 E6 variants modulate the transciption of specific genes. • This is the first comparison of global gene expression profile of HPV 16 E6 variants. • Each HPV 16 E6 variant appears to have its own molecular signature.

  17. Associations of Filaggrin Gene Loss-of-Function Variants with Urinary Phthalate Metabolites and Testicular Function in Young Danish Men

    DEFF Research Database (Denmark)

    Joensen, Ulla Nordström; Jørgensen, Niels; Meldgaard, Michael

    2014-01-01

    variants in a cross-sectional study of 861 young men from the general Danish population. METHODS: All men were genotyped for FLG R501X, 2282del4, and R2447X loss-of-function variants. We measured urinary concentrations of 14 phthalate metabolites and serum levels of reproductive hormones. We also evaluated...... not significantly associated with reproductive hormones or semen quality parameters. CONCLUSION: This study provides evidence that carriers of FLG loss-of-function alleles may have higher internal exposure to phthalates, possibly due to increased transepidermal absorption. FLG loss-of-function variants may indicate......BACKGROUND: Filaggrin is an epidermal protein that is crucial for skin barrier function. Up to 10% of Europeans and 5% of Asians carry at least one null allele in the filaggrin gene (FLG). Reduced expression of filaggrin in carriers of the null allele is associated with facilitated transfer...

  18. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa

    Science.gov (United States)

    Tosh, Kerrie; Campbell, Sarah J.; Fielding, Katherine; Sillah, Jackson; Bah, Boubacar; Gustafson, Per; Manneh, Kebba; Lisse, Ida; Sirugo, Giorgio; Bennett, Steve; Aaby, Peter; McAdam, Keith P. W. J.; Bah-Sow, Oumou; Lienhardt, Christian; Kramnik, Igor; Hill, Adrian V. S.

    2006-01-01

    The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans. PMID:16803959

  19. Rare Variants in Genes Encoding MuRF1 and MuRF2 Are Modifiers of Hypertrophic Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Ming Su

    2014-05-01

    Full Text Available Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM, but are still largely unknown. Muscle ring finger (MuRF proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2% vs. 1/307 (0.3%, p = 0.04; MuRF2 22/594 (3.7% vs. 2/307 (0.7%; p = 0.007. Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04 and had greater maximum left ventricular wall thickness (p = 0.006 than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9% of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.

  20. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

    Directory of Open Access Journals (Sweden)

    Ammar Al-Chalabi

    Full Text Available BACKGROUND: Multiple system atrophy (MSA is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. METHODOLOGY/FINDINGS: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044, and rs3775444 (P = 0.012, although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6; rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7. A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4. The association with rs3822086 was replicated in the independent samples (P = 0.035. CONCLUSIONS/SIGNIFICANCE: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00211224.

  1. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, G.M.; Wasserman, C.R.; O`Malley, C.D. [California Birth Defects Monitoring Program, Emeryville, CA (United States)] [and others

    1996-03-01

    Results of studies determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting. Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa. We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked {ge} 20 cigarrettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups. Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks. This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele. 56 refs., 5 tabs.

  2. Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome.

    Directory of Open Access Journals (Sweden)

    Naoko Sato

    Full Text Available BACKGROUND: Corticotropin-releasing hormone (CRH acts mainly via the CRH receptor 1 (CRH-R1 and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS. Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients. METHODS: A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402 were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale. RESULTS: The TT genotype of rs7209436 (P = 0.01 and rs242924 (P = 0.02 was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms and the T allele of rs7209436 (P = 0.008, T allele of rs242924 (P = 0.019, A allele of rs110402 (P = 0.047, and TAT haplocopies (P = 0.048. Negative emotion was not associated with the examined CRH-R1 SNPs. CONCLUSION: These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.

  3. Fatty acid translocase gene CD36 rs1527483 variant influences oral fat perception in Malaysian subjects.

    Science.gov (United States)

    Ong, Hing-Huat; Tan, Yen-Nee; Say, Yee-How

    2017-01-01

    We determined whether single nucleotide polymorphisms (SNPs; rs1761667 and rs1527483) in the fatty acid translocase CD36 gene - a receptor for fatty acids - is associated with oral fat perception (OFP) of different fat contents in custards and commercially-available foods, and obesity measures in Malaysian subjects (n=313; 118 males, 293 ethnic Chinese; 20 ethnic Indians). A 170-mm visual analogue scale was used to assess the ratings of perceived fat content, oiliness and creaminess of 0%, 2%, 6% and 10% fat content-by-weight custards and low-fat/regular versions of commercially-available milk, mayonnaise and cream crackers. Overall, the subjects managed to significantly discriminate the fat content, oiliness and creaminess between low-fat/regular versions of milk and mayonnaise. Females rated the perception of fat content and oiliness of both milks higher, but ethnicity, obesity and adiposity status did not seem to play a role in influencing most of OFP. The overall minor allele frequencies for rs1761667 and rs1527483 were 0.30 and 0.26, respectively. Females and individuals with rs1527483 TT genotype significantly perceived greater creaminess of 10% fat-by-weight custard. Also, individuals with rs1527483 TT genotype and T allele significantly perceived greater fat content of cream crackers, independent of fat concentration. rs1761667 SNP did not significantly affect OFP, except for cream crackers. Both gene variants were also not associated with obesity measures. Taken together, this study supports the notion that CD36 - specifically rs1527483, plays a role in OFP, but not in influencing obesity in Malaysian subjects. Besides, gender is an important factor for OFP, where females had higher sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Sequence variants at the myostatin gene locus influence the body composition of Thoroughbred horses.

    Science.gov (United States)

    Tozaki, Teruaki; Sato, Fumio; Hill, Emmeline W; Miyake, Takeshi; Endo, Yoshiro; Kakoi, Hironaga; Gawahara, Hitoshi; Hirota, Kei-ichi; Nakano, Yasuko; Nambo, Yasuo; Kurosawa, Masahiko

    2011-12-01

    Myostatin is a member of the transforming growth factor-β family with a key role in inhibition of muscle growth by negative regulation of both myoblast proliferation and differentiation. Recently, a genomic region on ECA18, which includes the MSTN gene, was identified as a candidate region influencing racing performance in Thoroughbreds. In this study, four SNPs on ECA18, g.65809482T>C, g.65868604G>T, g.66493737C>T, and g.66539967A>G, were genotyped in 91 Thoroughbred horses-in-training to evaluate the association between genotype and body composition traits, including body weight, withers height, chest circumference, cannon circumference, and body weight/withers height. Of these, statistically differences in body weight and body weight/withers height were associated with specific genotypes in males. Specifically, body weight/withers height showed statistically significant differences depending on genotype at g.658604G>T, g.66493737C>T, and g.66539967A>G (PT, had the highest value (3.17 ± 0.05 kg·cm(-1)) for body weight/withers height in March, while those with a genotype associated with suitability for long-distance racing, T/T, had the lowest (2.99 ± 0.03 kg·cm(-1)). In females, the trends in the association of body weight/withers height with genotypes were similar to those observed in males. As the SNPs are not believed to be linked to coding variants in MSTN, these results suggest that regulation of MSTN gene expression influences skeletal muscle mass and hence racing performance, particularly optimum race distance, in Thoroughbred horses.

  5. Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects

    DEFF Research Database (Denmark)

    Grarup, Niels; Stender-Petersen, Kirstine L; Andersson, Ehm A

    2008-01-01

    OBJECTIVE: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS: We...... alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per.......03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively). CONCLUSIONS: We associate sequence variation in SREBF1 with a modestly...

  6. High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus

    DEFF Research Database (Denmark)

    Gjesing, Anette P; Rui, Gao; Lauenborg, Jeannet

    2017-01-01

    Context: Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of β-cell dysfunction. Objectives: We aimed to estimate the prevalence of possibly pathogenic...... variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS. Conclusions: Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1...... variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up. Design Setting and Patients: We sequenced the coding regions and intron/exon boundaries...

  7. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.

    Science.gov (United States)

    Pichler, Irene; Minelli, Cosetta; Sanna, Serena; Tanaka, Toshiko; Schwienbacher, Christine; Naitza, Silvia; Porcu, Eleonora; Pattaro, Cristian; Busonero, Fabio; Zanon, Alessandra; Maschio, Andrea; Melville, Scott A; Grazia Piras, Maria; Longo, Dan L; Guralnik, Jack; Hernandez, Dena; Bandinelli, Stefania; Aigner, Elmar; Murphy, Anthony T; Wroblewski, Victor; Marroni, Fabio; Theurl, Igor; Gnewuch, Carsten; Schadt, Eric; Mitterer, Manfred; Schlessinger, David; Ferrucci, Luigi; Witcher, Derrick R; Hicks, Andrew A; Weiss, Günter; Uda, Manuela; Pramstaller, Peter P

    2011-03-15

    The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.

  8. Evaluation of variants of melanoma-associated antigen genes and mRNA transcripts in melanomas of dogs.

    Science.gov (United States)

    Stell, Anneliese J; Dobson, Jane M; Scase, Timothy J; Catchpole, Brian

    2009-12-01

    OBJECTIVE-To characterize variability in melanoma-associated antigen (MAA) genes and gene expression in melanomas of dogs. ANIMALS-18 dogs with malignant melanomas and 8 healthy control dogs. PROCEDURES-cDNA was prepared from malignant melanoma biopsy specimens and from pigmented oral mucocutaneous tissues of healthy control dogs. Genomic DNA was extracted from poorly pigmented melanomas. A PCR assay was performed by use of Melan-A, SILV, or tyrosinase-specific primers. RESULTS-Splice variants of Melan-A and SILV were identified in malignant melanomas and also in healthy pigmented tissues, whereas a tyrosinase splice variant was detected in melanoma tissues only. A short interspersed nuclear element (SINE) insertion mutation was identified in the SILV gene in 1 of 10 poorly pigmented melanomas. Six novel exonic single nucleotide polymorphisms (SNPs; 3 synonymous and 3 nonsynonymous) were detected in the tyrosinase gene, and 1 nonsynonymous exonic SNP was detected in the SILV gene. CONCLUSIONS AND CLINICAL RELEVANCE-Variants of MAA mRNA were detected in malignant melanoma tissues of dogs. The importance of MAA alternative transcripts expressed in melanomas and normal pigmented tissues was unclear, but they may have represented a means of regulating melanin synthesis. The tyrosinase splice variant was detected only in melanomas and could potentially be a tumor-specific target for immunotherapy. A SILV SINE insertion mutation was identified in a melanoma from a Great Dane, a breed known to carry this mutation (associated with merle coat color). The nonsynonymous SNPs detected in tyrosinase and SILV transcripts did not appear to affect tumor pigmentation.

  9. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors.

    Science.gov (United States)

    Husemoen, Lise Lotte Nystrup; Fenger, Mogens; Friedrich, Nele; Tolstrup, Janne Schurmann; Beenfeldt Fredriksen, Stine; Linneberg, Allan

    2008-11-01

    Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure-disease associations in epidemiologic studies of health effects of alcohol drinking. In a Caucasian population, we examined the association of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genetic variants with alcohol drinking habits, biomarkers of alcohol exposure, and risk factors for cardiovascular disease. The study population consisted of 1,216 Danish men and women aged 15-77 years participating in a health examination in 1998. The health examination included a self-administered questionnaire (alcohol drinking habits), a physical examination (blood pressure), and various blood tests [alanine aminotransferase (ALAT), erythrocyte mean corpuscular volume (E-MCV), and lipids]. ADH and ALDH gene variants were determined by standard techniques. Data were analyzed by regression analyses adjusted for relevant confounders. Self-reported alcohol drinking was significantly associated with increasing levels of ALAT, E-MCV, high-density lipoprotein cholesterol, and blood pressure. The ALDH1b ala69val variant was associated with nondrinking and total alcohol intake. The ALDH2 promoter variant was associated with binge-drinking, and the ALDH1b1 ala69val polymorphism was associated with diastolic blood pressure. We did not find any statistically significant interactions between any of the gene variants and alcohol consumption in relation to the various outcomes. In this Caucasian population sample, we found evidence to support that genetic variation in ethanol metabolism may influence drinking habits, but no statistically significant gene-environment interactions. More large-scale epidemiologic studies are needed to confirm theses results and to further investigate genetic susceptibility to the effects of alcohol drinking.

  10. Association of fat mass and obesity-associated gene variant with lifestyle factors and body fat in Indian Children

    Directory of Open Access Journals (Sweden)

    Lavanya S Parthasarthy

    2017-01-01

    Full Text Available Context: Common intronic variants of the fat mass and obesity-associated (FTO gene have been associated with obesity-related traits in humans. Aims: (1 The aim of this study is to study the distribution of FTO gene variants across different body mass index (BMI categories and (2 to explore the association between FTO gene variants and lifestyle factors in obese and normal weight Indian children. Subjects and Methods: Fifty-six children (26 boys, mean age 10.3 ± 2.2 years were studied. Height, weight, and waist and hip circumference were measured. Physical activity (questionnaire and food intake (food frequency questionnaire were assessed. Body fat percentage (%BF was measured by dual-energy X-ray absorptiometry. FTO allelic variants at rs9939609 site were detected by SYBR Green Amplification Refractory Mutation System real-time polymerase chain reaction using allele-specific primers. Generalized linear model was used to investigate the simultaneous influence of genetic and lifestyle factors on %BF. Results: Mean height, weight, and BMI of normal and obese children were 130.6 ± 7.1 versus 143.2 ± 15.6, 24.0 ± 5.2 versus 53.1 ± 15.8, and 13.9 ± 2.1 versus 25.3 ± 3.2, respectively. The frequency of AA allele was 57% among obese children and 35% in normal weight children. Children with the AA allele who were obese had least physical activity, whereas children with AT allele and obesity had the highest intake of calories when compared to children who had AT allele and were normal. %BF was positively associated with AA alleles and junk food intake and negatively with healthy food intake and moderate physical activity. Conclusions: Healthy lifestyle with high physical activity and diet low in calories and fat may help in modifying the risk imposed by FTO variants in children.

  11. Gene polymorphism of aldosterone synthetase (CYP11B2 variants and main cardiovascular risk factors

    Directory of Open Access Journals (Sweden)

    L. Ye. Lobach

    2016-12-01

    significant differences between all groups. The level of total cholesterol in patients with postinfarction cardiosclerosis was significantly higher in the subgroup of patients with homozygous recessive variant CC (5.8±1.08 mmol/L, compared with heterozygotes TC (4.87±1.3 mmol/L, p=0.024 and had no statistical significance when compared with the dominant TT homozygotes (5.06±1.45 mmol. Higher levels of total cholesterol (5.76±1.5 mmol/L in TT homozygotes compared with TC (4.92±1.27 mmol/L, p=0.027 and CC (4.74±1.23 mmol/L, p=0.022 were found. In the group of patients with postinfarction cardiosclerosis, LDL cholesterol in the subgroup homozygous recessive variant CC was higher (3.43±0.87 mmol/L (not significant compared with a TT variant (3.02±1.3 mmol/L and compared with heterozygotes TC (2.78±1.2 mmol/L, p=0.08. The level of TG in patients with stable coronary heart disease was the lowest in dominant homozygotes TT (1.13±0.56 mmol/L compared with CT heterozygotes (1.54±0.97 mmol/L, p=0.08 and CC homozygotes (1.36±0.58 mmol/L, p=0.2. Conclusions. 1. Group of high cardiovascular risk patients requires special attention in the prevention of cardiovascular diseases, because this group showed the worst control of cardiovascular risk factors (level of total cholesterol, LDL cholesterol, glucose, SBP in the absence of appropriate treatment. 2. Ingroup of patients with stable coronary artery disease and postinfarction cardiosclerosis the link CC variant gene polymorphism of aldosterone synthase CYP11B2-344C/T with higher levels of total cholesterol, LDL cholesterol was established, which increases the cardio-vascular risk in this group. 3. CC polymorphism of aldosterone synthase gene CYP11B2-344C/T was associated with higher levels of SBP in patients with stable coronary artery disease and postinfarction cardiosclerosis, which increases the cardiovascular risk such as the development of hypertension.

  12. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

    NARCIS (Netherlands)

    Lawrenson, K.; Iversen, E.S.; Tyrer, J.; Weber, R.P.; Concannon, P.; Hazelett, D.J.; Li, Q.; Marks, J.R.; Berchuck, A.; Lee, J.M.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Bandera, E.V.; Bean, Y.; Beckmann, M.W.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A; Chen, Z.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Plisiecka-Halasa, J.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Eccles, D.; Easton, D.T.; Edwards, R.P.; Eilber, U.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Gronwald, J.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Jakubowska, A.; Paul, J.; Jensen, A.; Karlan, B.Y.; Kjaer, S.K.; Kelemen, L.E.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.; Krakstad, C.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Cannioto, R.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.; Moysich, K.B.; Narod, S.A.; Nedergaard, L.; Ness, R.B.; Azmi, M.A. Noor; Odunsi, K.; Olson, S.H.

    2015-01-01

    Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair

  13. Common variants in the gene for the serotonin receptor 6 (HTR6) do ...

    Indian Academy of Sciences (India)

    Statistical analysis revealed no significant associations with obesity for all variants that were tested. Our data therefore indicate that common HTR6 variants do not contribute to obesity in the tested population. Obesity has become a worldwide health problem in the past decades. This disease is not only caused by a Western ...

  14. Expression Cloning of Recombinant Escherichia coli lacZ Genes Encoding Cytoplasmic and Nuclear β-galactosidase Variants.

    Science.gov (United States)

    Naderian, Homayoun; Rezvani, Zahra; Atlasi, Mohammad Ali; Nikzad, Hossein; Antoine, Af de Vries

    2011-07-01

    Nonviral vector can be an attractive alternative to gene delivery in experimental study. In spite of some advantages in comparison with the viral vectors, there are still some limitations for efficiency of gene delivery in nonviral vectors. To determine the effective expression, the recombinant Escherichia coli lacZ genes were cloned into the different variants of pcDNA3.1 and then the mammalian cells were transfected. The coding sequences of cytoplasmic and nuclear variants of lacZ gene were inserted downstream of the human cytomegalovirus immediate-early gene promoter of plasmid pcDNA3.1/myc-His C. The new cytoplasmic and nuclear constricts of E. coli β-galactosidase-coding sequences were introduced into HeLa cells with the aid of linear polyethylenimine and at 2 days post-transfection the cells were stained using 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal). Restriction enzyme analyses revealed the proper insertion of E. coli β-galactosidase-coding sequences into the multiple cloning site of pcDNA3.1/myc-His C. The functionality of the resulting constructs designated pcDNA3.1-cyt.lacZ and pcDNA3.1-nls.lacZ(+) was confirmed by X-gal staining of HeLa cells transfected with these recombinant plasmids. While pcDNA3.1-cyt.lacZ directed the synthesis of cytoplasmically located β-galactosidase molecules, the β-galactosidase protein encoded by pcDNA3.1-nls.lacZ(+) was predominantly detected in the cell nucleus. The expression of cytoplasmic and nuclear variant of LacZ gene confirmed the ability of pcDNA3.1 as versatility nonviral vector for the experimental gene delivery study in mammalian cells.

  15. PPARα gene variants as predicted performance-enhancing polymorphisms in professional Italian soccer players

    Directory of Open Access Journals (Sweden)

    Proia P

    2014-12-01

    demonstrated an association of intron 7 G allele as well as the GG genotype in endurance athletes. Our result suggests that this is the case also in professional soccer players. Keywords: PCR-RFLP, gene variants, endurance athlete, G allele

  16. Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes.

    Science.gov (United States)

    Jacobsson, Josefin A; Danielsson, Pernilla; Svensson, Victoria; Klovins, Janis; Gyllensten, Ulf; Marcus, Claude; Schiöth, Helgi B; Fredriksson, Robert

    2008-04-11

    Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P=0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.

  17. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lotte B; Pörksen, Sven; Andersen, Marie Louise M

    2011-01-01

    . We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, Zn......The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes......T8Ab) in children during the first year after diagnosis of type 1 diabetes....

  18. Identified OAS3 gene variants associated with coexistence of HBsAg and anti-HBs in chronic HBV infection.

    Science.gov (United States)

    Wang, Sa; Wang, Jing; Fan, Mengjie; Li, Tengyan; Pan, Hong; Wang, Xi; Liu, Hankui; Lin, Qiongfen; Zhang, Jianguo; Guan, Liping; Zhernakova, Daria V; O'Brien, Stephen J; Feng, Zhenru; Chang, Le; Dai, Erhei; Lu, Jianhua; Xi, Hongli; Zeng, Zheng; Yu, Yanyan; Wang, Binbin

    2018-03-27

    The underlying mechanism of coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen antibody (anti-HBs) is still controversial. To identify the host genetic factors related to this unusual clinical phenomenon, a two-staged study was conducted in the Chinese Han population. In the first stage, we performed a case-control (1:1) age, gender matched study of 101 cases with concurrent HBsAg and anti-HBs and 102 controls with negative HBsAg and positive anti-HBs using whole exome sequencing. In the second validation stage, we directly sequence the 16 exomes on the OAS3 gene in two dependent cohorts of 48 cases and 200 controls. Although in the first stage, a genome-wide association study of 58,563 polymorphism variants in 101 cases and 102 controls found no significant loci (P-value ≤ 0.05/58563), and neither locus achieved a conservative genome-wide significance threshold (P-value ≤ 5e-08), gene burden analysis showed that OAS3 gene rare variants were associated with the coexistence of HBsAg and anti-HBs. (P-value =4.127e-06 ≤ 0.05/6994). 16 rare variants were screened out from 21 cases and 3 controls. In the second validation stage, one case with a new different rare variant was identified. Fisher's exact test of all 149 cases and 302 controls showed that the rare coding-sequence mutations were more frequent in cases versus controls [P-value=7.299e-09, OR=17.27, 95% CI (5.01-58.72)]. Protein-coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti-HBs in patients with chronic HBV infection in Chinese Han population. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.

    Science.gov (United States)

    Hunter, Jesse M; Ahearn, Mary Ellen; Balak, Christopher D; Liang, Winnie S; Kurdoglu, Ahmet; Corneveaux, Jason J; Russell, Megan; Huentelman, Matthew J; Craig, David W; Carpten, John; Coons, Stephen W; DeMello, Daphne E; Hall, Judith G; Bernes, Saunder M; Baumbach-Reardon, Lisa

    2015-07-01

    Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.

  20. Can common functional gene variants affect visual discrimination in metacontrast masking?

    Science.gov (United States)

    Maksimov, Margus; Vaht, Mariliis; Harro, Jaanus; Bachmann, Talis

    2013-01-01

    Mechanisms of visual perception should be robustly fast and provide veridical information about environmental objects in order to facilitate survival and successful coping. Because species-specific brain mechanisms for fast vision must have evolved under heavy pressure for efficiency, it has been held that different human individuals see the physical world in the same way and produce psychophysical functions of visual discrimination that are qualitatively the same. For many years, this assumption has been implicitly accepted in vision research studying extremely fast, basic visual processes, including studies of visual masking. However, in recent studies of metacontrast masking surprisingly robust individual differences in the qualitative aspects of subjects' performance have been found. As the basic species-specific visual functions very likely are based on universal brain mechanisms of vision, these differences probably are the outcome of variability in ontogenetic development (i.e., formation of idiosyncrasic skills of perception). Such developmental differences can be brought about by variants of genes that are differentially expressed in the course of CNS development. The objective of this study was to assess whether visual discrimination in metacontrast masking is related to three widely studied genetic polymorphisms implicated in brain function and used here as independent variables. The findings suggest no main effects of BDNF Val66Met, NRG1/rs6994992, or 5-HTTLPR polymorphisms on metacontrast performance, but several notable interactions of genetic variables with gender, stage of the sequence of experimental trials, perceptual strategies, and target/mask shape congruence were found. Thus, basic behavioral functions of fast vision may be influenced by common genetic variability. Also, when left uncontrolled, genetic factors may seriously confound variables in vision research using masking, obscure clear theoretical interpretation, lead to unexplicable inter

  1. Can common functional gene variants affect visual discrimination in metacontrast masking?

    Directory of Open Access Journals (Sweden)

    Margus Maksimov

    Full Text Available Mechanisms of visual perception should be robustly fast and provide veridical information about environmental objects in order to facilitate survival and successful coping. Because species-specific brain mechanisms for fast vision must have evolved under heavy pressure for efficiency, it has been held that different human individuals see the physical world in the same way and produce psychophysical functions of visual discrimination that are qualitatively the same. For many years, this assumption has been implicitly accepted in vision research studying extremely fast, basic visual processes, including studies of visual masking. However, in recent studies of metacontrast masking surprisingly robust individual differences in the qualitative aspects of subjects' performance have been found. As the basic species-specific visual functions very likely are based on universal brain mechanisms of vision, these differences probably are the outcome of variability in ontogenetic development (i.e., formation of idiosyncrasic skills of perception. Such developmental differences can be brought about by variants of genes that are differentially expressed in the course of CNS development. The objective of this study was to assess whether visual discrimination in metacontrast masking is related to three widely studied genetic polymorphisms implicated in brain function and used here as independent variables. The findings suggest no main effects of BDNF Val66Met, NRG1/rs6994992, or 5-HTTLPR polymorphisms on metacontrast performance, but several notable interactions of genetic variables with gender, stage of the sequence of experimental trials, perceptual strategies, and target/mask shape congruence were found. Thus, basic behavioral functions of fast vision may be influenced by common genetic variability. Also, when left uncontrolled, genetic factors may seriously confound variables in vision research using masking, obscure clear theoretical interpretation, lead to

  2. Gene silencing for epidermal growth factor receptor variant III induces cell-specific cytotoxicity.

    Science.gov (United States)

    Yamoutpour, Farnaz; Bodempudi, Vidya; Park, Shay E; Pan, Weihong; Mauzy, Mary Jean; Kratzke, Robert A; Dudek, Arkadiusz; Potter, David A; Woo, Richard A; O'Rourke, Donald M; Tindall, Donald J; Farassati, Faris

    2008-11-01

    Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant form of EGFR that is expressed in 40% to 50% of gliomas and several other malignancies. Here, we describe the therapeutic effects of silencing EGFRvIII on glioma cell lines in vitro and in vivo. A small interfering RNA molecule against EGFRvIII was introduced into EGFRvIII-expressing glioma cells (U87Delta) by electroporation resulting in complete inhibition of expression of EGFRvIII as early as 48 h post-treatment. During EGFRvIII silencing, a decrease in the proliferation and invasiveness of U87Delta cells was accompanied by an increase in apoptosis (P < 0.05). Notably, EGFRvIII silencing inhibited the signal transduction machinery downstream of EGFRvIII as evidenced by decreases in the activated levels of Ras and extracellular signal-regulated kinase. A lentivirus capable of expressing anti-EGFRvIII short hairpin RNA was also able to achieve progressive silencing of EGFRvIII in U87Delta cells in addition to inhibiting cell proliferation, invasiveness, and colony formation in a significant manner (P < 0.05). Silencing EGFRvIII in U87Delta cultures with this virus reduced the expression of factors involved in epithelial-mesenchymal transition including N-cadherin, beta-catenin, Snail, Slug, and paxillin but not E-cadherin. The anti-EGFRvIII lentivirus also affected the cell cycle progression of U87Delta cells with a decrease in G(1) and increase in S and G(2) fractions. In an in vivo model, tumor growth was completely inhibited in severe combined immunodeficient mice (n = 10) injected s.c. with U87Delta cells treated with the anti-EGFRvIII lentivirus (P = 0.005). We conclude that gene specific silencing of EGFRvIII is a promising strategy for treating cancers that contain this mutated receptor.

  3. Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study.

    Science.gov (United States)

    Viitasalo, Anna; Eloranta, Aino-Maija; Atalay, Mustafa; Romeo, Stefano; Pihlajamäki, Jussi; Lakka, Timo A

    2016-11-01

    We studied for the first time among children differences in plasma alanine aminotransferase (ALT) among genotypes of the rs641738 polymorphism in the MBOAT7 gene that has been associated with increased risk of nonalcoholic fatty liver disease among adults. We also investigated the associations of a genetic risk score combining information from the MBOAT7, PNPLA3, and TM6SF2 polymorphisms with plasma ALT. We performed a 2-y follow-up study in 467 Caucasian children aged 6-9 y, genotyped the MBOAT7, PNPLA3, and TM6SF2 polymorphisms, calculated a genetic risk score from these polymorphisms (scored 0-3) and assessed plasma ALT. Children carrying the T allele of the MBOAT7 polymorphism had 7% higher plasma ALT at baseline (17.8 vs. 19.1 U/l, P = 0.022) and 10% higher plasma ALT at 2-y follow-up (18.0 vs. 19.7 U/l, P = 0.022) than the noncarriers. A higher genetic risk score was associated with higher plasma ALT at baseline (17.5, 18.5, 19.2, and 22.8 U/l, P = 0.008 for linear trend) and 2-y follow-up (18.2, 18.9, 18.9, and 32.8 U/l, P = 0.017 for linear trend). Children carrying the T allele of the MBOAT7 polymorphism had higher plasma ALT than the noncarriers. Children with the MBOAT7, PNPLA3, and TM6SF2 variants had the highest plasma ALT.

  4. Folate-related gene variants in Irish families affected by neural tube defects

    Directory of Open Access Journals (Sweden)

    Ridgely eFisk Green

    2013-11-01

    Full Text Available Periconceptional folic acid use can often prevent neural tube defects (NTDs. Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (risk genotypes and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p=0.017. We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential

  5. The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

    Directory of Open Access Journals (Sweden)

    Vanelli Maurizio

    2011-03-01

    Full Text Available Abstract Background The protein tyrosine phosphatase nonreceptor type 2 (PTPN22 has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c, glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab in children during the first year after diagnosis of type 1 diabetes. Methods The C1858T variant was genotyped in an international cohort of children (n = 257 patients with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset. Results A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03 for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002, which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03. Conclusions The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

  6. Augmented hyperaemia and reduced tissue injury in response to ischaemia in subjects with the 34C > T variant of the AMPD1 gene.

    NARCIS (Netherlands)

    Riksen, N.P.; Franke, B.; Oyen, W.J.G.; Borm, G.F.; Broek, P. van den; Boerman, O.C.; Smits, P.; Rongen, G.A.

    2007-01-01

    AIMS: In patients with coronary artery disease, the 34C > T variant of the adenosine mono-phosphate deaminase gene (AMPD1), encoding a dysfunctional protein, predicts improved survival. We hypothesized that in subjects with this variant allele, ischaemia-induced intracellular adenosine formation

  7. The 625G>A SCAD gene variant is common but not associated with increased C4-carnitine in newborn blood spots

    NARCIS (Netherlands)

    van Maldegem, B. T.; Waterham, H. R.; Duran, M.; van der Vlies, M.; van Woerden, C. S.; Bobu, L. L.; Wanders, R. J. A.; Wijburg, F. A.

    2005-01-01

    The 625G>A variant of the short-chain acyl-CoA dehydrogenase (SCAD) gene is considered to confer susceptibility for developing 'clinical SCAD deficiency' and appears to be common in the general population. To determine the frequency of the 625G>A variant in The Netherlands, we analysed 1036

  8. Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp

    NARCIS (Netherlands)

    van Vliet-Ostaptchouk, J.V.; van Haeften, T.W.; Landman, G.W.D.; Reiling, E.; Kleefstra, N.; Bilo, H.J.G.; Klungel, O.H.; de Boer, A.; van Diemen, C.C.; Wijmenga, C.; Boezen, H.M.; Dekker, J.M.; van 't Riet, E.; Nijpels, G.; Welschen, L.M.C.; Zavrelová, H.; Bruin, E.J.; Elbers, C.C.; Bauer, F.; Onland-Moret, N.C.; van der Schouw, Y.T.; Grobbee, D.E.; Spijkerman, A.M.W.; van der Aa, D.L.; Bik-Simonis, A.M.C.; Eekhoff, E.M.W.; Diamant, M.; Kramer, M.H.H.; Boomsma, D.I.; de Geus, E.J.C.; Willemsen, G.; Slagboom, P.E.; Hofker, M.H.; Hart, L.M.

    2012-01-01

    Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on

  9. Common variants in the type 2 diabetes KCNQ1 gene are associated with impairments in insulin secretion during hyperglycaemic glucose clamp

    NARCIS (Netherlands)

    van Vliet-Ostaptchouk, Jana V; van Haeften, Timon W; Landman, Gijs W D; Reiling, Erwin; Kleefstra, Nanne; Bilo, Henk J G; Klungel, Olaf H; de Boer, Anthonius; van Diemen, Cleo C; Wijmenga, Cisca; Boezen, Hendrika; Dekker, Jacqueline M; van 't Riet, Esther; Nijpels, Giel; Welschen, Laura M C; Zavrelova, Hata; Bruin, Elinda J; Elbers, Clara C; Bauer, Florianne; Onland-Moret, N Charlotte; van der Schouw, Yvonne T; Grobbee, Diederick E; Spijkerman, Annemieke M W; van der A, Daphne L; Simonis-Bik, Annemarie M; Eekhoff, Elisabeth M W; Diamant, Michaela; Kramer, Mark H H; Boomsma, Dorret I; de Geus, Eco J; Willemsen, Gonneke; Slagboom, P Eline; Hofker, Marten H; 't Hart, Leen M

    2012-01-01

    BACKGROUND: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on

  10. Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

    NARCIS (Netherlands)

    Visschedijk, Marijn C.; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J.; Pierik, Marieke; Spekhorst, Lieke M.; Imhann, Floris; van der Meulen-de Jong, Andrea E.; van der Woude, C. Janneke; van Bodegraven, Adriaan A.; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A.; Franke, Andre; van Diemen, Cleo C.; Weersma, Rinse K.

    2016-01-01

    Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch

  11. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    Directory of Open Access Journals (Sweden)

    Pina Julieta

    2009-09-01

    Full Text Available Abstract Background MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. Methods We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH. Results Using unconditional logistic regression we found that MLH3 (L844P, G>A polymorphism GA (Leu/Pro and AA (Pro/Pro genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95 (p = 0.03 and OR = 0.62 (0.41-0.94 (p = 0.03, respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83, p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49, p = 0.01], GG/AA [OR = 2.11 (1.12-3,98, p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15, p = 0.02] all associated with an increased risk for breast cancer. Conclusion It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.

  12. New Unstable Variants of Green Fluorescent Protein for Studies of Transient Gene Expression in Bacteria

    OpenAIRE

    Andersen, Jens Bo; Sternberg, Claus; Poulsen, Lars Kongsbak; Bjørn, Sara Petersen; Givskov, Michael; Molin, Søren

    1998-01-01

    Use of the green fluorescent protein (Gfp) from the jellyfish Aequorea victoria is a powerful method for nondestructive in situ monitoring, since expression of green fluorescence does not require any substrate addition. To expand the use of Gfp as a reporter protein, new variants have been constructed by the addition of short peptide sequences to the C-terminal end of intact Gfp. This rendered the Gfp susceptible to the action of indigenous housekeeping proteases, resulting in protein variant...

  13. A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements

    Directory of Open Access Journals (Sweden)

    Hicks Chindo

    2010-01-01

    Full Text Available Abstract Background Polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5'GC splice site (SS sensor used in our tool allows inference on non-canonical exons. Results Our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD. SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer's and breast cancer could be explained by changes in predicted splicing patterns. Conclusions We have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorder.

  14. A Systematic Assessment of Accuracy in Detecting Somatic Mosaic Variants by Deep Amplicon Sequencing: Application to NF2 Gene.

    Directory of Open Access Journals (Sweden)

    Elisa Contini

    Full Text Available The accurate detection of low-allelic variants is still challenging, particularly for the identification of somatic mosaicism, where matched control sample is not available. High throughput sequencing, by the simultaneous and independent analysis of thousands of different DNA fragments, might overcome many of the limits of traditional methods, greatly increasing the sensitivity. However, it is necessary to take into account the high number of false positives that may arise due to the lack of matched control samples. Here, we applied deep amplicon sequencing to the analysis of samples with known genotype and variant allele fraction (VAF followed by a tailored statistical analysis. This method allowed to define a minimum value of VAF for detecting mosaic variants with high accuracy. Then, we exploited the estimated VAF to select candidate alterations in NF2 gene in 34 samples with unknown genotype (30 blood and 4 tumor DNAs, demonstrating the suitability of our method. The strategy we propose optimizes the use of deep amplicon sequencing for the identification of low abundance variants. Moreover, our method can be applied to different high throughput sequencing approaches to estimate the background noise and define the accuracy of the experimental design.

  15. 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.

  16. 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.

  17. Analysis of cosmid clones of nuclear DNA from Trypanosome brucei shows that the genes for variant surface glycoproteins are clustered in the genome.

    NARCIS (Netherlands)

    D. Valerio (Dinko); T. de Lange; P. Borst (Piet); F.G. Grosveld (Frank); L.H.T. van der Ploeg

    1982-01-01

    textabstractTrypanosoma brucei contains more than a hundred genes coding for the different variant surface glycoproteins (VSGs). Activation of some of these genes involves the duplication of the gene (the basic copy or BC) and transposition of the duplicate to an expression site (yielding the

  18. A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Je-Hyuk Lee

    2009-11-01

    Full Text Available Normal variation in gene expression due to regulatory polymorphisms is often masked by biological and experimental noise. In addition, some regulatory polymorphisms may become apparent only in specific tissues. We derived human induced pluripotent stem (iPS cells from adult skin primary fibroblasts and attempted to detect tissue-specific cis-regulatory variants using in vitro cell differentiation. We used padlock probes and high-throughput sequencing for digital RNA allelotyping and measured allele-specific gene expression in primary fibroblasts, lymphoblastoid cells, iPS cells, and their differentiated derivatives. We show that allele-specific expression is both cell type and genotype-dependent, but the majority of detectable allele-specific expression loci remains consistent despite large changes in the cell type or the experimental condition following iPS reprogramming, except on the X-chromosome. We show that our approach to mapping cis-regulatory variants reduces in vitro experimental noise and reveals additional tissue-specific variants using skin-derived human iPS cells.

  19. A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells.

    Science.gov (United States)

    Lee, Je-Hyuk; Park, In-Hyun; Gao, Yuan; Li, Jin Billy; Li, Zhe; Daley, George Q; Zhang, Kun; Church, George M

    2009-11-01

    Normal variation in gene expression due to regulatory polymorphisms is often masked by biological and experimental noise. In addition, some regulatory polymorphisms may become apparent only in specific tissues. We derived human induced pluripotent stem (iPS) cells from adult skin primary fibroblasts and attempted to detect tissue-specific cis-regulatory variants using in vitro cell differentiation. We used padlock probes and high-throughput sequencing for digital RNA allelotyping and measured allele-specific gene expression in primary fibroblasts, lymphoblastoid cells, iPS cells, and their differentiated derivatives. We show that allele-specific expression is both cell type and genotype-dependent, but the majority of detectable allele-specific expression loci remains consistent despite large changes in the cell type or the experimental condition following iPS reprogramming, except on the X-chromosome. We show that our approach to mapping cis-regulatory variants reduces in vitro experimental noise and reveals additional tissue-specific variants using skin-derived human iPS cells.

  20. [Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder].

    Science.gov (United States)

    Ortega-Rojas, Jenny; Arboleda-Bustos, Carlos E; Morales, Luis; Benítez, Bruno A; Beltrán, Diana; Izquierdo, Álvaro; Arboleda, Humberto; Vásquez, Rafael

    Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  1. Genetic variants in FGFR2 and TNRC9 genes are associated with breast cancer risk in Pakistani women.

    Science.gov (United States)

    Mazhar, Ayesha; Jamil, Farrukh; Bashir, Qamar; Ahmad, Munawar Saleem; Masood, Misbah; Tanvir, Imrana; Rashid, Naeem; Waheed, Abdul; Afzal, Muhammad Naveed; Tariq, Muhammad Akram

    2016-10-01

    Single nucleotide polymorphisms (SNPs) lead to genetic differences in breast cancer (BC) susceptibility among women from different ethnicities. The present study aimed at investigating the involvement of SNPs of three genes, including fibroblast growth factor receptor 2 (FGFR2), trinucleotide-repeat-containing 9 (TNRC9) and mitogen-activated protein kinase kinase kinase 1 (MAP3K1), as risk factors for the development of BC. A case‑control study (90‑100 cases; 90‑100 controls) was performed to evaluate five genetic variants of three genes, including FGFR2 (SNPs: rs1219648, rs2981582), TNRC9 (SNPs: rs8051542, rs3803662) and MAP3K1 (SNP: rs889312) as BC risk factors in Pakistani women. Significant associations were observed between BC risk and two SNPs of FGFR2 [rs2981582 (P=0.005), rs1219648 (P=9.08e‑006)] and one SNP of TNRC9 [rs3803662) (P=0.012)] in Pakistani women. On examining the different interactions of these SNPs with various clinicopathological characteristics, all three associated genetic variants, rs2981582 rs1219648 and rs3803662, exhibited a greater predisposition to sporadic, in comparison to familial, BC. Furthermore, there was an increased effect of BC risk between haplotype combinations of the two SNPs of FGFR2 (rs2981582 and rs1219648) in Pakistani women. The results of the present study suggest that variants of FGFR2 and TNRC9 may contribute to the genetic susceptibility of BC in Pakistani women.

  2. Identification and functional analysis of variant haplotypes in the 5'-flanking region of protein phosphatase 2A-Bδ gene.

    Directory of Open Access Journals (Sweden)

    Hui-Feng Chen

    Full Text Available Serine-threonine protein phosphatase 2A (PP2A is a trimeric holoenzyme that plays an integral role in the regulation of cell growth, differentiation, and apoptosis. The substrate specificity and (subcellular localization of the PP2A holoenzymes are highly regulated by interaction with a family of regulatory B subunits (PP2A-Bs. The regulatory subunit PP2A-B/PR55δ (PP2A-Bδ is involving in the dephosphorylation of PP2A substrates and is crucial for controlling entry into and exit from mitosis. The molecular mechanisms involved in the regulation of expression of PP2A-Bδ gene (PPP2R2D remain largely unknown. To explore genetic variations in the 5'-flanking region of PPP2R2D gene as well as their frequent haplotypes in the Han Chinese population and determine whether such variations have an impact on transcriptional activity, DNA samples were collected from 70 healthy Chinese donors and sequenced for identifying genetic variants in the 5'-flanking region of PPP2R2D. Four genetic variants were identified in the 1836 bp 5'-flanking region of PPP2R2D. Linkage disequilibrium (LD patterns and haplotype profiles were constructed for the genetic variants. Using serially truncated human PPP2R2D promoter luciferase constructs, we found that a 601 bp (-540 nt to +61 nt fragment constitutes the core promoter region. The subcloning of individual 5'-flanking fragment revealed the existence of three haplotypes in the distal promoter of PPP2R2D. The luciferase reporter assay showed that different haplotypes exhibited distinct promoter activities. The EMSA revealed that the -462 G>A variant influences DNA-protein interactions involving the nuclear factor 1 (NF1. In vitro reporter gene assay indicated that cotransfection of NF1/B expression plasmid could positively regulate the activity of PPP2R2D proximal promoter. Introduction of exogenous NF1/B expression plasmid further confirmed that the NF1 involves in the regulation of PPP2R2D gene expression. Our findings

  3. DNA Sequence Variants in the Five Prime Untranslated Region of the Cyclooxygenase-2 Gene Are Commonly Found in Healthy Dogs and Gray Wolves.

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    Noa Safra

    Full Text Available The aim of this study was to investigate the frequency of regional DNA variants upstream to the translation initiation site of the canine Cyclooxygenase-2 (Cox-2 gene in healthy dogs. Cox-2 plays a role in various disease conditions such as acute and chronic inflammation, osteoarthritis and malignancy. A role for Cox-2 DNA variants in genetic predisposition to canine renal dysplasia has been proposed and dog breeders have been encouraged to select against these DNA variants. We sequenced 272-422 bases in 152 dogs unaffected by renal dysplasia and found 19 different haplotypes including 11 genetic variants which had not been described previously. We genotyped 7 gray wolves to ascertain the wildtype variant and found that the wolves we analyzed had predominantly the second most common DNA variant found in dogs. Our results demonstrate an elevated level of regional polymorphism that appears to be a feature of healthy domesticated dogs.

  4. DNA Sequence Variants in the Five Prime Untranslated Region of the Cyclooxygenase-2 Gene Are Commonly Found in Healthy Dogs and Gray Wolves.

    Science.gov (United States)

    Safra, Noa; Hayward, Louisa J; Aguilar, Miriam; Sacks, Benjamin N; Westropp, Jodi L; Mohr, F Charles; Mellersh, Cathryn S; Bannasch, Danika L

    2015-01-01

    The aim of this study was to investigate the frequency of regional DNA variants upstream to the translation initiation site of the canine Cyclooxygenase-2 (Cox-2) gene in healthy dogs. Cox-2 plays a role in various disease conditions such as acute and chronic inflammation, osteoarthritis and malignancy. A role for Cox-2 DNA variants in genetic predisposition to canine renal dysplasia has been proposed and dog breeders have been encouraged to select against these DNA variants. We sequenced 272-422 bases in 152 dogs unaffected by renal dysplasia and found 19 different haplotypes including 11 genetic variants which had not been described previously. We genotyped 7 gray wolves to ascertain the wildtype variant and found that the wolves we analyzed had predominantly the second most common DNA variant found in dogs. Our results demonstrate an elevated level of regional polymorphism that appears to be a feature of healthy domesticated dogs.

  5. 4G/5G variant of plasminogen activator inhibitor-1 gene and severe pregnancy-induced hypertension: subgroup analyses of variants of angiotensinogen and endothelial nitric oxide synthase.

    Science.gov (United States)

    Kobashi, Gen; Ohta, Kaori; Yamada, Hideto; Hata, Akira; Minakami, Hisanori; Sakuragi, Noriaki; Tamashiro, Hiko; Fujimoto, Seiichiro

    2009-01-01

    Pregnancy-induced hypertension (PIH) is a common cause of perinatal mortality. It is believed to result from the interaction of several factors, including those related to the blood coagulation system. We performed genotyping and subgroup analyses to determine if the 4G/5G genotypes of the plasminogen activator inhibitor-1 gene (PAI-1) play a role in the pathogenesis of PIH, and to evaluate possible interactions of the PAI-1 polymorphisms with those of the angiotensinogen gene (AGT) and the endothelial nitric oxide synthase gene (NOS3). An association study of PAI-1 polymorphism, and subgroup analyses of common variants of AGT and NOS3, among 128 patients with PIH and 376 healthy pregnant controls. No significant differences were found between the cases and controls in the frequencies of allele 4G or the 4G/4G genotype. In subgroup analyses, after adjustment for multiple comparison, a significant association with the AGT TT genotype was found among women with the PAI-1 4G/4G genotype, and an association with the NOS3 GA+AA genotype was found among women with the 5G/5G or 4G/5G genotypes. Our findings suggest that there are at least 2 pathways in the pathogenesis of severe PIH. However, with respect to early prediction and prevention of severe PIH, although the PAI-1 4G/4G genotype alone was not a risk factor for severe PIH, the fact that PAI-1 genotypes are associated with varying risks for severe PIH suggests that PAI-1 genotyping of pregnant women, in combination with other tests, may be useful in the development of individualized measures that may prevent severe PIH.

  6. Ischemic stroke in Ukrainian population: possible involvement of the F2 G20210A, F5 G1691A and MTHFR C677T gene variants

    Directory of Open Access Journals (Sweden)

    Kuznetsova S. M.

    2010-07-01

    Full Text Available Aim. To evaluate a possible involvement of the F2, F5, MTHFR gene variants into ischemic stroke pathogenesis in population of Ukraine. Methods. Polymorphic variants were analyzed in unrelated 183 stroke patients, 100 individuals from the general population of Ukraine and 88 healthy individuals elder than 65 years using PCR followed by RFLP analysis. Results. Unfavourable polymorphic variants F2 20210A, F5 1691A and MTHFR 677T were observed more frequently in patients with ischemic stroke comparing to control groups. Conclusions. F5 1691A and MTHFR 677T polymorphic variants are associated with the occurrence of ischemic stroke in women. F2 20210A is associated with the occurrence of ischemic stroke in men. Cumulative risk factor for stroke development is revealed in a combination of unfavorable polymorphic variants 20210A, 1691A and 677T of F2, F5 and MTHFR genes.

  7. Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys.

    Science.gov (United States)

    Ayers, Katie L; Bouty, Aurore; Robevska, Gorjana; van den Bergen, Jocelyn A; Juniarto, Achmad Zulfa; Listyasari, Nurin Aisyiyah; Sinclair, Andrew H; Faradz, Sultana M H

    2017-02-16

    Congenital hypogonadotrophic hypogonadism (CHH) and Kallmann syndrome (KS) are caused by disruption to the hypothalamic-pituitary-gonadal (H-P-G) axis. In particular, reduced production, secretion or action of gonadotrophin-releasing hormone (GnRH) is often responsible. Various genes, many of which play a role in the development and function of the GnRH neurons, have been implicated in these disorders. Clinically, CHH and KS are heterogeneous; however, in 46,XY patients, they can be characterised by under-virilisation phenotypes such as cryptorchidism and micropenis or delayed puberty. In rare cases, hypospadias may also be present. Here, we describe genetic mutational analysis of CHH genes in Indonesian 46,XY disorder of sex development patients with under-virilisation. We present 11 male patients with varying degrees of under-virilisation who have rare variants in known CHH genes. Interestingly, many of these patients had hypospadias. We postulate that variants in CHH genes, in particular PROKR2, PROK2, WDR11 and FGFR1 with CHD7, may contribute to under-virilisation phenotypes including hypospadias in Indonesia.

  8. Genome-wide analysis of Epstein-Barr virus identifies variants and genes associated with gastric carcinoma and population structure.

    Science.gov (United States)

    Yao, Youyuan; Xu, Miao; Liang, Liming; Zhang, Haojiong; Xu, Ruihua; Feng, Qisheng; Feng, Lin; Luo, Bing; Zeng, Yi-Xin

    2017-10-01

    Epstein-Barr virus is a ubiquitous virus and is associated with several human malignances, including the significant subset of gastric carcinoma, Epstein-Barr virus-associated gastric carcinoma. Some Epstein-Barr virus-associated diseases are uniquely prevalent in populations with different geographic origins. However, the features of the disease and geographically associated Epstein-Barr virus genetic variation as well as the roles that the variation plays in carcinogenesis and evolution remain unclear. Therefore, in this study, we sequenced 95 geographically distinct Epstein-Barr virus isolates from Epstein-Barr virus-associated gastric carcinoma biopsies and saliva of healthy donors to detect variants and genes associated with gastric carcinoma and population structure from a genome-wide spectrum. We demonstrated that Epstein-Barr virus revealed the population structure between North China and South China. In addition, we observed population stratification between Epstein-Barr virus strains from gastric carcinoma and healthy controls, indicating that certain Epstein-Barr virus subtypes are associated with different gastric carcinoma risks. We identified that the BRLF1, BBRF3, and BBLF2/BBLF3 genes had significant associations with gastric carcinoma. LMP1 and BNLF2a genes were strongly geographically associated genes in Epstein-Barr virus. Our study provides insights into the genetic basis of oncogenic Epstein-Barr virus for gastric carcinoma, and the genetic variants associated with gastric carcinoma can serve as biomarkers for oncogenic Epstein-Barr virus.

  9. MTHFR gene C677T and A1298C variants are associated with FMF risk in a Turkish cohort.

    Science.gov (United States)

    Nursal, Ayse Feyda; Kaya, Süheyla; Sezer, Ozlem; Karakus, Nevin; Yigit, Serbulent

    2018-02-01

    Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine (Hcy) metabolism. We aimed to evaluate a possible relationship between MTHFR gene C677T (rs 1801133), A1298C (rs 1801131) variants and susceptibility to FMF in a Turkish cohort. This case-control study included 198 Turkish FMF patients and 100 healthy subjects as controls. MTHFR C677T and A1298C were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The genotype distribution and allele frequency of the MTHFR C677T were statistically different between the patients and the control group (P=.006, P=.001, respectively). The frequency of the TT genotype and T allele of MTHFR C677T was significantly higher in the patients than in the controls. The genotype distribution of MTHFR A1298C variant did not show any statistically significant difference between the patients and the controls (P›.05). The patients had statistically different frequencies in allele C of MTHFR A1298C variant compared with the control (P=.032). We also examined the risk associated with inheriting the combined genotypes for the two MTHFR variants. According to these results, individuals who were CC homozygous at C677T locus and AA homozygous at A1298C locus have a lower risk of developing FMF (P=.002). Individuals who were TT homozygous at C677T locus and AC heterozygous at A1298C locus have higher risk of developing FMF (P=.033). Our findings clearly showed there was an association the MTHFR C677T/A1298C variants and susceptibility to FMF in the Turkish sample. © 2017 Wiley Periodicals, Inc.

  10. Protective Low-Frequency Variants for Preeclampsia in the Fms Related Tyrosine Kinase 1 Gene in the Finnish Population.

    Science.gov (United States)

    Lokki, A Inkeri; Daly, Emma; Triebwasser, Michael; Kurki, Mitja I; Roberson, Elisha D O; Häppölä, Paavo; Auro, Kirsi; Perola, Markus; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Salmon, Jane E; Meri, Seppo; Daly, Mark; Atkinson, John P; Laivuori, Hannele

    2017-08-01

    Preeclampsia is a common pregnancy-specific vascular disorder characterized by new-onset hypertension and proteinuria during the second half of pregnancy. Predisposition to preeclampsia is in part heritable. It is associated with an increased risk of cardiovascular disease later in life. We have sequenced 124 candidate genes implicated in preeclampsia to pinpoint genetic variants contributing to predisposition to or protection from preeclampsia. First, targeted exomic sequencing was performed in 500 preeclamptic women and 190 controls from the FINNPEC cohort (Finnish Genetics of Preeclampsia Consortium). Then 122 women with a history of preeclampsia and 1905 parous women with no such history from the National FINRISK Study (a large Finnish population survey on risk factors of chronic, noncommunicable diseases) were included in the analyses. We tested 146 rare and low-frequency variants and found an excess (observed 13 versus expected 7.3) nominally associated with preeclampsia ( P preeclampsia. © 2017 American Heart Association, Inc.

  11. Clinical variant of Tangier disease in Japan: mutation of the ABCA1 gene in hypoalphalipoproteinemia with corneal lipidosis.

    Science.gov (United States)

    Ishii, Jun; Nagano, Makoto; Kujiraoka, Takeshi; Ishihara, Mitsuaki; Egashira, Tohru; Takada, Daisuke; Tsuji, Masahiro; Hattori, Hiroaki; Emi, Mitsuru

    2002-01-01

    Despite progress in molecular characterization, specific diagnoses of disorders belonging to a group of inherited hypoalphalipoproteinemias, i.e., apolipoprotein AI deficiency, lecithin-cholesterol acyltransferase deficiency, Tangier disease (TD), and familial high-density lipoprotein (HDL) deficiency, remain difficult on a purely clinical basis. Several TD patients were recently found to be homozygous for mutations in the ABCA1 gene. We have documented here a clinical variant of TD in a Japanese patient who manifested corneal lipidosis and premature coronary artery disease as well as an almost complete absence of HDL-cholesterol, by identifying a novel homozygous ABCA1 mutation (R1680W). We propose that patients with apparently isolated HDL deficiency who are found to carry ABCA1 mutations may in fact belong to a category of TD patients whose phenotypic features are only partially expressed, and that a number of hidden clinical variants of TD might exist among other HDL deficiency patients who have escaped correct clinical diagnosis.

  12. Pharmacodynamic Impact of Carboxylesterase 1 Gene Variants in Patients with Congestive Heart Failure Treated with Angiotensin-Converting Enzyme Inhibitors

    DEFF Research Database (Denmark)

    Nelveg-Kristensen, Karl Emil; Bie, Peter; Ferrero, Laura

    2016-01-01

    1Var, and three other CES1 variants were examined. METHODS: Patients with CHF, and clinical indication for ACEIs were categorized according to their CES1 genotype. Differences in mean plasma ATII/ATI ratios between genotype groups after ACEI dose titration, expressed as the least square mean (LSM......BACKGROUND: Variation in the carboxylesterase 1 gene (CES1) may contribute to the efficacy of ACEIs. Accordingly, we examined the impact of CES1 variants on plasma angiotensin II (ATII)/angiotensin I (ATI) ratio in patients with congestive heart failure (CHF) that underwent ACEI dose titrations......) with 95% confidence intervals (CIs), were assessed by analysis of variance. RESULTS: A total of 200 patients were recruited and 127 patients (63.5%) completed the study. The mean duration of the CHF drug dose titration was 6.2 (SD 3.6) months. After ACEI dose titration, there was no difference in mean...

  13. Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians.

    Science.gov (United States)

    Ahluwalia, Tarunveer Singh; Khullar, Madhu; Ahuja, Monica; Kohli, Harbir Singh; Bhansali, Anil; Mohan, Viswanathan; Venkatesan, Radha; Rai, Taranjit Singh; Sud, Kamal; Singal, Pawan K

    2009-01-01

    Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients. Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002). The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

  14. Xenobiotic metabolizing gene variants, dietary heterocyclic amine intake, and risk of prostate cancer.

    Science.gov (United States)

    Koutros, Stella; Berndt, Sonja I; Sinha, Rashmi; Ma, Xiaomei; Chatterjee, Nilanjan; Alavanja, Michael C R; Zheng, Tongzhang; Huang, Wen-Yi; Hayes, Richard B; Cross, Amanda J

    2009-03-01

    We recently reported that heterocyclic amines (HCA) are associated with prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We now use extensive genetic data from this resource to determine if risks associated with dietary HCAs {2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx); and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)} from cooked meat are modified by single nucleotide polymorphisms (SNP) in genes involved in HCA metabolism (CYP1A1, CYP1A2, CYP1B1, GSTA1, GSTM1, GSTM3, GSTP1, NAT1, NAT2, SULT1A1, SULT1A2, and UGT1A locus). We conducted a nested case-control study that included 1,126 prostate cancer cases and 1,127 controls selected for a genome-wide association study for prostate cancer. Unconditional logistic regression was used to estimate odds ratios (OR), 95% confidence intervals (95% CI), and P values for the interaction between SNPs, HCA intake, and risk of prostate cancer. The strongest evidence for an interaction was noted between DiMeIQx and MeIQx and the polymorphism rs11102001 downstream of the GSTM3 locus (P(interaction) = 0.001 for both HCAs; statistically significant after correction for multiple testing). Among men carrying the A variant, the risk of prostate cancer associated with high DiMeIQx intake was 2-fold greater than that with low intake (OR, 2.3; 95% CI, 1.2-4.7). The SNP rs11102001, which encodes a nonsynonymous amino acid change P356S in EPS8L3, is a potential candidate modifier of the effect of HCAs on prostate cancer risk. The observed effect provides evidence to support the hypothesis that HCAs may act as promoters of malignant transformation by altering mitogenic signaling.

  15. KCNQ1 gene variants in the risk for type 2 diabetes and impaired renal function in the Spanish Renastur cohort.

    Science.gov (United States)

    Riobello, Cristina; Gómez, Juan; Gil-Peña, Helena; Tranche, Salvador; Reguero, Julián R; de la Hera, Jesús M; Delgado, Elías; Calvo, David; Morís, César; Santos, Fernando; Coto-Segura, Pablo; Iglesias, Sara; Alonso, Belén; Alvarez, Victoria; Coto, Eliecer

    2016-05-15

    Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta-cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non-diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFRKCNQ1 gene in 100 individuals with the extreme eGFR values. We found two rare amino acid changes (p.K393N and p.P408A) and the 393 Asn variant was found only among diabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Prevalence of endothelial nitric oxide synthase (eNOS) gene exon 7 Glu298Asp variant in North Eastern India

    Science.gov (United States)

    Shankarishan, Priyanka; Borah, Prasanta Kumar; Ahmed, Giasuddin; Mahanta, Jagadish

    2011-01-01

    Background & objectives Endothelial nitric oxide is a potent vasodilator and impairment of its generation brought about by gene polymorphism is considered a major predictor for several diseases. A single nucleotide polymorphism G894T within exon 7 of endothelial nitric oxide synthase (eNOS-7) gene, resulting in a replacement of glutamic acid by aspartic acid, has been studied as a putative candidate gene for cardiovascular diseases. The pattern of eNOS-7 Glu298Asp variant in the Indian population is poorly known. The present study was planned to determine the prevalence of the variant of this gene among tea garden community in Assam, North-East India with high prevalence of hypertension. Methods Study participants of both sex aged ≥18 yr were recruited randomly from temporary field clinics established in tea gardens of Dibrugarh, Assam. Genomic DNA was extracted from 409 subjects by the conventional phenol-chloroform method. The prevalence of the eNOS exon 7 Glu298Asp variant was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Results The study population was in Hardy-Weinberg Equilibrium. The frequency of the eNOS GG, GT and TT genotypes was found to be 75, 22 and 3 per cent respectively and did not show any significant difference in gender wise analysis. Interpretation & conclusions Our results showed that the prevalence of the homozygous GG genotype was high (75%) and the rare mutant genotype (homozygous, TT) was 3 per cent in a population at risk with cardiovascular disease. Such population-based data on various polymorphisms can ultimately be exploited in pharmacogenomics. PMID:21623032

  17. Germline variants in the ATM gene and breast cancer susceptibility in Moroccan women: A meta-analysis

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    Chaymaa Marouf

    2017-10-01

    Full Text Available Background: The ATM gene encoding a large protein kinase is mutated in ataxia-telangiectasia (AT, an autosomale recessive disease characterized by neurological and immunological symptoms, and cancer predisposition. Previous studies suggest that heterozygous carriers of ATM mutations have an increased risk of breast cancer compared with non carriers, but the contribution of specific variants has been difficult to estimate. However, two functional ATM variants, c.7271T > G and c.1066–6T > G (IVS10–6T > G, are associated with increased risk for the development of breast cancer. Methods: To investigate the role of ATM in breast cancer susceptibility, we genotyped 163 case patients with breast cancer and 150 healthy control individuals for the c.7271T > G and c.1066–6T > G (IVS10–6T > G ATM variants using polymerase chain reaction (PCR-restriction fragment length polymorphism (RFLP analysis. Results: We did not detect the ATM c.7271T > G and c.1066–6T > G (IVS10–6T > G mutations in any of 150 healthy control individuals and 163 breast cancer patients, including 59 women diagnosed with breast cancer at an early age ( G (IVS10–6T > G mutation and the rare c.7271T > G variant are not a risk factor for developing breast cancer in the Moroccan population. Larger and/or combined association studies are needed to clarify this issue. Keywords: Breast cancers, ATM gene, Germline mutation, Genetic susceptibility, Moroccan population

  18. Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway.

    Science.gov (United States)

    Puisac, Beatriz; Ramos, Mónica; Arnedo, María; Menao, Sebastián; Gil-Rodríguez, María Concepción; Teresa-Rodrigo, María Esperanza; Pié, Angeles; de Karam, Juan Carlos; Wesselink, Jan-Jaap; Giménez, Ignacio; Ramos, Feliciano J; Casals, Nuria; Gómez-Puertas, Paulino; Hegardt, Fausto G; Pié, Juan

    2012-04-01

    The genes HMGCS2 and HMGCL encode the two main enzymes for ketone-body synthesis, mitochondrial HMG-CoA synthase and HMG-CoA lyase. Here, we identify and describe possible splice variants of these genes in human tissues. We detected an alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively. All splice variants maintained the reading frame. However, Western blot studies and overexpression measurements in eukaryotic or prokaryotic cell models did not reveal HL or mHS protein variants. Both genes showed a similar distribution of the inactive variants in different tissues. Surprisingly, the highest percentages were found in tissues where almost no ketone bodies are synthesized: heart, skeletal muscle and brain. Our results suggest that alternative splicing might coordinately block the two main enzymes of ketogenesis in specific human tissues.

  19. A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes.

    Directory of Open Access Journals (Sweden)

    Rory Johnson

    Full Text Available Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies-various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation-these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP-seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism.

  20. A Genome-Wide Screen for Genetic Variants That Modify the Recruitment of REST to Its Target Genes

    Science.gov (United States)

    Johnson, Rory; Richter, Nadine; Bogu, Gireesh K.; Bhinge, Akshay; Teng, Siaw Wei; Choo, Siew Hua; Andrieux, Lise O.; de Benedictis, Cinzia; Jauch, Ralf; Stanton, Lawrence W.

    2012-01-01

    Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies—various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation—these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP–seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism. PMID:22496669

  1. Expression of Caspase-1 Gene Transcript Variant mRNA in Peripheral Blood Mononuclear Cells of Patients with Primary Gout in Different TCM Syndromes

    Directory of Open Access Journals (Sweden)

    Wan-Tai Dang

    2015-01-01

    Full Text Available A large number of studies have shown that cysteinyl aspartate specific protease-1 (CASP1 played an important role in the inflammatory response of primary gout, but the decreased expression of different CASP1 transcript variant could inhibit the activation of IL-1β. Our study mainly analyzed the expression level and function of CASP1 gene transcript variant mRNA in peripheral blood mononuclear cells of patients with gout in different TCM syndromes. The expression of CASP1 gene transcript variant and IL-1β mRNA in PBMCs were detected in patients with PG [acute phase (AP: 44 cases; nonacute phase (NAP: 52 cases] and healthy controls (HC: 30 cases by reverse transcription-polymerase chain reaction and/or real-time quantitative polymerase chain reaction. The expressions of plasma IL-1β in patients with PG and HC were detected by enzyme-linked immunosorbent assay. Dysregulated expression of the CASP1 gene and its transcript variant, plasma proinflammatory cytokines in all patients with primary gout in different TCM syndromes, correlation analysis showed that there was negative correlation between the expression of CASP1-gamma gene transcript variant mRNA and IL-1β protein in APPG group. The study suggested that CASP1 gene and its transcript variant may play a critical role in the inflammatory response of patients with PG in different phases and TCM syndromes.

  2. New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene.

    Science.gov (United States)

    Sobreira, Nara; Schiettecatte, François; Boehm, Corinne; Valle, David; Hamosh, Ada

    2015-04-01

    Identifying the causative variant from among the thousands identified by whole-exome sequencing or whole-genome sequencing is a formidable challenge. To make this process as efficient and flexible as possible, we have developed a Variant Analysis Module coupled to our previously described Web-based phenotype intake tool, PhenoDB (http://researchphenodb.net and http://phenodb.org). When a small number of candidate-causative variants have been identified in a study of a particular patient or family, a second, more difficult challenge becomes proof of causality for any given variant. One approach to this problem is to find other cases with a similar phenotype and mutations in the same candidate gene. Alternatively, it may be possible to develop biological evidence for causality, an approach that is assisted by making connections to basic scientists studying the gene of interest, often in the setting of a model organism. Both of these strategies benefit from an open access, online site where individual clinicians and investigators could post genes of interest. To this end, we developed GeneMatcher (http://genematcher.org), a freely accessible Website that enables connections between clinicians and researchers across the world who share an interest in the same gene(s). © 2015 WILEY PERIODICALS, INC.

  3. Genetic analyses of the NF1 gene in Turkish neurofibromatosis type I patients and definition of three novel variants

    Directory of Open Access Journals (Sweden)

    Ulusal SD

    2017-06-01

    Full Text Available Neurofibromatosis Type I (NF1 is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA and next generation sequencing (NGS for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS.

  4. Determination of Stearoyl-Coenzyme A Desaturase 1 Gene Variants in South Anatolian Red and East Anatolian Red Cattle

    Directory of Open Access Journals (Sweden)

    İjlal İpek PAYA

    2015-07-01

    Full Text Available Fat composition in ruminant’s milk is one of the factors that can affect human health in positive or adverse ways. Optimizing ruminant feed to achieve ideal fatty acid composition in milk has been an ongoing area of research in recent years, without satisfactory results to date. It has been argued that in addition to changes in feed, genetic information can also be utilized to improve milk fatty acid composition. The aim of the study is to investigate the incidence of stearoyl-CoA-desaturase 1 (SCD gene variants, which are claimed to affect fat content and quality of milk in Turkish native cattle breeds. Fifty South Anatolian Red (SAR and 50 East Anatolian Red (EAR cattle were used in the study. The 5th exon of SCD gene was amplified using polymerase chain reaction (PCR and the PCR products were subjected to sequencing analysis. Among the samples sequenced polymorphism at three nucleotide positions have been observed on the 5th exon of the SCD gene, namely A702G, T762C and C878T. Of these three, the polymorphic position C878T was utilized to determine peptide variants of A (293Ala or the V (293 Val of individual samples. Frequency of A variant and AA genotype in SAR and EAR cattle breeds was 0.91 and 0.77 as well as 0.43 and 0.29, respectively. In particular the SAR exhibits a very low frequency of the V allele, believed to have been an ancestral allele. In both samples, 2 individuals were identified to have the VV genotype. The results suggested that high frequency of A allele and AA genotype which confers great advantage on milk composition and meat fatty acid composition was present in SAR and EAR cattle breeds

  5. Fatty-acid binding protein 4 gene variants and childhood obesity: potential implications for insulin sensitivity and CRP levels

    Directory of Open Access Journals (Sweden)

    Bhattacharjee Rakesh

    2010-02-01

    Full Text Available Abstract Introduction Obesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to measure FABP4 plasma levels, assess FABP4 allelic variants, and explore potential associations with fasting glucose and insulin levels in young school-age children with and without obesity. Methods A total of 309 consecutive children ages 5-7 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >1.65 and non-obese (NOB. Fasting plasma glucose, lipids, insulin, hsCRP, and FABP4 levels were measured. HOMA was used as correlate of insulin sensitivity. Four SNPs of the human FABP4 gene (rs1051231, rs2303519, rs16909233 and rs1054135, corresponding to several critical regions of the encoding FABP4 gene sequence were genotyped. Results Compared to NOB, circulating FABP4 levels were increased in OB, as were LDL, hsCRP and HOMA. FABP4 levels correlated with BMI, and also contributed to the variance of HOMA and hsCRP, but not serum lipids. The frequency of rs1054135 allelic variant was increased in OB, and was associated with increased FABP4 levels, while the presence of rs16909233 variant allele, although similar in OB and NOB, was associated with increased HOMA values. Conclusions Childhood obesity is associated with higher FABP4 levels that may promote cardiometabolic risk. The presence of selective SNPs in the FABP4 gene may account for increased risk for insulin resistance or systemic inflammation in the context of obesity.

  6. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Pruss, Dmitry; Morris, Brian; Hughes, Elisha; Eggington, Julie M; Esterling, Lisa; Robinson, Brandon S; van Kan, Aric; Fernandes, Priscilla H; Roa, Benjamin B; Gutin, Alexander; Wenstrup, Richard J; Bowles, Karla R

    2014-08-01

    BRCA1 and BRCA2 sequencing analysis detects variants of uncertain clinical significance in approximately 2 % of patients undergoing clinical diagnostic testing in our laboratory. The reclassification of these variants into either a pathogenic or benign clinical interpretation is critical for improved patient management. We developed a statistical variant reclassification tool based on the premise that probands with disease-causing mutations are expected to have more severe personal and family histories than those having benign variants. The algorithm was validated using simulated variants based on approximately 145,000 probands, as well as 286 BRCA1 and 303 BRCA2 true variants. Positive and negative predictive values of ≥99 % were obtained for each gene. Although the history weighting algorithm was not designed to detect alleles of lower penetrance, analysis of the hypomorphic mutations c.5096G>A (p.Arg1699Gln; BRCA1) and c.7878G>C (p.Trp2626Cys; BRCA2) indicated that the history weighting algorithm is able to identify some lower penetrance alleles. The history weighting algorithm is a powerful tool that accurately assigns actionable clinical classifications to variants of uncertain clinical significance. While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.

  7. Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants

    DEFF Research Database (Denmark)

    Shi, Min; Christensen, Kaare; Weinberg, Clarice R

    2007-01-01

    Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings...

  8. Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

    NARCIS (Netherlands)

    Wheeler, Heather E.; Gamazon, Eric R.; Frisina, Robert D.; Perez-Cervantes, Carlos; El Charif, Omar; Mapes, Brandon; Fossa, Sophie D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Fung, Chunkit; Kollmannsberger, Christian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence H.; Cox, Nancy J.; Dolan, M. Eileen; Travis, Lois B.

    2017-01-01

    Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using

  9. Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant.

    Science.gov (United States)

    Lebrun, N; Parent, P; Gendras, J; Billuart, P; Poirier, K; Bienvenu, T

    2017-12-01

    Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Clinical characteristics and analysis of HFE gene variants (C282Y ...

    African Journals Online (AJOL)

    Asem Alkhateeb

    2012-11-24

    Nov 24, 2012 ... Bevacizumab for treatment and 11 (30%) were not receiving treatment. We genotyped patient and control samples using PCR of the region continuing the variants followed by restriction en- zyme digestion of the amplified product. Band patterns were scored and samples genotyped (Fig. 1). We sequenced ...

  11. Screening for CYP2C19 Gene variants in a healthy Jordanian ...

    African Journals Online (AJOL)

    Purpose: To genotype healthy Jordanian population from three different provinces (Amman, Zarqa and Irbid) for cytochrome P4502C19 and to identify the allelic distribution of CYP2C19 variants in comparison with other findings around the world. Methods: Healthy Jordanian volunteers were recruited from government ...

  12. The histone variant macroH2A is an epigenetic regulator of key developmental genes

    DEFF Research Database (Denmark)

    Buschbeck, Marcus; Uribesalgo, Iris; Wibowo, Indra

    2009-01-01

    The histone variants macroH2A1 and macroH2A2 are associated with X chromosome inactivation in female mammals. However, the physiological function of macroH2A proteins on autosomes is poorly understood. Microarray-based analysis in human male pluripotent cells uncovered occupancy of both macroH2A ...

  13. PLA2G10 Gene Variants, sPLA2 Activity, and Coronary Heart Disease Risk

    NARCIS (Netherlands)

    Guardiola, Montse; Exeter, Holly J.; Perret, Claire; Folkersen, Lasse; van't Hooft, Ferdinand; Eriksson, Per; Franco-Cereceda, Anders; Paulsson-Berne, Gabrielle; Palmen, Jutta; Li, KaWah; Cooper, Jackie A.; Khaw, Kay-Tee; Mallat, Ziad; Ninio, Ewa; Karabina, Sonia-Athina; Humphries, Steve E.; Boekholdt, S. Matthijs; Holmes, Michael V.; Talmud, Philippa J.

    2015-01-01

    Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding

  14. Two variants in STK11 gene in Chinese patients with Peutz–Jeghers ...

    Indian Academy of Sciences (India)

    of the two families are shown in figure 1. Sample collecting and variant detection. After informed consent was obtained from the family mem- bers, venous blood samples were collected from the two probands and their family members. Meanwhile, 150 blood samples from unrelated healthy persons were selected as controls.

  15. Molecular Cloning and Expression of Sequence Variants of Manganese Superoxide Dismutase Genes from Wheat

    Science.gov (United States)

    Reactive oxygen species (ROS) are very harmful to living organisms due to the potential oxidation of membrane lipids, DNA, proteins, and carbohydrates. Transformed E.coli strain QC 871, superoxide dismutase (SOD) double-mutant, with three sequence variant MnSOD1, MnSOD2, and MnSOD3 manganese supero...

  16. Analysis of association of gene variants with obesity traits in New Zealand European children at 6 years of age.

    Science.gov (United States)

    Krishnan, Mohanraj; Thompson, John M D; Mitchell, Edwin A; Murphy, Rinki; McCowan, Lesley M E; Shelling, Andrew N; On Behalf Of The Children Of Scope Study Group, G

    2017-07-25

    Childhood obesity is a public health problem, which is associated with a long-term increased risk of cardiovascular disease and premature mortality. Several gene variants have previously been identified that have provided novel insights into biological factors that contribute to the development of obesity. As obesity tracks through childhood into adulthood, identification of the genetic factors for obesity in early life is important. The objective of this study was to identify putative associations between genetic variants and obesity traits in children at 6 years of age. We recruited 1208 children of mothers from the New Zealand centre of the international Screening for Pregnancy Endpoints (SCOPE) study. Eighty common genetic variants associated with obesity traits were evaluated by the Sequenom assay. Body mass index standardised scores (BMI z-scores) and percentage body fat (PBF; measured by bio-impedance assay (BIA)) were used as anthropometric measures of obesity. A positive correlation was found between BMI z-scores and PBF (p obesity and obesity traits in New Zealand European children.

  17. Frequency of a FAS ligand gene variant associated with inherited feline autoimmune lymphoproliferative syndrome in British shorthair cats in New Zealand.

    Science.gov (United States)

    Aberdein, D; Munday, J S; Dittmer, K E; Heathcott, R W; Lyons, L A

    2017-11-01

    AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as

  18. Mutagenic Analysis of an Adeno-Associated Virus Variant Capable of Simultaneously Promoting Immune Resistance and Robust Gene Delivery.

    Science.gov (United States)

    Kim, Yoojin; Kim, Eunmi; Oh, Seokmin; Yoon, Ye-Eun; Jang, Jae-Hyung

    2018-01-01

    In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated virus (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: (i) efficiently delivering therapeutic genes to many clinically valuable cells (e.g., stem or cancer cells) and (ii) effectively bypassing immunoglobulin (IgG) neutralization. Detailed interpretation of the structural features of AAVr3.45, which was previously engineered from AAV2, demonstrated that the LATQVGQKTA peptide at the heparan sulfate proteoglycan binding domain, especially the presence of cationic lysine on the peptide, served as a key motif for dramatically enhancing its gene delivery capabilities, ultimately broadening its tropisms for many cancer cell lines. Furthermore, the substitution of valine on the AAV2 capsid at the amino acid 719 site to methionine functioned as a coordinator for promoting viral resistance against IgG inactivation. The NAb-resistant characteristics of AAVr3.45 were possibly associated with the LATQVGQKTA sequence itself, indicating that its synergistic cooperation with the point mutation (V719M) is required for maximizing its ability to evade NAb inactivation. The potential of AAVr3.45 as a cancer gene therapy agent was confirmed by provoking apoptosis in breast adenocarcinoma by efficiently delivering a pro-apoptotic gene, BIM (Bcl-2-like protein 11), under high titers of human IgG. Thus, the superior aspects of the NAb-resistant AAVr3.45 as a potential therapeutic agent for systemic injection approaches, especially for cancer gene therapy, were highlighted in this study.

  19. Inter-individual gene variants associated with trabecular bone plasticity: A step forward in the personal genomics of degenerative bone disease.

    Science.gov (United States)

    Caso, Enrique; Sabiers, Cristina C; López-Guillén, Daniel; Caso, Jaime; Toledano, Manuel; Osorio, Raquel; Osorio, Estrella; Lozano, Carmen; Guerado, Enrique

    2017-11-01

    Continuing tissue destruction in osteoarthrosis is maintained by molecular pathways related to an unbalanced chondrocyte metabolism, the loss of reactive oxygen species (ROS) homeostasis, increase catabolism in a degraded matrix and the limited response to growth factors due to cell aging. Rare deleterious gene variants driving relevant molecular pathways may play a key role in the pathogenesis and genetic control of common diseases and may also influence the common gene variants observed in GWAS. We use molecular profiling technologies based on massive sequencing of genes to interrogate clinical samples for a variety of molecules involved in the pathogenesis pathways of OA and also to derive new insights for drug targeting discovery at an early stage of the disease. By whole-exome sequencing performed in OA patients with extreme phenotypes and in non-related individuals without clinical evidence of OA, the most predominant of the rare gene variants found were non-synonymous single-nucleotide variants (SNV) from exonic DNA regions and with missense functional effects predicting a moderate impact on protein function. A total of 629, 577, and 639 gene variants for the TPF, COA, and ANHNF patients, respectively, were found not to be shared with the 20 non-disease-related individuals. After subtraction of the 306 variants shared among the OA patients, we obtained the individual profiles of 323, 271, and 333 gene variants, for the TPF, COA, and ANHNF patients, respectively. After filtering by the bioinformatics, genetic, and biological criteria established to assess the clinical consequences, comparative analysis of trio sequences using integrative genome visualization tool clearly demonstrate the differences between patients. Analysis of the collagen gene variants identified 78, 20, and 43 genetic collagen variants for the three extreme phenotypes. Rare gene variants encoding for proteins that are less abundant in the trabecular bone matrix, together with those

  20. Common type 2 diabetes risk gene variants associate with gestational diabetes

    DEFF Research Database (Denmark)

    Lauenborg, Jeannet; Grarup, Niels; Damm, Peter

    2009-01-01

    Objective: We aimed to examine the association between gestational diabetes (GDM) and eleven recently identified type 2 diabetes susceptibility loci. Research Design and Methods: Type 2 diabetes risk variants in TCF7L2, CDKAL1, SLC30A8, HHEX/IDE, CDKN2A/2B, IGF2BP2, FTO, TCF2, PPARG, KCNJ11 and WFS......1 loci were genotyped in a cohort of women with a history of GDM (n=283) and in glucose tolerant women of the population-based Inter99 cohort (n=2,446). Results: All the risk alleles in the 11 examined type 2 diabetes risk variants showed an odds ratio greater than 1 for the GDM group compared...... previously proven type 2 diabetes risk alleles equals the findings from association studies on type 2 diabetes. This supports the hypothesis that GDM and type 2 diabetes are two of the same entity....

  1. Role of nicotine dependence on the relationship between variants in the nicotinic receptor genes and risk of lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Tung-Sung Tseng

    Full Text Available Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4 previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53, which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10(-10 and 1.1×10(-10, respectively. Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007. Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for

  2. Evaluation of amplification refractory mutation system (ARMS technique for quick and accurate prenatal gene diagnosis of CHM variant in choroideremia

    Directory of Open Access Journals (Sweden)

    Yang L

    2017-12-01

    Full Text Available Lisha Yang,1 Iqra Ijaz,1 Jingliang Cheng,1,2 Chunli Wei,1,3 Xiaojun Tan,4 Md Asaduzzaman Khan,1 Xiaodong Fu,5 Junjiang Fu1–3 1Key Laboratory of Epigenetics and Oncology, the Research Center for Precision Medicine, Southwest Medical University, Luzhou, 2Department of Pathology, Hunan Normal University College of Medicine, Changsha, 3State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR, 4Reproductive and Genetic Center, the Central Hospital of Xiangtan City, Xiangtan, 5Department of Obstetrics and Gynecology, First Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China Abstract: Choroideremia is a rare X-linked recessive inherited disorder that causes chorioretinal dystrophy leading to visual impairment in its early stages which finally causes total blindness in the affected person. It is caused due to mutations in the CHM gene. In this study, we have recruited a pedigree with choroideremia and detected a nonsense variant (c.C799T:p.R267X in CHM of the proband (I:1. Different primer sets for amplification refractory mutation system (ARMS were designed and PCR conditions were optimized. Then, we evaluated the sequence variant in the patient, carrier, and a fetus by using ARMS technique to identify if they inherited the pathogenic gene from parental generation; we used amniotic fluid DNA for the diagnosis of the gene in the fetus. The primer pairs, WT2+C and MT+C, amplified high specific products in different DNAs which were verified by Sanger sequencing. Based on our results, ARMS technique is fast, accurate, and reliable prenatal gene diagnostic tool to assess CHM variants. Taken together, our study indicates that ARMS technique can be used as a potential molecular tool in the diagnosis of prenatal mutation for choroideremia as well as other genetic diseases in undeveloped and developing countries, where there might be shortage of medical resources

  3. The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease.

    Science.gov (United States)

    Ledmyr, Helena; McMahon, Alex D; Ehrenborg, Ewa; Nielsen, Lars B; Neville, Matt; Lithell, Hans; MacFarlane, Peter W; Packard, Christopher J; Karpe, Fredrik

    2004-05-18

    The microsomal triglyceride transfer protein (MTP) transfers lipids into apolipoprotein B-containing lipoproteins for secretion from liver, intestine, and heart. The T-variant of a functional polymorphism in the MTP promoter, MTP-493G/T, has been associated with reduced low-density lipoprotein cholesterol concentrations. We hypothesize that this polymorphism impacts on coronary heart disease (CHD) risk. The effect of the polymorphism was therefore tested in the West of Scotland Coronary Prevention Study biobank (580 cases and 1160 controls). MTP-493T carrier status was associated with significantly increased risk of CHD despite a small reduction in total cholesterol. Compared with the genotypic group with the lowest event rate (MTP-493GG, pravastatin treatment), the respective odds ratios (95% confidence interval) in the placebo group for CHD events were: GG, 1.23 (0.92 to 1.63); GT, 1.53 (1.12 to 2.08); and TT, 2.78 (1.53 to 5.05), suggestive of a gene-dose effect. The excess risk for CHD of the MTP-493T-variant was eliminated by pravastatin treatment. The Uppsala Longitudinal Study of Adult Men (ULSAM), which is a 20-year follow-up study of CHD, was used as an independent confirmatory database. These unexpected findings prompted the investigation of non-plasma lipid factors that could associate the MTP gene with CHD risk. In a limited number of subjects (n=18), heart muscle biopsies showed a MTP-493T genotype-specific depression of MTP mRNA expression. The MTP-493T variant confers an increased risk of CHD that is unrelated to plasma lipids and lipoproteins, but eliminated by pravastatin treatment. A direct effect of the MTP polymorphism on myocardial lipid metabolism and vulnerability upon ischemic damage cannot be excluded.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. IDO1 and IDO2 non-synonymous gene variants: correlation with crohn's disease risk and clinical phenotype.

    Directory of Open Access Journals (Sweden)

    Alexander Lee

    Full Text Available Crohn's disease (CD is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1 is one of the most over-expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog are important either as CD risk alleles or as modifiers of CD phenotype.Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734 and non-IBD controls (n = 354 were genotyped for established IDO1 and IDO2 non-synonymous single nucleotide polymorphisms (SNPs and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T.IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS and not linked to Crohn's disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohn's disease (p = 0.025. No IDO2 SNPs associated with a particular Crohn's disease clinical phenotype.This work highlights the functional importance of IDO enzymes in human Crohn's disease and establishes relative rates of IDO genetic variants in a US population.

  6. Coexistencia de variantes HIV-1 com insercao dipeptidica no gene da transcriptase reversa

    Directory of Open Access Journals (Sweden)

    Aline Aki Tanikawa

    2013-08-01

    Full Text Available O objetivo desta comunicação foi descrever a detecção de coexistência de variantes HIV-1 com inserções de dois aminoácidos entre os códons 69 e 70 da transcriptase reversa. Tais variantes foram isoladas de paciente do sexo masculino, 16 anos de idade, em tratamento no interior do estado de São Paulo. Após confirmação de falha terapêutica, foi realizado teste de resistência a antirretrovirais, a partir do qual foram detectadas duas variantes contendo inserções dos aminoácidos Ser-Gly/Ser-Ala no códon 69 da transcriptase reversa, além da mutação T69S. Tais inserções possuem baixa prevalência, não foram relatadas em caráter de coexistência no Brasil e estão relacionadas com a resistência a múltiplas drogas, tornando o achado relevante do ponto de vista epidemiológico.

  7. Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the POLH gene.

    Science.gov (United States)

    De Palma, Armando; Morren, Marie-Anne; Ged, Cécile; Pouvelle, Caroline; Taïeb, Alain; Aoufouchi, Said; Sarasin, Alain

    2017-09-01

    We describe the characterization of Xeroderma Pigmentosum variant (XPV) in a young Caucasian patient with phototype I, who exhibited a high sensitivity to sunburn and multiple cutaneous tumors at the age of 15 years. Two novel mutations in the POLH gene, which encodes the translesion DNA polymerase η, with loss of function due to two independent exon skippings, are reported to be associated as a compound heterozygous state in the patient. Western blot analysis performed on proteins from dermal fibroblasts derived from the patient and analysis of the mutation spectrum on immunoglobulin genes produced during the somatic hypermutation process in his memory B cells, show the total absence of translesion polymerase η activity in the patient. The total lack of Polη activity, necessary to bypass in an error-free manner UVR-induced pyrimidine dimers following sun exposure, explains the early unusual clinical appearance of this patient. © 2017 Wiley Periodicals, Inc.

  8. Positive association of ace i/d gene variants with genetic ...

    African Journals Online (AJOL)

    Background: Pre-disposition to diabetes is possibly associated with gene polymorphisms of the renin–angiotensin system (RAS). Angiotensin-converting enzyme (ACE) gene is one of the genes of the RAS system whose polymorphisms have been suggested to be risk factors for type 2 diabetes melitus (T2DM).

  9. A functional variant in the OAS1 gene is associated with Sjögren's syndrome complicated with HBV infection.

    Science.gov (United States)

    Liu, Xianjun; Xing, Hongcun; Gao, Wenjing; Yu, Di; Zhao, Yuming; Shi, Xiaoju; Zhang, Kun; Li, Pingya; Yu, Jiaao; Xu, Wei; Shan, Hongli; Zhang, Kaiyu; Bao, Wanguo; Fu, Xueqi; Yang, Sirui; Wang, Shafeng

    2017-12-14

    Hepatitis B virus (HBV) has been suspected to contribute to several autoimmune diseases, including Sjögren's syndrome (SS), although the exact mechanism is unknown. The 2'-5' oligoadenylate synthetase (OAS1) is one of the most important components of the immune system and has significant antiviral functions. We studied a polymorphism rs10774671 of OAS1 gene in Han Chinese descent. The minor allele G was significantly associated with a decreased risk for SS, anti-SSA-positive SS, and anti-SSA-positive SS complicated with HBV infection, which have not been seen in anti-SSA-negative SS and HBcAb-negative SS patients. Gene expression analysis showed that the risk-conferring A allele was correlated with lower expression of p46 and increased expression of p42, p48, and p44. A functional study of enzymatic activities revealed that the p42, p44, and p48 isoforms display a reduced capacity to inhibit HBV replication in HepG2 cells compared to the normal p46 isoform. Our data demonstrated that the functional variant, rs10774671, is associated with HBV infection and anti-SSA antibody-positive SS. The SAS variant switches the primary p46 isoform to three alternatives with decreased capacities to inhibit HBV replication. These data indicated that individuals harboring the risk allele might be susceptible to hepatitis B infection and SS development.

  10. Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder.

    Science.gov (United States)

    Freitag, Christine M; Agelopoulos, Konstantin; Huy, Ellen; Rothermundt, Matthias; Krakowitzky, Petra; Meyer, Jobst; Deckert, Jürgen; von Gontard, Alexander; Hohoff, Christa

    2010-01-01

    Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.

  11. A variant on promoter of the cannabinoid receptor 1 gene (CNR1) moderates the effect of valence on working memory.

    Science.gov (United States)

    Fairfield, Beth; Mammarella, Nicola; Franzago, Marica; Di Domenico, Alberto; Stuppia, Liborio; Gatta, Valentina

    2018-02-01

    Cannabinoid receptor 1 gene (CNR1) variants have been related to affective information processing and, in particular, to stress release. Here, we aimed to examine whether the endocannabinoid system via CNR1 signaling modulates affective working memory, the memory system that transiently maintains and manipulates emotionally charged material. We focused on rs2180619 (A > G) polymorphism and examined genotype data collected from 231 healthy females. Analyses showed how a general positivity bias in working memory (i.e., better memory for positive words) emerged as task strings lengthened only in carriers of the major allele (AA/AG). Differently, GG carriers showed better memory for affective items in general (i.e., positive and negative words). These findings are some of the first to directly highlight the role of variant on promoter of the CNR1 gene in affective working memory and to evidence a differentiation among CNR1 genotypes in terms of larger difficulties in disengaging from negative stimuli in GG carriers.

  12. The role of genetic variants in genes regulating the oxytocin-vasopressin neurohumoral system in childhood-onset aggression.

    Science.gov (United States)

    Malik, Ayesha I; Zai, Clement C; Berall, Laura; Abu, Zihad; Din, Farah; Nowrouzi, Behdin; Chen, Sheng; Beitchman, Joseph H

    2014-10-01

    The genetic etiology of aggressive behaviors remains elusive, but growing evidence suggests that they are heritable, and certain genetic variants have been implicated as contributing factors. The oxytocin-vasopressin (OXT-AVP) neurohumoral system has recently been implicated in social behaviors. Oxytocin, especially, has been linked to prosocial behaviors such as trust and social bonds. Hence, the aim of this study was to determine whether genes regulating this system were also associated with childhood-onset aggressive behaviors. Our sample included 182 White children showing extreme, persistent, and pervasive aggressive behavior. These cases were matched with 182 White controls on the basis of sex and age. We used PCR to determine the genotype for 28 single nucleotide polymorphisms within eight genes regulating the OXT-AVP system, including CD38 polymorphisms. Genotypic analyses were carried out using STATA, whereas differences in haplotypic and allelic frequencies were analyzed using Unphased. None of the results reached significance after correction for multiple testing. However, nominally significant allelic effects were observed for OXTR rs6770632T (P=0.028) and AVPR1A rs11174811G (P=0.040) in females, and OXTR rs237898A (P=0.006), rs237902C (P=0.007), and AVP rs3761249A (P=0.008) in males. Genetic variants regulating the OXT-AVP system may be associated with childhood-onset aggression.

  13. SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a)

    DEFF Research Database (Denmark)

    Yang, Xiaoping; Sethi, Amar A; Yanek, Lisa R

    2016-01-01

    BACKGROUND: SR-B1 (scavenger receptor class B type 1), encoded by the gene SCARB1, is a lipoprotein receptor that binds both high-density lipoprotein (HDL) and low-density lipoprotein. We reported that SR-B1 is also a receptor for lipoprotein (a) (Lp(a)), mediating cellular uptake of Lp(a) in vitro...... variants in 6. Functional studies with 4 of the SCARB1 variants (c.386C>T, c.631-14T>G, c.4G>A, and c.631-53(m)C>T & c.726+55(m)CG>CA) showed decreased receptor function in vitro. CONCLUSIONS: Human SCARB1 gene variants are associated with a new lipid phenotype, characterized by high levels of both HDL...... cholesterol and Lp(a). SCARB1 exonic variants often result in diminished function of translated SR-B1 via reduced binding/intracellular transport of Lp(a)....

  14. Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease.

    Science.gov (United States)

    Erlich, Porat M; Lunetta, Kathryn L; Cupples, L Adrienne; Abraham, Carmela R; Green, Robert C; Baldwin, Clinton T; Farrer, Lindsay A

    2012-05-01

    Previous studies have shown association of single nucleotide polymorphisms (SNPs) in 3 contiguous genes (PON1, PON2, and PON3) encoding paraoxonase with risk of Alzheimer disease (AD). We evaluated the association of serum paraoxonase activity measured by phenyl acetate (PA) and thiobutyl butyrolactone (TBBL) with risk of AD and with 26 SNPs spanning the PON gene cluster in 266 AD cases and 306 sibling controls from the MIRAGE study. The odds of AD (adjusted for age, gender, and ethnicity) increased 20% for each standard deviation decrease in PA or TBBL activity. There were association signals with activity in all 3 genes. Haplotypes including SNPs spanning the PON genes were generally more significant than haplotypes comprising SNPs from 1 gene. Significant interactions were observed between SNP pairs located across the PON cluster with either serum activity measure as the outcome, and between several PON SNPs and PA activity with AD status as the outcome. Our results suggest that low serum paraoxonase activity is a risk factor for AD. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking.

    Directory of Open Access Journals (Sweden)

    Nicola Pirastu

    Full Text Available Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

  16. Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking.

    Science.gov (United States)

    Pirastu, Nicola; Kooyman, Maarten; Traglia, Michela; Robino, Antonietta; Willems, Sara M; Pistis, Giorgio; d'Adamo, Pio; Amin, Najaf; d'Eustacchio, Angela; Navarini, Luciano; Sala, Cinzia; Karssen, Lennart C; van Duijn, Cornelia; Toniolo, Daniela; Gasparini, Paolo

    2014-01-01

    Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs) variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R) on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

  17. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Jennifer S. Yokoyama

    2015-01-01

    Full Text Available The serotonin transporter length polymorphism (5-HTTLPR short allele (5-HTTLPR-s has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by reducing gene expression, which slows the reuptake of serotonin, and is associated with distinct morphological and functional effects. Serotonergic systems are also shown to be dysfunctional in behavioral variant frontotemporal dementia (bvFTD, a disease characterized by marked socioemotional dysfunction. However, studies of 5-HTTLPR-s effects in bvFTD have been inconsistent. Our objective was to investigate the patterns of gray matter volume by 5-HTTLPR-s genotype in both healthy older controls and bvFTD patients. We performed voxel-based morphometry of 179 cognitively normal older adults and 24 bvFTD cases to determine brain changes associated with dose (0/1/2 of 5-HTTLPR-s allele. 5-HTTLPR-s frequency did not differ between controls and bvFTD. We found a significant interaction effect whereby carrying more 5-HTTLPR-s alleles in bvFTD was associated with smaller volume in left inferior frontal gyrus (T = 4.86, PFWE = 0.03 and larger volume in right temporal lobe (T = 5.01, PFWE = 0.01. These results suggest that the 5-HTTLPR-s allele differentially influences brain morphology in bvFTD. We propose that patients with bvFTD and 5-HTTLPR-s have altered volumes in regions that support socioemotional behavior, which may be a developmental or disease-related compensation for altered serotonergic activity.

  18. A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

    Science.gov (United States)

    Thompson, Bryony A; Goldgar, David E; Paterson, Carol; Clendenning, Mark; Walters, Rhiannon; Arnold, Sven; Parsons, Michael T; Michael D, Walsh; Gallinger, Steven; Haile, Robert W; Hopper, John L; Jenkins, Mark A; Lemarchand, Loic; Lindor, Noralane M; Newcomb, Polly A; Thibodeau, Stephen N; Young, Joanne P; Buchanan, Daniel D; Tavtigian, Sean V; Spurdle, Amanda B

    2013-01-01

    Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ~12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing. © 2012 Wiley Periodicals, Inc.

  19. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5

    DEFF Research Database (Denmark)

    Baker, Peter R; Friederich, Marisa W; Swanson, Michael A

    2014-01-01

    -onset spastic paraplegia, spinal lesion, and optic atrophy. Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy. Patients with lipoate synthase...... phylogenetically conserved, and transfection with native genes corrected the biochemical deficiency proving pathogenicity. Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. The recognition of variant nonketotic hyperglycinemia is important...

  20. Large-scale studies of the functional K variant of the butyrylcholinesterase gene in relation to Type 2 diabetes and insulin secretion

    DEFF Research Database (Denmark)

    Johansen, A; Nielsen, E-M D; Andersen, G

    2004-01-01

    Polymorphisms of the butyrylcholinesterase gene (BCHE) are reported to associate with Alzheimer's disease and a recent study found a significant association of the BCHE K variant (G1615A/Ala539Thr) with Type 2 diabetes. The objectives of our study were to examine whether the BCHE K variant...... is associated with Type 2 diabetes or estimates of pancreatic beta cell function in large-scale populations of glucose-tolerant Caucasians....

  1. Novel variant (bla(VIM-4)) of the metallo-beta-lactamase gene bla(VIM-1) in a clinical strain of Pseudomonas aeruginosa.

    Science.gov (United States)

    Pournaras, Spyros; Tsakris, Athanassios; Maniati, Maria; Tzouvelekis, Leonidas S; Maniatis, Antonios N

    2002-12-01

    A Pseudomonas aeruginosa isolate highly resistant to carbapenems was collected from a patient with postsurgical cerebrospinal infection in Greece. The isolate carried a class 1 integron that contained as a sole cassette the gene bla(VIM-4), a novel variant of bla(VIM-1), with one nucleotide difference resulting in a Ser-to-Arg change at amino acid position 175 of the VIM-1 enzyme. This is the first detection of a VIM-1 variant after its appearance in Italy.

  2. Xenobiotic Sensor- and Metabolism-Related Gene Variants in Environmental Sensitivity-Related Illnesses: A Survey on the Italian Population

    Directory of Open Access Journals (Sweden)

    Daniela Caccamo

    2013-01-01

    Full Text Available In the environmental sensitivity-related illnesses (SRIs, multiple chemical sensitivity (MCS, chronic fatigue syndrome (FCS, and fibromyalgia (FM, the search for genetic polymorphisms of phase I/II xenobiotic-metabolizing enzymes as suitable diagnostic biomarkers produced so far inconclusive results, due to patient heterogeneity, geographic/ethnic differences in genetic backgrounds, and different methodological approaches. Here, we compared the frequency of gene polymorphisms of selected cytochrome P450 (CYP metabolizing enzymes and, for the first time, the frequency of the xenobiotic sensor Aryl hydrocarbon receptor (AHR in the three cohorts of 156 diagnosed MCS, 94 suspected MCS, and 80 FM/FCS patients versus 113 healthy controls. We found significantly higher frequency of polymorphisms CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2D6*4 and CYP2D6*41 in patients compared with controls. This confirms that these genetic variants represent a genetic risk factor for SRI. Moreover, the compound heterozygosity for CYP2C9*2 and *3 variants was useful to discriminate between either MCS or FM/CFS versus SMCS, while the PM *41/*41 genotype discriminated between MCS and either SMCS or FM/CFS. The compound heterozygosity for CYP2C9 *1/*3 and CYP2D6 *1/*4 differentiated MCS and SMCS cases from FM/CFS ones. Interestingly, despite the distribution of the AHR Arg554Lys variant did not result significantly different between SRI cases and controls, it resulted useful for the discrimination between MCS and SMCS cases when considered within haplotypes in combination with CYP2C19 *1/*2 and CYP2D6 *1/*4. Results allowed us to propose the genotyping for these specific CYP variants, together with the AHR Arg554Lys variant, as reliable, cost-effective genetic parameters to be included in the still undefined biomarkers' panel for laboratory diagnosis of the main types of environmental-borne SRI.

  3. Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians.

    Directory of Open Access Journals (Sweden)

    Tarunveer Singh Ahluwalia

    Full Text Available BACKGROUND: Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients. METHODOLOGY/PRINCIPAL FINDINGS: Eight single nucleotide polymorphisms (SNPs of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9 were genotyped in two independently ascertained type 2 diabetic cohorts with (DN and without nephropathy (DM; consisting of patients from North India (n = 495 and South India (n = 188. Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR, PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR software. Serum high sensitive CRP (hs-CRP levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05. The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05 and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2, DD (CCR5 and 279Gln/Gln (MMP9 conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002. CONCLUSION: The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

  4. Variant translocation of the bcl-2 gene to immunoglobulin λ light chain gene in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Adachi, M.; Cossman, J.; Longo, D.; Croce, C.M.; Tsujimoto, Y.

    1989-01-01

    The bcl-2 gene has been identified as a gene directly involved in the consistent chromosome translocation t(14;18), which is found in ∼ 90% of human follicular lymphoma cases, and is a prime candidate for the oncogene playing a crucial role in follicular lymphomagenesis. In this paper, the authors describe a case of chronic lymphocytic leukemia showing the juxtaposition of the bcl-2 gene on chromosome 18 to immunoglobulin λ light chain (Igλ) gene on chromosome 22 in a head-to-head configuration. Sequencing analysis of the joining site of the bcl-2 gene and Igλ gene has shown that the breakpoint is within the 5' flanking region of the bcl-2 gene and about 2.2 kilobases 5' to the joining segment of Igλ locus in a germ-line configuration. The extranucleotide, commonly appearing at the joining site of the t(14;18) translocation involving the IgH locus, is absent from the joining site of bcl-2 and Igλ. The lack of extranucleotide suggests that the juxtaposition of the bcl-2 and Igλ genes occurred during physiological rearrangement of the Igλ gene since it has been shown that the rearrangement of the Igλ locus is not accompanied by extranucleotides

  5. The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host-parasite interaction

    KAUST Repository

    Jackson, Andrew P.

    2014-05-05

    Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5? ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct. 2014 The Author(s) 2014.

  6. MODY3, renal cysts, and Dandy-Walker variants with a microdeletion spanning the HNF1A gene.

    Science.gov (United States)

    Matsukura, Hiro; Nagamori, Mariko; Miya, Kazushi; Yorifuji, Tohru

    2017-09-01

    Heterozygous hepatocyte nuclear factor-1-α gene (HNF1A) mutations are the most common cause of maturity-onset diabetes of the young (MODY), but they rarely involve extrahepatic manifestations. Renal cysts and diabetes syndrome can be caused by HNF1B mutations. No association between MODY3 and Dandy-Walker variants (DWV) has been reported. HNF1A mutations might be responsible for renal malformations. In a Japanese girl with glycosuria, developmental delay, mental retardation, renal cysts, and DWV, the HNF1B gene had no mutations. Array comparative genomic hybridization analysis identified a de-novo interstitial 12q24.22-q24.31 deletion of 5.6 Mb encompassing the HNF1A gene, which is compatible with a diagnosis of MODY3. The variety of phenotypes suggests a novel microdeletion syndrome spanning the HNF1A gene. Because HNF1B functions as an HNF1A/HNF1B heterodimer, haploinsufficient HNF1A interacts with a certain HNF1B haplotype. The resulting truncated heterodimer might engender renal cysts. More patients with well-defined deletion within 12q.24.31 must be evaluated to produce a detailed genotype-phenotype correlation and to elucidate this emerging microdeletion syndrome.
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  7. Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

    OpenAIRE

    Muiños Gimeno, Margarita; Guidi, Mònica; Kagerbauer, Birgit; Martín Santos, Rocío; Navinés, Ricard; Alonso, Pino; Menchón, José M.; Gratacós Mayora, Mònica; Estivill, Xavier, 1955-; Espinosa Parrilla, Yolanda

    2009-01-01

    Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genet...

  8. Beta-adducin and sodium-calcium exchanger 1 gene variants are associated with systemic lupus erythematosus and lupus nephritis.

    Science.gov (United States)

    Ramirez, Giuseppe A; Lanzani, Chiara; Bozzolo, Enrica P; Zagato, Laura; Citterio, Lorena; Casamassima, Nunzia; Canti, Valentina; Sabbadini, Maria Grazia; Rovere-Querini, Patrizia; Manunta, Paolo; Manfredi, Angelo A

    2015-12-01

    Genetic research in systemic lupus erythematosus (SLE) is rapidly developing, and numerous sets of genes are being associated with specific clinical subphenotypes in the setting of SLE. On the other hand, basic science studies are revealing strong connections between salt-water balance and inflammation. The aim of this study was to evaluate whether variants of genes known to influence the individual susceptibility to hypertension also influence the renal function in a cohort of SLE patients with and without lupus nephritis (LN). This study is a case-control study with candidate gene approach. A total of 111 patients with SLE (50 with SLE without nephritis, 55 with LN and 6 with simple urinary sediment abnormalities) and 62 healthy controls (HC) were genotyped for NCX1 rs11893826 (NCX1a) and rs434082 (NCX1b) and ADD2 rs4984 SNPs. Patients with ADD2 CT genotype were protected from LN and skin involvement; ADD2 CC | NCX1a AA/AG genotypes were associated with the presence of anti-cardiolipin antibodies; NCX1a AA genotype was slightly more frequent in lupus patients than in HC and associated with relapse risk and higher creatinine in patients with LN. NCX1b GG patients with LN had increased chances to reach complete remission. NCX1b GG | NCX1a GG genotype is associated with joint involvement. ADD2 and NCX1 variants influence the risk and the clinical features of SLE and LN, highlighting their potential role in regulating systemic inflammation and/or the local response to immune-mediated injury.

  9. Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

    Science.gov (United States)

    Win, Aung Ko; Hopper, John L.; Buchanan, Daniel D.; Young, Joanne P.; Tenesa, Albert; Dowty, James G.; Giles, Graham G.; Goldblatt, Jack; Winship, Ingrid; Boussioutas, Alex; Young, Graeme P.; Parry, Susan; Baron, John A.; Duggan, David; Gallinger, Steven; Newcomb, Polly A.; Haile, Robert W.; Le Marchand, Loïc; Lindor, Noralane M.; Jenkins, Mark A.

    2013-01-01

    Background Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. Methods A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the SNPs: rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). Results Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88–1.07, p=0.52). Conclusions We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome. PMID:23434150

  10. Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico

    Science.gov (United States)

    Contreras-Cubas, Cecilia; Sánchez-Hernández, Beatríz E.; García-Ortiz, Humberto; Martínez-Hernández, Angélica; Barajas-Olmos, Francisco; Cid, Miguel; Mendoza-Caamal, Elvia C.; Centeno-Cruz, Federico; Ortiz-Cruz, Gabriela; Jiménez-López, José Concepción; Córdova, Emilio J.; Salas-Bautista, Eva Gabriela; Saldaña-Alvarez, Yolanda; Fernández-López, Juan Carlos; Mutchinick, Osvaldo M.

    2016-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs) and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs), from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups), and in a geographically-matched Mexican Mestizo population (MEZ, n = 638). The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ. PMID:27649570

  11. Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico.

    Directory of Open Access Journals (Sweden)

    Cecilia Contreras-Cubas

    Full Text Available Methylenetetrahydrofolate reductase (MTHFR is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs, from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups, and in a geographically-matched Mexican Mestizo population (MEZ, n = 638. The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ.

  12. ABCA1 gene variants regulate postprandial lipid metabolism in healthy men.

    Science.gov (United States)

    Delgado-Lista, Javier; Perez-Martinez, Pablo; Perez-Jimenez, Francisco; Garcia-Rios, Antonio; Fuentes, Francisco; Marin, Carmen; Gómez-Luna, Purificación; Camargo, Antonio; Parnell, Laurence D; Ordovas, Jose Maria; Lopez-Miranda, Jose

    2010-05-01

    Genetic variants of ABCA1, an ATP-binding cassette (ABC) transporter, have been linked to altered atherosclerosis progression and fasting lipid concentration, mainly high-density lipoproteins and apolipoprotein A1; however, results from different studies have been inconsistent. To further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of 3 single nucleotide polymorphisms (i27943 [rs2575875]; i48168 [rs4149272]; R219K [rs2230806]) in the postprandial lipemia of 88 normolipidemic young men who were given a fatty meal. For i27943 and i48168 single nucleotide polymorphisms, fasting and postprandial values of apolipoprotein A1 were higher and postprandial lipemia was much lower in homozygotes for the major alleles, total triglycerides in plasma, and large triglyceride-rich lipoprotein triglycerides. These persons also showed a higher apolipoprotein A1/apolipoprotein B ratio. Major allele homozygotes for i48168 and i27943 showed additionally higher high-density lipoproteins and lower postprandial apolipoprotein B. Our work shows that major allele homozygotes for ABCA1 single nucleotide polymorphisms i27943 and i48168 have a lower postprandial response as compared to minor allele carriers. This finding may further characterize the role of ABCA1 in lipid metabolism.

  13. Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes

    Directory of Open Access Journals (Sweden)

    Cannon Christopher P

    2004-06-01

    Full Text Available Abstract Background Elevated white blood cell counts (WBC in acute coronary syndromes (ACS increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP in an ACS population. Methods WBC and genotype of interleukin 6 (IL-6 G-174C and of interleukin-1 receptor antagonist (IL1RN intronic repeat polymorphism were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event. Results An increased white blood cell count (WBC was associated with an increased C-reactive protein (r = 0.23, p 3 (95% CI = -0.41, 0.77, and -0.03/mm3 (95% CI = -0.55, 0.86 for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p = 0.61 or IL6 (p = 0.48 genotype. Conclusions Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients.

  14. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

    NARCIS (Netherlands)

    Simpson, Claire L.; Lemmens, Robin; Miskiewicz, Katarzyna; Broom, Wendy J.; Hansen, Valerie K.; van Vught, Paul W. J.; Landers, John E.; Sapp, Peter; Van Den Bosch, Ludo; Knight, Joanne; Neale, Benjamin M.; Turner, Martin R.; Veldink, Jan H.; Ophoff, Roel A.; Tripathi, Vineeta B.; Beleza, Ana; Shah, Meera N.; Proitsi, Petroula; Van Hoecke, Annelies; Carmeliet, Peter; Horvitz, H. Robert; Leigh, P. Nigel; Shaw, Christopher E.; van den Berg, Leonard H.; Sham, Pak C.; Powell, John F.; Verstreken, Patrik; Brown, Robert H.; Robberecht, Wim; Al-Chalabi, Ammar

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both

  15. Association of MC4R gene variants with carcass and meat quality ...

    African Journals Online (AJOL)

    MC4R belongs to a seven-transmembrane G-protein-coupled receptor which may regulate body composition and insulin action. Many mutations in the MC4R gene are associated with obesity, energy expenditure and serum triglyceride levels in human and animals. Six mutations in the MC4R gene were identified in our ...

  16. Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

    DEFF Research Database (Denmark)

    Saunders, Edward J; Dadaev, Tokhir; Leongamornlert, Daniel A

    2016-01-01

    BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants...... identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated......Ca aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous...

  17. 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

    2018-03-08

    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. Published by Elsevier B.V.

  18. Genetic variants in NTCP exon gene are associated with HBV infection status in a Chinese Han population.

    Science.gov (United States)

    Wu, Wennan; Zeng, Yongbin; Lin, Jinpiao; Wu, Yingying; Chen, Tianbin; Xun, Zhen; Ou, Qishui

    2018-04-01

    Sodium taurocholate co-transporting polypeptide (NTCP) plays an important role in the enterohepatic circulation of bile acids. Recently, NTCP was identified as a hepatitis B virus (HBV) receptor. The aim of this study is to investigate the association of NTCP polymorphisms with HBV clinical outcomes and investigate the relationship between NTCP polymorphisms and the serum bile acid level in a Chinese Han population. The single nucleotide polymorphisms rs2296651 and rs4646285 were genotyped in 1619 Chinese Han individuals. Improved multiple ligase detection reaction was utilized to genotype. The level of bile acids was measured by the enzymatic cycling method. Quantitative polymerase chain reaction analysis was carried out to analyze the potential function. In logistic regression analysis, the frequency of rs2296651 (S267F) CT genotype was higher in HBV immune recovery and healthy control groups than in the chronic HBV infection group (P = 0.001 and P HBV infection group (P = 0.011). No difference in serum bile acid was detected between the rs4646285 wild-type patients and mutant-type patients. Quantitative reverse transcription-polymerase chain reaction showed the NTCP mRNA levels were lower in rs4646285 variants than wild types. NTCP gene polymorphisms may be associated with the natural course of HBV infection in a Chinese Han population. The S267F variant may be a protective factor to resist chronic hepatitis B progression which showed a higher bile acid level in Chinese Han chronic HBV infection patients. The rs4646285 variants could influence the expression of NTCP at the level of transcription, and ultimately may be associated with HBV infection immune recovery. © 2017 The Japan Society of Hepatology.

  19. Screening the visual system homeobox 1 gene in keratoconus and posterior polymorphous dystrophy cohorts identifies a novel variant.

    Science.gov (United States)

    Vincent, Andrea L; Jordan, Charlotte; Sheck, Leo; Niederer, Rachel; Patel, Dipika V; McGhee, Charles N J

    2013-01-01

    Mutations in the visual system homeobox 1 (VSX1) gene have been described at a low frequency in keratoconus and posterior polymorphous corneal dystrophy (PPCD). The putative role is controversial for several reasons, including a lack of mutations detected in other population cohorts. This study aims to determine whether VSX1 contributes to the genetic pathogenesis of keratoconus and PPCD in a New Zealand population, and includes analysis of a Polynesian population. Recruitment of patients with keratoconus and PPCD, comprehensive clinical examination including corneal topography and pachymetry, and collection of biologic samples for DNA extraction were undertaken. Mutational analysis of VSX1 (exons 1-7) with PCR and sequencing with bioinformatic assessment of variants was performed. Probable pathogenic variants were screened for in a control population using high-resolution melting analysis. Forty-seven patients with keratoconus, including 15 familial cases, and ten unrelated patients with PPCD were recruited. Two pathogenic changes were detected; a novel change c.173C>T (p.Pro58Leu) was found in a patient with PPCD, predicted to be pathogenic, and not seen in 200 ethnically matched control alleles. The previously reported c.731A>G (p.His244Arg) was detected in a patient with sporadic keratoconus, and not present in the controls. No family members were available for segregation analysis. This study reports the presence of pathogenic mutations in VSX1 in PPCD and keratoconus, including a novel disease-causing variant. The affected numbers are small, but given the growing body of evidence of pathogenic segregating changes in VSX1 in disease cohorts, the expression in keratocytes as part of wound healing, and the documented association of PPCD and keratoconus, it seems likely that the role of VSX1 as a genetic factor contributing to disease is real.

  20. Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure: The GenSalt study.

    Science.gov (United States)

    Zhao, Qi; Gu, Dongfeng; Hixson, James E; Liu, De-Pei; Rao, Dabeeru C; Jaquish, Cashell E; Kelly, Tanika N; Lu, Fanghong; Ma, Jixiang; Mu, Jianjun; Shimmin, Lawrence C; Chen, Jichun; Mei, Hao; Hamm, L Lee; He, Jiang

    2011-08-01

    Rare mutations of the epithelial sodium channel (ENaC) lead to mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt sensitivity of blood pressure (BP). A total of 1906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/d) followed by a 7-day high-sodium intake (307.8 mmol sodium/d). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, α, β, and γ (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, P=1.7×10(-5); rs4073291, P=1.1×10(-5); rs7404408, P=1.9×10(-5); rs5735, P=3.0×10(-4); rs4299163, P=0.004; and rs4499238, P=0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention. This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00721721.

  1. Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia.

    Science.gov (United States)

    Bastida, J M; Benito, R; Janusz, K; Díez-Campelo, M; Hernández-Sánchez, J M; Marcellini, S; Girós, M; Rivera, J; Lozano, M L; Hortal, A; Hernández-Rivas, J M; González-Porras, J R

    2017-09-01

    Essentials Diagnosis of sitosterolemia, a rare recessive or syndromic disorder, is usually delayed. Peripheral blood smear is extremely useful for establishing the suspicion of sitosterolemia. High-throughput sequencing technology enables the molecular diagnosis of inherited thrombocytopenias. Accurate characterization of sitosterolemia helps us determine appropriate management. Background Sitosterolemia (STSL) is a recessive inherited disorder caused by pathogenic variants in the ABCG5 and ABCG8 genes. Increased levels of plasma plant sterols (PSs) usually result in xanthomas and premature coronary atherosclerosis, although hematologic abnormalities may occasionally be present. This clinical picture is unfamiliar to many physicians, and patients may be at high risk of misdiagnosis. Objectives To report two novel ABCG5 variants causing STSL in a Spanish patient, and review the clinical and mutational landscape of STSL. Patient/Methods A 46-year-old female was referred to us with lifelong macrothrombocytopenia. She showed familial hypercholesterolemia-related xanthomas. Molecular analysis was performed with high-throughput sequencing. Plasma PS levels were evaluated with gas-liquid chromatography. The STSL landscape was reviewed with respect to specific online databases and all reports published since 1974. Results A blood smear revealed giant platelets and stomatocytes. Novel compound heterozygous variants were detected in exons 7 (c.914C>G) and 13 (c.1890delT) of ABCG5. The patient showed an increased plasma level of sitosterol. These findings support the diagnosis of STSL. In our review, we identified only 25 unrelated STLS patients who presented with hematologic abnormalities including macrothrombocytopenia. It remains unknown why only some patients develop hematologic abnormalities. Conclusions This is the first Spanish STSL patient to be reported and molecularly characterized. The early diagnosis of STLS is strongly supported by the presence of stomatocytes

  2. Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.

    Science.gov (United States)

    Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E; Wilmot, Beth; Smith, Joshua D; Patterson, Karynne E; Coe, Bradley P; Li, Yatong K; Bamshad, Michael J; Nikolas, Molly; Eichler, Evan E; Swanson, James M; Nigg, Joel T; Nickerson, Deborah A; Jarvik, Gail P

    2017-06-01

    Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Tumor necrosis factor alpha and alpha-1 antitrypsin gene variants in Serbian pediatric arterial ischemic stroke patients

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available The etiology of arterial ischemic stroke (AIS in children is complex, and different from that in adults. Although rare, stroke in children is an important cause of mortality and morbidity. There is increasing evidence that genetic factors, including inflammation mediators, have a role in occurrence and outcome of stroke. We have chosen to assess the role of polymorphism -308G/A in the promoter of tumor necrosis factor α (TNFα gene and S and Z mutations in alpha 1-antitrypsin (AAT gene in the etiology of stroke in children. TNFα polymorphism affects plasma levels of this proinflamatory cytokine, and this could contribute to stroke pathology. It has been shown that increased AAT concentration may present a risk for AIS in children. Since S and Z mutations in AAT gene reduce its levels in plasma they could have a protective role in pediatric stroke. In this study twenty six children with AIS and 100 unrelated individuals from Serbian general population were investigated by PCR/RFLP for these gene variations. No statistically significant difference was observed between patients and general population in distribution of genotypes for -308G/A TNFα polymorphism, so its contributory role in the etiology of stroke was not evident in our group of patients. None of the tested AAT gene mutations were found in patients, which is in concordance with the proposed protective role of deficient AAT variants. AIS is a multifactorial disease, with many genes having a modest role in its pathophysiology, so further analyses of their combined effect are needed to elucidate genetic risk factors in the etiology and outcome of stroke in pediatric patients.

  4. New sequence variants in BRCA1 and BRCA2 genes detected by high-resolution melting analysis in an elderly healthy female population in Croatia.

    Science.gov (United States)

    Cvok, Mirela Levacic; Cretnik, Maja; Musani, Vesna; Ozretic, Petar; Levanat, Sonja

    2008-01-01

    Mutations in BRCA1 and BRCA2 genes are associated with family predisposition to breast and ovarian cancer. Novel screening methods are required for efficient and rapid detection of sequence variants in cancer patients and their family members. The screening for variants in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 in Croatia was performed by a high-resolution melting approach, which is based on differences in melting curves caused by variations in nucleotide sequence. This is the first screening in Croatia on elderly healthy women with no family history of cancer. BRCA1 screening was performed on 220 and BRCA2 screening on 115 samples. In a population well beyond the average age of breast/ovarian cancer onset, 21 different sequence variants in the BRCA1 gene (one novel: c.5193+49_50delTA) and 36 variants in the BRCA2 gene (7 novel: c.459A>C, c.3318C>A, c.4412_ 4414delGAA, c.4790C>A, c.6264T>C, c.9087G>A, and c.9864A>G) were detected. Nine BRCA1 and seven BRCA2 known variants appeared with such high frequencies that they could be declared as harmless in this population. Eight BRCA1 high frequency variants, located further from the promoter region, appear to be strongly correlated. Three novel variants that changed the amino acid sequence of the BRCA2 protein (two missense base substitutions, c.3318C>A and c.4790C>A, and one codon deletion c.4412_4414delGAA), appearing only once, were predicted to have no potential effect on protein structure and function.

  5. BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression.

    Directory of Open Access Journals (Sweden)

    Nic Waddell

    2008-05-01

    Full Text Available The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases. 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS. BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%, poor for BRCAX with an LCS (40-50%, and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%. This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.

  6. Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.

    Directory of Open Access Journals (Sweden)

    Sher L Hendrickson

    2010-09-01

    Full Text Available The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.Here we explore whether single nucleotide polymorphisms (SNPs within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4 on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI on chromosome 6.Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.

  7. Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese

    OpenAIRE

    Mayumi Enya; Yukio Horikawa; Katsumi Iizuka; Jun Takeda

    2014-01-01

    Background: None of the high frequency variants of the incretin-related genes has been found by genome-wide association study (GWAS) for association with occurrence of type 2 diabetes in Japanese. However, low frequency and rare and/or high frequency variants affecting glucose metabolic traits remain to be investigated. Method: We screened all exons of the incretin-related genes (GCG, GLP1R, DPP4, PCSK1, GIP, and GIPR) in 96 patients with type 2 diabetes and investigated for association of...

  8. Role of allelic variants of FK506-binding protein 51 (FKBP5) gene in the development of anxiety disorders.

    Science.gov (United States)

    Minelli, Alessandra; Maffioletti, Elisabetta; Cloninger, Claude Robert; Magri, Chiara; Sartori, Riccardo; Bortolomasi, Marco; Congiu, Chiara; Bignotti, Stefano; Segala, Matilde; Giacopuzzi, Mario; Gennarelli, Massimo

    2013-12-01

    Anxiety disorders exhibit remarkably high rates of comorbidity with major depressive disorder (MDD). Mood and anxiety disorders are considered stress-related diseases. Genetic variations in the co-chaperone FK506-binding protein 51, FKBP5, which modulates the function of glucocorticoid receptors, have been associated with an increased risk for the development of posttraumatic stress disorder, but data regarding its role in MDD are controversial. The aims of this study were to clarify the role of the FKBP5 gene in depression and anxiety disorders through a case-control study and an association study with personality traits using the Temperament and Character Inventory (TCI) in healthy subjects. Six hundred fifty-seven MDD patients, with or without an anxiety disorder in comorbidity, and 462 healthy volunteers were enrolled in the study. Two hundred fifty-six controls agreed to fill out the TCI. The results showed that the T allele of rs1360780 was more frequent among the patients affected by MDD with a comorbidity of anxiety disorders, compared to those without (P anxiety. These results support the hypothesis that allelic variants of FKBP5 are a risk factor for anxiety disorders. The identification of genetic variants involved in anxiety may have implications for the optimization of therapeutic interventions. © 2013 Wiley Periodicals, Inc.

  9. Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference.

    Science.gov (United States)

    Newell, K A; Formica, R N; Gill, J S; Schold, J D; Allan, J S; Covington, S H; Wiseman, A C; Chandraker, A

    2017-04-01

    Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end-stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence-based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision-making process were considered. This report summarizes the group's deliberations. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  10. Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.

    Science.gov (United States)

    Masellis, Mario; Collinson, Shannon; Freeman, Natalie; Tampakeras, Maria; Levy, Joseph; Tchelet, Amir; Eyal, Eli; Berkovich, Elijahu; Eliaz, Rom E; Abler, Victor; Grossman, Iris; Fitzer-Attas, Cheryl; Tiwari, Arun; Hayden, Michael R; Kennedy, James L; Lang, Anthony E; Knight, Jo

    2016-07-01

    The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in

  11. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin-responsive GLUT4 genes in NIDDM

    DEFF Research Database (Denmark)

    Bjørbaek, C; Echwald, Søren Morgenthaler; Hubricht, P

    1994-01-01

    regions and regions of importance for translation, as well as coding sequences of the two genes, were studied using single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. The genetic analyses were performed in subgroups of 52 Caucasian NIDDM patients and 25 age-matched healthy......To examine the hypothesis that variants in the regulatory or coding regions of the glycogen synthase (GS) and insulin-responsive glucose transporter (GLUT4) genes contribute to insulin-resistant glucose processing of muscle from non-insulin-dependent diabetes mellitus (NIDDM) patients, promoter......'-untranslated region, and the coding region of the GLUT4 gene showed four polymorphisms, all single nucleotide substitutions, positioned at -581, 1, 30, and 582. None of the three changes in the regulatory region of the gene had any major influence on expression of the GLUT4 gene in muscle. The variant at 582...

  12. SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease.

    Science.gov (United States)

    Fowler, Sharyle A; Ananthakrishnan, Ashwin N; Gardet, Agnes; Stevens, Christine R; Korzenik, Joshua R; Sands, Bruce E; Daly, Mark J; Xavier, Ramnik J; Yajnik, Vijay

    2014-08-01

    More than 80% of Crohn's disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p=0.022) and penetrating behavior (HR 3.97, p=0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p=0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p=0.001). NOD2 was not associated with increased risk of surgical recurrence. Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence. Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  13. CARD8 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease.

    Science.gov (United States)

    Germain, Adeline; Guéant, Rosa-Maria; Chamaillard, Mathias; Bresler, Laurent; Guéant, Jean-Louis; Peyrin-Biroulet, Laurent

    2015-11-01

    Post-operative recurrence is frequent in Crohn's disease. Genetic factors associated with post-operative recurrence remain poorly understood. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. Crohn's disease patients who had at least one bowel resection were retrospectively identified from the "Nancy IBD cohort". Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for 200 genetic variants and analyzed with the log-rank test. 137 patients had at least 1 resection in our cohort: 38 had a surgical recurrence (28%). In multivariate analysis, current smoker status (OR 6.97, 95% CI 1.85-26.22, p=0.004), post-operative complications after prior surgery (OR 2.72, 95% CI 1.02-7.22, p=0.044), and Caspase recruitment domain-containing protein 8 (CARD8) homozygosity for the risk allele (OR 7.56, 95% CI 1.13-50.37, p=0.036) remained significantly and independently associated with surgical recurrence. Current smoker status was associated with increased risk of surgical recurrence. A novel association between CARD8 and increased risk of surgical recurrence in Crohn's disease was observed. CARD8 could be a new marker for risk stratification and prevention of recurrent surgery. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  14. Hypoxia inducible factor 1α gene (HIF-1α splice variants: potential prognostic biomarkers in breast cancer

    Directory of Open Access Journals (Sweden)

    Bonnier Pascal

    2010-07-01

    Full Text Available Abstract Background Hypoxia-inducible factor 1 (HIF-1 is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear translocator (ARNT subunits. The prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known. Methods Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1α and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign and 53 primary carcinomas. In breast cancers HIF-1α splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival. Results HIF-1α isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1αTAG and HIF-1α736 mRNAs were found expressed at higher levels in oestrogen receptor (OR-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively. In breast carcinoma specimens, lymph node status was significantly associated with HIF-1αTAG mRNA levels (P = 0.037. Significant statistical association was found between tumour grade and HIF-1αTAG (P = 0.048, and total HIF-1α (P = 0.048 mRNA levels. HIF-1αTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively. Univariate analysis showed that high HIF-1αTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01. Conclusions Our results show for the first time that mRNA expression of a HIF-1αTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis. See commentary: http://www.biomedcentral.com/1741-7015/8/45

  15. Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal).

    Science.gov (United States)

    Spínola, Carla; Brehm, António; Spínola, Hélder

    2011-01-01

    Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that results from mutations in the HFE gene. Almost all patients with hereditary hemochromatosis show a C282Y mutation in homozygosity or in compound heterozygosity with H63D. Also, the mutation S65C has been shown to be associated to a milder iron overload. Since allele and genotype frequencies of these three variants of the HFE gene vary between populations, the determination of their prevalence in Madeira Island will clarify the population susceptibility to hereditary hemochromatosis. One hundred and fifty-four samples from Madeira Island were genotyped for the three most common HFE gene mutations, H63D, C282Y, and S65C, by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results have shown a prevalence of 20.5%, 0.33%, and 1% for H63D, C282Y, and S65C, respectively. Accordingly to our estimates, both genotypes associated to hereditary hemochromatosis, C282Y homozygotes and C282/H63D compound heterozygotes, could be present in Madeira Island population in 1,648 individuals, which represents 0.65% of the total population.

  16. Association analysis of bovine Foxa2 gene single sequence variant and haplotype combinations with growth traits in Chinese cattle.

    Science.gov (United States)

    Liu, Mei; Li, Mijie; Wang, Shaoqiang; Xu, Yao; Lan, Xianyong; Li, Zhuanjian; Lei, Chuzhao; Yang, Dongying; Jia, Yutang; Chen, Hong

    2014-02-25

    Forkhead box A2 (Foxa2) has been recognized as one of the most potent transcriptional activators that is implicated in the control of feeding behavior and energy homeostasis. However, similar researches about the effects of genetic variations of Foxa2 gene on growth traits are lacking. Therefore, this study detected Foxa2 gene polymorphisms by DNA pool sequencing, PCR-RFLP and PCR-ACRS methods in 822 individuals from three Chinese cattle breeds. The results showed that four sequence variants (SVs) were screened, including two mutations (SV1, g. 7005 C>T and SV2, g. 7044 C>G) in intron 4, one mutation (SV3, g. 8449 A>G) in exon 5 and one mutation (SV4, g. 8537 T>C) in the 3'UTR. Notably, association analysis of the single mutations with growth traits in total individuals (at 24months) revealed that significant statistical difference was found in four SVs, and SV4 locus was highly significantly associated with growth traits throughout all three breeds (PFoxa2 gene that was predictive of molecular markers in cattle breeding for the first time. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Common variant in myocilin gene is associated with high myopia in isolated population of Korcula Island, Croatia.

    LENUS (Irish Health Repository)

    Vatavuk, Zoran

    2012-01-31

    AIM: To study the association between genetic variants in myocilin and collagen type I alpha 1 genes and high myopia in an isolated island population. METHODS: A total of 944 examinees from the genetic epidemiology study conducted on the island of Korcula, Croatia, were included in the study. We selected 2 short nucleotide polymorphisms (SNP) available in our genome-wide scan set of SNPs that were previously associated with high myopia and used them to replicate previous claims of possible association. RESULTS: Nineteen cases of high myopia, defined as the refraction of <\\/=-6.00 diopters, were identified and included in the analysis. We showed that rs2075555 in the COL1A1 gene was not associated with high myopia. In contrast, rs2421853 in the myocilin gene was significantly associated in both bivariate (P=0.006) and age- and sex-adjusted analysis (P=0.049). CONCLUSION: Myocilin seems to be a very strong candidate for explaining some of the pathophysiological pathways leading to the development of both glaucoma and high myopia. As our finding was obtained in a relatively under-powered sample, further research and replication of these results is needed.

  18. Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina.

    Science.gov (United States)

    Meguro, Akira; Ideta, Hidenao; Ota, Masao; Ito, Norihiko; Ideta, Ryuichi; Yonemoto, Junichi; Takeuchi, Masaki; Uemoto, Riyo; Nishide, Tadayuki; Iijima, Yasuhito; Kawagoe, Tatsukata; Okada, Eiichi; Shiota, Tomoko; Hagihara, Yuta; Oka, Akira; Inoko, Hidetoshi; Mizuki, Nobuhisa

    2012-01-01

    Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS) using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls) led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4) gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls) using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 × 10(-6), OR = 0.63 and Pc = 1.0 × 10(-5), OR = 0.69 in a total of 574 patients and 608 controls, respectively). Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina.

  19. Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina.

    Directory of Open Access Journals (Sweden)

    Akira Meguro

    Full Text Available Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4 gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 × 10(-6, OR = 0.63 and Pc = 1.0 × 10(-5, OR = 0.69 in a total of 574 patients and 608 controls, respectively. Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina.

  20. Melanocortin-4 receptor gene variants are not associated with binge-eating behavior in nonobese patients with eating disorders.

    Science.gov (United States)

    Gamero-Villarroel, Carmen; Rodriguez-Lopez, Raquel; Jimenez, Mercedes; Carrillo, Juan A; Garcia-Herraiz, Angustias; Albuquerque, David; Flores, Isalud; Gervasini, Guillermo

    2015-02-01

    We aimed to determine whether variability in the melanocortin-4 receptor (MC4R) gene, predisposing to hyperphagia and obesity, may also be present in nonobese patients with binge-eating behavior or be related to anthropometric or psychopathological parameters in these patients. The coding region of the MC4R gene was sequenced in nonobese patients with binge-eating behavior diagnosed with bulimia nervosa or binge-eating disorder (n=77); individuals with severe early-onset obesity (n=170); and lean women with anorexia nervosa (n=20). A psychometric evaluation (Eating Disorders Inventory-2 and Symptom Checklist 90 Revised inventories) was carried out for all the patients with eating disorders. In the obesity group, 10 different variants were identified, whereas in the binge-eating patients, only two individuals with bulimia nervosa were found to carry the I251L polymorphism, which did not correlate with weight, BMI, or psychopathological features. We found no evidence that mutations in the MC4R gene are associated with binge-eating behavior in nonobese eating disorder patients.

  1. 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

    in this gene, we investigated the association between the LPL S447X variant with lipids and risk of coronary heart disease (CHD) in 3 independent, prospective studies. Methods The S447X variant was genotyped in case-control studies of incident CHD nested within the Nurses' Health Study (NHS), the Health...... Professionals Follow-up Study (HPFS), and the Danish Diet, Cancer and Health (DCH) study, totaling 245, 258, and 962 cases, respectively. Results S447X carriers tended to have lower TG and higher HDL-C concentrations than noncarriers. The S447X variant was associated with a lower risk of CHD 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...

  2. Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants?

    Science.gov (United States)

    Gunes, Muhammed; Cekic, Sukru; Kilic, Sara Sebnem

    2017-06-01

    Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most frequent repetitive fever syndrome in childhood. It is characterized by fever episodes lasting for approximately 3-6 days, once every 3-8 weeks. Clinical and laboratory data for PFAPA syndrome patients between January 2010 and December 2014 followed up at a tertiary pediatric care hospital were reviewed. Four hundred children (256 male, 144 female; mean age at diagnosis, 4.2 ± 2.2 years), were enrolled in the study. During the episodes, mean leukocyte number was high (12 725/mm 3 ) with predominant neutrophils. The mean number of monocytes was 1256/mm 3 , and 90.2% had monocytosis. Serum amyloid A and C-reactive protein were high in 84.6% and in 77.8% of the patients, respectively. Mediterranean fever (MEFV) gene heterozygous mutation was identified in 57 of the 231 patients (24.7%) in whom genetic analysis had been performed. The most frequent mutation was heterozygous M694V (10%, n = 23). Extension of between-episode interval following prophylaxis was noted in 85% of those on regular colchicine treatment (n = 303). In the colchicine group, between-episode interval was prolonged from 18.8 ± 7.9 days (before colchicine treatment) to 49.5 ± 17.6 days on prophylactic colchicine therapy; also, prophylactic treatment was more effective in reducing episode frequency in patients with MEFV gene variant (n = 54, 96%) than in those without (n = 122, 80%; P = 0.003). This study has involved the largest number of PFAPA syndrome patients in the literature. It is particularly important to assess and to demonstrate the high rate of response to colchicine prophylaxis in PFAPA syndrome patients, especially those with MEFV variant. On blood screening, neutrophilia associated with monocytosis and low procalcitonin could contribute to diagnosis. © 2017 Japan Pediatric Society.

  3. CYP2D6 gene variants in urban/admixed and Amerindian populations of Venezuela: pharmacogenetics and anthropological implications.

    Science.gov (United States)

    Griman, Pedro; Moran, Yeinmy; Valero, Gabriela; Loreto, Mariana; Borjas, Lisbeth; Chiurillo, Miguel A

    2012-03-01

    Differences in genes encoding enzymes involved in the biotransformation of a large number of compounds, such as CYP2D6, are related to inter-individual and inter-ethnic variability in the metabolism of many drugs, which have also been linked to susceptibility to cancer and other health outcomes. Therefore, populations are likely to benefit from inclusion in pharmacogenetic research studies. To determine the frequency of functionally important allele variants of CYP2D6 gene in a sample of an Urban/admixed and five Amerindian Venezuelan populations. DNA of 328 unrelated volunteers was analysed for the presence of CYP2D6 *2, *3, *4, *5, *6 and *10 variants. The frequency in the Urban/admixed population for *2, *3, *4, *5, *6 and *10 alleles was 37.9%, 0%, 13.4%, 2.0%, 1.2% and 4.0%, respectively. In the Bari population, the prevalence of *4 allele associated with decreased enzyme activity was observed in 42.5%, whereas the poor metabolizer genotype *4/*4 was found in 25%. In the Panare, Pemon, Warao and Wayuu populations the *4 allele was found in 5.4%, 2.5%, 1.7% and 4.2%, respectively. The *10 allele frequency found in Amerindians (0.0-6.3%) was lower than reported for Asians. The results are consistent with the known genetic admixture origin of most Venezuela populations. Nevertheless, the observed significant differences among Amerindians highlight the need for pharmacogenetic studies taking into account biogeographical and anthropological considerations.

  4. Mutations in the control of virulence sensor gene from Streptococcus pyogenes after infection in mice lead to clonal bacterial variants with altered gene regulatory activity and virulence.

    Directory of Open Access Journals (Sweden)

    Jeffrey A Mayfield

    Full Text Available The cluster of virulence sensor (CovS/responder (CovR two-component operon (CovRS regulates ∼15% of the genes of the Group A Streptococcal pyogenes (GAS genome. Bacterial clones containing inactivating mutations in the covS gene have been isolated from patients with virulent invasive diseases. We report herein an assessment of the nature and types of covS mutations that can occur in both virulent and nonvirulent GAS strains, and assess whether a nonvirulent GAS can attain enhanced virulence through this mechanism. A group of mice were infected with a globally-disseminated clonal M1T1 GAS (isolate 5448, containing wild-type (WT CovRS (5448/CovR+S+, or less virulent engineered GAS strains, AP53/CovR+S+ and Manfredo M5/CovR+S+. SpeB negative GAS clones from wound sites and/or from bacteria disseminated to the spleen were isolated and the covS gene was subjected to DNA sequence analysis. Numerous examples of inactivating mutations were found in CovS in all regions of the gene. The mutations found included frame-shift insertions and deletions, and in-frame small and large deletions in the gene. Many of the mutations found resulted in early translation termination of CovS. Thus, the covS gene is a genomic mutagenic target that gives GAS enhanced virulence. In cases wherein CovS- was discovered, these clonal variants exhibited high lethality, further suggesting that randomly mutated covS genes occur during the course of infection, and lead to the development of a more invasive infection.

  5. Primary Angle Closure and Sequence Variants within MicroRNA Binding Sites of Genes Involved in Eye Development.

    Directory of Open Access Journals (Sweden)

    Haihong Shi

    Full Text Available The formation of primary angle closure (PAC and primary angle closure glaucoma (PACG is regulated by a tissue remodeling pathway that plays a critical role in eye development. MicroRNAs (miRNAs are powerful gene expression regulators and may exert their effects on tissue remodeling genes. This study investigated the associations between gene variants (single-nucleotide polymorphism, SNP in miRNA binding sites in the 3'-UTR region of genes involved in eye development and PAC.The sample consisted of 232 PAC subjects and 306 controls obtained from a population-based cohort in the Funing District of Jiangsu, China. The markers include 9 SNPs in the COL11A1, PCMTD1, ZNRF3, MTHFR, and ALPPL2 genes respectively. SNP genotyping was performed with a TaqMan-MGB probe using an RT-PCR system.Of the 9 SNPs studied, the frequency of the minor A allele of COL11A1 rs1031820 was higher in the PAC group than in the control group in allele analysis (p = 0.047. The genotype analysis indicated that MTHFR rs1537514 is marginally associated with PAC (p = 0.014. The CC genotype of rs1537514 was present solely in the PAC group. However, the differences lost significance after Bonferroni correction.Our study reveals a possible association of COL11A1 and MTHFR with PAC in the Han Chinese population. These results will contribute to an improved understanding of the genetic basis of PACG.

  6. Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty.

    Science.gov (United States)

    Howard, Sasha R; Guasti, Leonardo; Poliandri, Ariel; David, Alessia; Cabrera, Claudia P; Barnes, Michael R; Wehkalampi, Karoliina; O'Rahilly, Stephen; Aiken, Catherine E; Coll, Anthony P; Ma, Marcella; Rimmington, Debra; Yeo, Giles S H; Dunkel, Leo

    2018-02-01

    Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/- mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP. Copyright © 2017 Endocrine Society

  7. More than 150 novel variants of HLA class I genes detected in German Stem Cell Donor Registry and UCLA International Cell Exchange samples.

    Science.gov (United States)

    Balz, V; Krause, S; Fischer, J; Enczmann, J

    2018-03-01

    High throughput analysis using amplicon-based next-generation sequencing (NGS) of HLA class I genes in samples of registered stem cell donors of the German Stem Cell Donor Registry Düsseldorf revealed 151 novel variants. In addition, four new variants were identified in well-defined samples obtained from the UCLA International Cell Exchange program. New alleles included 37 HLA-A, 57 HLA-B, and 61 HLA-C variant alleles. All variants were confirmed by NGS of HLA-A, HLA-B, and HLA-C genes including the respective 5' and 3' untranslated regions as well as Sanger sequence analysis. Mainly, the variants encompass single nucleotide changes in intronic as well as exonic parts of the genes. We identified intronic variations in 114 new alleles, nonsynonymous nucleotide changes in 25 alleles, synonymous nucleotide changes in nine alleles, and three hybrid alleles. Four alleles carry exonic deletions or insertions resulting in frameshift of peptide translation. Two novel alleles of HLA-C were shown to result in splicing defects of the transcript. Two alleles showed exonic as well as intronic changes. Thirty-four of the new alleles were found in multiple samples. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes.

    Directory of Open Access Journals (Sweden)

    Bhavi P Modi

    Full Text Available Preterm premature rupture of membranes (PPROM is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES on neonatal DNA derived from pregnancies complicated by PPROM (49 cases and healthy term deliveries (20 controls to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225 of damaging/potentially damaging rare variants was identified in the genes of interest-fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans.

  9. Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes.

    Science.gov (United States)

    Modi, Bhavi P; Teves, Maria E; Pearson, Laurel N; Parikh, Hardik I; Chaemsaithong, Piya; Sheth, Nihar U; York, Timothy P; Romero, Roberto; Strauss, Jerome F

    2017-01-01

    Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225) of damaging/potentially damaging rare variants was identified in the genes of interest-fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans.

  10. Replication of the association between variants in the WFS1 gene and risk of type 2 diabetes in European populations

    Science.gov (United States)

    Franks, P.W.; Rolandsson, O.; Debenham, S.L.; Fawcett, K.A.; Payne, F.; Dina, C.; Froguel, P.; Mohlke, K.L.; Willer, C.; Olsson, T.; Wareham, N.J.; Hallmans, G.; Barroso, I; Sandhu, M.S.

    2009-01-01

    Aims/hypothesis: Mutations at the Wolframin encoding gene, WFS1, cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. In the present study, we sought to replicate those associations in a northern Swedish case-control study for type 2 diabetes. We also meta-analyzed published and previously unpublished data from Sweden, Finland and France to obtain updated summary effect estimates. Methods: Four WFS1 SNPs (rs10010131, rs6446482, rs752854, rs734312 [R611H]) were genotyped in a type 2 diabetes case-control study (N=1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex, and body mass index. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 cases and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. Results: In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk (OR=0.85; 95% CI=0.75-0.96; p=0.010). Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131, or its proxy variants, showed evidence for statistical association (OR=0.87; 95% CI=0.82-0.93; p=4.5×10−5). In an updated meta-analysis of all 11 studies, comprising 14,139 cases and 16,109 controls, strong evidence for statistical association was also observed (OR=0.89; 95% CI=0.86-0.92; p=4.9×10−11). Conclusion: In this study of WFS1 gene variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and risk of type 2 diabetes. PMID:18040659

  11. A synbio approach for selection of highly expressed gene variants in Gram-positive bacteria.

    Science.gov (United States)

    Ferro, Roberto; Rennig, Maja; Hernández-Rollán, Cristina; Daley, Daniel O; Nørholm, Morten H H

    2018-03-08

    The market for recombinant proteins is on the rise, and Gram-positive strains are widely exploited for this purpose. Bacillus subtilis is a profitable host for protein production thanks to its ability to secrete large amounts of proteins, and Lactococcus lactis is an attractive production organism with a long history in food fermentation. We have developed a synbio approach for increasing gene expression in two Gram-positive bacteria. First of all, the gene of interest was coupled to an antibiotic resistance gene to create a growth-based selection system. We then randomised the translation initiation region (TIR) preceding the gene of interest and selected clones that produced high protein titres, as judged by their ability to survive on high concentrations of antibiotic. Using this approach, we were able to significantly increase production of two industrially relevant proteins; sialidase in B. subtilis and tyrosine ammonia lyase in L. lactis. Gram-positive bacteria are widely used to produce industrial enzymes. High titres are necessary to make the production economically feasible. The synbio approach presented here is a simple and inexpensive way to increase protein titres, which can be carried out in any laboratory within a few days. It could also be implemented as a tool for applications beyond TIR libraries, such as screening of synthetic, homologous or domain-shuffled genes.

  12. Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1

    Directory of Open Access Journals (Sweden)

    D'Souza Ursula M

    2005-01-01

    Full Text Available Abstract Background The 10-repeat allele of a variable number tandem repeat (VNTR polymorphism in the 3'-untranslated region of the dopamine transporter gene (DAT1 has been associated with a range of psychiatric phenotypes, most notably attention-deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study we have characterised the genomic structure of the 9- and 10-repeat VNTR alleles, and directly examined the role of the polymorphism in mediating gene expression by measuring comparative in vitro cellular expression using a reporter-gene assay system. Results Differences in the sequence of the 9- and 10- repeat alleles were confirmed but no polymorphic differences were observed between individuals. There was no difference in expression of reporter gene constructs containing the two alleles. Conclusions Our data suggests that this VNTR polymorphism may not have a direct effect on DAT1 expression and that the associations observed with psychiatric phenotypes may be mediated via linkage disequilibrium with other functional polymorphisms.

  13. Immune disease-associated variants in gene enhancers point to BET epigenetic mechanisms for therapeutic intervention.

    Science.gov (United States)

    Tough, David F; Prinjha, Rab K

    2017-04-01

    Genome-wide association studies have identified thousands of single nucleotide polymorphisms in the human genome that are statistically associated with particular disease traits. In this Perspective, we review emerging data suggesting that most single nucleotide polymorphisms associated with immune-mediated diseases are found in regulatory regions of the DNA - parts of the genome that control expression of the protein encoding genes - rather than causing mutations in proteins. We discuss how the emerging understanding of particular gene regulatory regions, gene enhancers and the epigenetic mechanisms by which they are regulated is opening up new opportunities for the treatment of immune-mediated diseases, focusing particularly on the BET family of epigenetic reader proteins as potential therapeutic targets.

  14. Variants of the HNF1α gene: a molecular approach concerning diabetic patients from southern Brazil

    Directory of Open Access Journals (Sweden)

    Naieli Bonatto

    2012-01-01

    Full Text Available Maturity Onset Diabetes of the Young (MODY presents monogenic inheritance and mutation factors which have already been identified in six different genes. Given the wide molecular variation present in the hepatocyte nuclear factor-1α gene (HNF1α MODY3, the aimof this study was to amplify and sequence the coding regions of this gene in seven patients from the Campos Gerais region, Paraná State, Brazil, presenting clinical MODY3 features. Besides the synonymous variations, A15A, L17L, Q141Q, G288G and T515T, two missense mutations, I27L and A98V, were also detected. Clinical and laboratory data obtained from patients were compared with the molecular findings, including the I27L polymorphism that was revealed in some overweight/obese diabetic patients of this study, this corroborating with the literature. We found certain DNA variations that could explain the hyperglycemic phenotype of the patients.

  15. Systematic Identification of Genes Required for Expression of Androgen Receptor Splice Variants

    Science.gov (United States)

    2016-08-01

    It has several advantages over the existing ones and one of them is the ability to make a very large number (tenth of thousands) of gene knockouts...each of reporters in LNCaP and CWR22Rv1 cells, respectively. See Task 2 To identify genes required for the full length AR or AR3, we took advantage of...splicing, and are important determinants of mRNA export , localization, translation, and stability [28]. Several members of this family have been

  16. Combined analysis of 19 common validated type 2 diabetes susceptibility gene variants shows moderate discriminative value and no evidence of gene-gene interaction

    DEFF Research Database (Denmark)

    Sparsø, T; Grarup, N; Andreasen, C.

    2009-01-01

    study; and additional type 2 diabetic patients and glucose-tolerant individuals. The case-control studies involved 4,093 type 2 diabetic patients and 5,302 glucose-tolerant individuals. RESULTS: Single-variant analyses demonstrated allelic odds ratios ranging from 1.04 (95% CI 0.98-1.11) to 1.33 (95% CI...... 1.22-1.45). When combining the 19 variants, subgroups with extreme risk profiles showed a threefold difference in the risk of type 2 diabetes (lower 10% carriers with or =22 risk alleles, OR 2.93 (95% CI 2.38-3.62, p = 1.6 x 10(-25)). We calculated......AIMS/HYPOTHESIS: The list of validated type 2 diabetes susceptibility variants has recently been expanded from three to 19. The variants identified are common and have low penetrance in the general population. The aim of the study is to investigate the combined effect of the 19 variants by applying...

  17. Molecular cloning and characterization of Antheraea mylitta cytoplasmic polyhedrosis virus polyhedrin gene and its variant forms

    International Nuclear Information System (INIS)

    Sinha-Datta, Uma; Chavali, Venkata Ramana Murthy; Ghosh, Ananta K.

    2005-01-01

    The segments 10 (S10) of the 11 double stranded RNA genomes from Antheraea mylitta cytoplasmic polyhedrosis virus (AmCPV) encoding a novel polyhedrin polypeptide was converted to cDNA, cloned, and sequenced. Three cDNA clones consisting of 1502 (AmCPV10-1), 1120 (AmCPV10-2), and 1415 (AmCPV10-3) nucleotides encoding polyhedrin of 254, 339, and 319 amino acids with molecular masses of 29, 39, and 37 kDa, respectively, were obtained, and verified by Northern analysis. These clones showed 70-94% sequence identity among them but none with any sequences in databases. The expression of AmCPV10-1 cDNA encoded polyhedrin in Sf-9 cells was detected by immunoblot analysis and formation of polyhedra by electron microscopy, as observed in AmCPV-infected gut cells, but no expression of AmCPV10-2 or AmCPV10-3 cDNA was detected, indicating that during AmCPV replication, along with functional S10 RNA, some defective variant forms of S10 RNAs are packaged in virion particles

  18. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, Lydia; Dafou, Dimitra; Ramus, Susan J

    2009-01-01

    Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediat...

  19. Clinical characteristics and analysis of HFE gene variants (C282Y ...

    African Journals Online (AJOL)

    Age-related macular degeneration (AMD) is a complex genetic disorder with multiple etiologies. Multiple genes as well as environmental effects are thought to play a role in causing AMD. Recent evidence pointed that elevated iron overload, resulting from hereditary defects of iron homeostasis, is associated with retinal ...

  20. A Database to Support the Interpretation of Human Mismatch Repair Gene Variants

    NARCIS (Netherlands)

    Ou, Jianghua; Niessen, Renee C.; Vonk, Jan; Westers, Helga; Hofstra, Robert M. W.; Sijmons, Rolf H.

    2008-01-01

    Germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2 can cause Lynch syndrome. This syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominantly-inherited disorder predominantly characterized by colorectal and endometrial cancer.