WorldWideScience

Sample records for disease highlights genetic

  1. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

    NARCIS (Netherlands)

    Liu, Jimmy Z.; van Sommeren, Suzanne; Huang, Hailiang; Ng, Siew C.; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C.; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Daryani, Naser E.; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C.; Juyal, Garima; Kim, Won Ho; Morris, Andrew P.; Poustchi, Hossein; Newman, William G.; Midha, Vandana; Orchard, Timothy R.; Vahedi, Homayon; Sood, Ajit; Sung, Joseph J. Y.; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C.; Franke, Andre; Alizadeh, Behrooz Z.; Parkes, Miles; Thelma, B. K.; Daly, Mark J.; Kubo, Michiaki; Anderson, Carl A.; Weersma, Rinse K.

    Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first transancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846

  2. Highlighting nonlinear patterns in population genetics datasets

    KAUST Repository

    Alanis Lobato, Gregorio; Cannistraci, Carlo Vittorio; Eriksson, Anders; Manica, Andrea; Ravasi, Timothy

    2015-01-01

    Detecting structure in population genetics and case-control studies is important, as it exposes phenomena such as ecoclines, admixture and stratification. Principal Component Analysis (PCA) is a linear dimension-reduction technique commonly used for this purpose, but it struggles to reveal complex, nonlinear data patterns. In this paper we introduce non-centred Minimum Curvilinear Embedding (ncMCE), a nonlinear method to overcome this problem. Our analyses show that ncMCE can separate individuals into ethnic groups in cases in which PCA fails to reveal any clear structure. This increased discrimination power arises from ncMCE's ability to better capture the phylogenetic signal in the samples, whereas PCA better reflects their geographic relation. We also demonstrate how ncMCE can discover interesting patterns, even when the data has been poorly pre-processed. The juxtaposition of PCA and ncMCE visualisations provides a new standard of analysis with utility for discovering and validating significant linear/nonlinear complementary patterns in genetic data.

  3. Highlighting nonlinear patterns in population genetics datasets

    KAUST Repository

    Alanis Lobato, Gregorio

    2015-01-30

    Detecting structure in population genetics and case-control studies is important, as it exposes phenomena such as ecoclines, admixture and stratification. Principal Component Analysis (PCA) is a linear dimension-reduction technique commonly used for this purpose, but it struggles to reveal complex, nonlinear data patterns. In this paper we introduce non-centred Minimum Curvilinear Embedding (ncMCE), a nonlinear method to overcome this problem. Our analyses show that ncMCE can separate individuals into ethnic groups in cases in which PCA fails to reveal any clear structure. This increased discrimination power arises from ncMCE\\'s ability to better capture the phylogenetic signal in the samples, whereas PCA better reflects their geographic relation. We also demonstrate how ncMCE can discover interesting patterns, even when the data has been poorly pre-processed. The juxtaposition of PCA and ncMCE visualisations provides a new standard of analysis with utility for discovering and validating significant linear/nonlinear complementary patterns in genetic data.

  4. Systems Genetic Analyses Highlight a TGFβ-FOXO3 Dependent Striatal Astrocyte Network Conserved across Species and Associated with Stress, Sleep, and Huntington's Disease.

    Science.gov (United States)

    Scarpa, Joseph R; Jiang, Peng; Losic, Bojan; Readhead, Ben; Gao, Vance D; Dudley, Joel T; Vitaterna, Martha H; Turek, Fred W; Kasarskis, Andrew

    2016-07-01

    Recent systems-based analyses have demonstrated that sleep and stress traits emerge from shared genetic and transcriptional networks, and clinical work has elucidated the emergence of sleep dysfunction and stress susceptibility as early symptoms of Huntington's disease. Understanding the biological bases of these early non-motor symptoms may reveal therapeutic targets that prevent disease onset or slow disease progression, but the molecular mechanisms underlying this complex clinical presentation remain largely unknown. In the present work, we specifically examine the relationship between these psychiatric traits and Huntington's disease (HD) by identifying striatal transcriptional networks shared by HD, stress, and sleep phenotypes. First, we utilize a systems-based approach to examine a large publicly available human transcriptomic dataset for HD (GSE3790 from GEO) in a novel way. We use weighted gene coexpression network analysis and differential connectivity analyses to identify transcriptional networks dysregulated in HD, and we use an unbiased ranking scheme that leverages both gene- and network-level information to identify a novel astrocyte-specific network as most relevant to HD caudate. We validate this result in an independent HD cohort. Next, we computationally predict FOXO3 as a regulator of this network, and use multiple publicly available in vitro and in vivo experimental datasets to validate that this astrocyte HD network is downstream of a signaling pathway important in adult neurogenesis (TGFβ-FOXO3). We also map this HD-relevant caudate subnetwork to striatal transcriptional networks in a large (n = 100) chronically stressed (B6xA/J)F2 mouse population that has been extensively phenotyped (328 stress- and sleep-related measurements), and we show that this striatal astrocyte network is correlated to sleep and stress traits, many of which are known to be altered in HD cohorts. We identify causal regulators of this network through Bayesian network

  5. Genetics and Rheumatic Disease

    Science.gov (United States)

    ... Well with Rheumatic Disease Genetics and Rheumatic Disease Genetics and Rheumatic Disease Fast Facts Studying twins has ... 70%, and for non-identical pairs, even lower. Genetics and ankylosing spondylitis Each rheumatic disease has its ...

  6. HIV and Cancer Interaction Highlights Need to Address Disease Stigma

    Science.gov (United States)

    The global landscape of disease highlights disparities that exist between nations. An estimated 36 million people worldwide live with HIV and AIDS, of which only 1 million are located within the United States. While the diagnosis of a life-threatening disease can be devastating, individuals with HIV and AIDS frequently bear an additional burden of stigma and discrimination.

  7. Genetics of complex diseases

    DEFF Research Database (Denmark)

    Mellerup, Erling; Møller, Gert Lykke; Koefoed, Pernille

    2012-01-01

    A complex disease with an inheritable component is polygenic, meaning that several different changes in DNA are the genetic basis for the disease. Such a disease may also be genetically heterogeneous, meaning that independent changes in DNA, i.e. various genotypes, can be the genetic basis...... for the disease. Each of these genotypes may be characterized by specific combinations of key genetic changes. It is suggested that even if all key changes are found in genes related to the biology of a certain disease, the number of combinations may be so large that the number of different genotypes may be close...... to the number of patients suffering from the disease. This hypothesis is based on a study of bipolar disorder....

  8. Genetics of gallstone disease.

    Directory of Open Access Journals (Sweden)

    Mittal B

    2002-04-01

    Full Text Available Gallstone disease is a complex disorder where both environmental and genetic factors contribute towards susceptibility to the disease. Epidemiological and family studies suggest a strong genetic component in the causation of this disease. Several genetically derived phenotypes in the population are responsible for variations in lipoprotein types, which in turn affect the amount of cholesterol available in the gall bladder. The genetic polymorphisms in various genes for apo E, apo B, apo A1, LDL receptor, cholesteryl ester transfer and LDL receptor-associated protein have been implicated in gallstone formation. However, presently available information on genetic differences is not able to account for a large number of gallstone patients. The molecular studies in the animal models have not only confirmed the present paradigm of gallstone formation but also helped in identification of novel genes in humans, which might play an important role in pathogenesis of the disease. Precise understanding of such genes and their molecular mechanisms may provide the basis of new targets for rational drug designs and dietary interventions.

  9. Genetics of celiac disease

    NARCIS (Netherlands)

    Ricano-Ponce, Isis; Wijmenga, Cisca; Gutierrez-Achury, Javier

    New insights into the underlying molecular pathophysiology of celiac disease (CeD) over the last few years have been guided by major advances in the fields of genetics and genomics. The development and use of the Immunochip genotyping platform paved the way for the discovery of 39 non-HLA loci

  10. Genetic epidemiology of Scheuermann's disease

    DEFF Research Database (Denmark)

    Damborg, Frank; Engell, Vilhelm; Nielsen, Jan

    2011-01-01

    The genetic/environmental etiology of Scheuermann's disease is unclear. We estimated the heritability of the disease using an etiological model adjusted for sex and time of diagnosis, and examined whether the prevalence of Scheuermann's disease was constant over time.......The genetic/environmental etiology of Scheuermann's disease is unclear. We estimated the heritability of the disease using an etiological model adjusted for sex and time of diagnosis, and examined whether the prevalence of Scheuermann's disease was constant over time....

  11. The genetics of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Silverman Edwin K

    2001-01-01

    Full Text Available Abstract Chronic obstructive pulmonary disease (COPD is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.

  12. Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

    OpenAIRE

    de la Hoya, Miguel; Soukarieh, Omar; L��pez-Perolio, Irene; Vega, Ana; Walker, Logan C.; van Ierland, Yvette; Baralle, Diana; Santamari��a, Marta; Lattimore, Vanessa; Wijnen, Juul; Whiley, Philip; Blanco, Ana; Raponi, Michela; Hauke, Jan; Wappenschmidt, Barbara

    2016-01-01

    A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, ...

  13. Genetics in Ophthalmology III – Posterior Segment Diseases

    Directory of Open Access Journals (Sweden)

    Canan Aslı Utine

    2012-10-01

    Full Text Available Genetic diseases are congenital or acquired hereditary diseases that result from structural/functional disorders of the human genome. Today, the genetic factors that play a role in many diseases are being highlighted with the rapid progress in the field of genetics science. It becomes increasingly important that physicians from all disciplines have knowledge about the basic principles of genetics, patterns of inheritance, etc., so that they can follow the new developments. In genetic eye diseases, ophthalmologists should know the basic clinical and recently rapidly developing genetic characteristics of these diseases in order to properly approach the diagnosis and treatment and to provide genetic counseling. In this paper, posterior segment eye diseases of genetic origin are reviewed, and retinoblastoma, mitochondrial diseases, retinal dysplasia, retinitis pigmentosa, choroideremia, gyrate atrophy, Alström disease, ocular albinism, optic nerve hypoplasia, anophthalmia/microphthalmia and Leber’s congenital amaurosis are covered. (Turk J Ophthalmol 2012; 42: 386-92

  14. RARE DISEASES AND GENETIC DISCRIMINATION

    Directory of Open Access Journals (Sweden)

    Mariela Yaneva – Deliverska

    2011-04-01

    physicians (not enough physicians involved in rare diseases clinical trials, and the absence of treatment consensus recommendations.It is fundamental to realise that rare diseases can affect any family at any time. It is not just “something terrible that happens to other people”. It is a very cruel reality that can happen to anyone, either when having a child or in the course of one’s own life.In fact, the terminology “rare diseases” only highlights the characteristic of rarity of the complex and heterogeneous mosaic of an estimated 7,000 life-threatening and heavily debilitating conditions.The rare diseases for which a simple and effective preventive treatment is available are being screened for, as part of public health policy. But this is not enough, and it is essential for public authorities to consider rare diseases as a Public Health priority and take action to concretely support patients and families affected by rare diseases.As underlined in the Background Paper on Orphan Diseases for the World Health Organisation Report on Priority Medicines for Europe and the World, “despite the growing public awareness of rare diseases in the last one or two decades, there are still many gaps in knowledge related to the development of treatment for rare diseases. Policymakers have to realise that rare diseases are a crucial health issue for about 30 million people in the EU”.A good medication for rare disease patients is a medication that is both available in the country where they live and affordable. If one of these two factors is missing, the drug is of little use.Personalized medicine however is an emerging term for a medical philosophy that uses a person’s individual clinical, genetic, genomic, and environmental information to tailor a treatment plan that will maximize efficacy and safety for that individual. While the technology offers much promise, it also is also challenged by some ethical and social questions in both its clinical application and in its

  15. Skin diseases highlighting essential global public health priorities.

    Science.gov (United States)

    Morrone, Aldo; Toma, Luigi; Franco, Gennaro

    2005-05-01

    Which are the essential global public health activities that should be carried out in order to attain the largest impact on poverty reduction and health improvement in the world? Since its foundation in 2001 the Human Mobile Population Committee (HMPC) has continued to devote its efforts to finding answers to this question, with a particular focus on the skin diseases of the Human Mobile Population (HMP) and other groups of disadvantaged people. In this article we present the model of socio-sanitary activity in the field of Migration, Poverty and Health of the Department of Preventive Medicine of Migration, Tourism and Tropical Dermatology (Dept.) at San Gallicano Institute--Research Institute for Hospitalization and Treatment (IRCCS)--in Rome (Italy). The activities of this dermatological centre are in the spirit of the HMPC's aims and we are of the opinion that this model is not only ethically valid, but also practically and economically convenient, and that there is evidence that our experience is worth repeating, in as many situations as possible, in the interest of public health.

  16. Genetics and Neuromuscular Diseases

    Science.gov (United States)

    ... Testing that reveals a young child’s genet- ic destiny may affect relationships within the family or may ... linked inheritance don’t apply at all. An embryo receives its mitochondria from the mother’s egg cell, ...

  17. Genetics Home Reference: Gaucher disease

    Science.gov (United States)

    ... 500 to 1,000 people of Ashkenazi Jewish heritage. The other forms of Gaucher disease are uncommon and do not occur more frequently in people of Ashkenazi Jewish descent. Related Information What information about a genetic condition can statistics provide? Why are some genetic ...

  18. Genetics Home Reference: Danon disease

    Science.gov (United States)

    ... are compartments in the cell that digest and recycle materials. The role the LAMP-2 protein plays ... Page Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet Med. 2011 Jun;13( ...

  19. Genetics Home Reference: Crohn disease

    Science.gov (United States)

    ... JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1; ... Health & Human Services National Institutes of Health National Library of Medicine Lister Hill National Center for Biomedical ...

  20. Genetic Aspects of Alzheimer Disease

    Science.gov (United States)

    Williamson, Jennifer; Goldman, Jill; Marder, Karen S.

    2011-01-01

    Background Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD. Review Summary In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD. Conclusions New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals. PMID:19276785

  1. Genetic Disease Foundation

    Science.gov (United States)

    ... has used its fundraising efforts to help further research programs at Mount Sinai. Spotlight: Gaucher Gaucher Disease is the most common of the lipid storage diseases. Learn about its symptoms, how it ...

  2. Quantitative genetics of disease traits.

    Science.gov (United States)

    Wray, N R; Visscher, P M

    2015-04-01

    John James authored two key papers on the theory of risk to relatives for binary disease traits and the relationship between parameters on the observed binary scale and an unobserved scale of liability (James Annals of Human Genetics, 1971; 35: 47; Reich, James and Morris Annals of Human Genetics, 1972; 36: 163). These two papers are John James' most cited papers (198 and 328 citations, November 2014). They have been influential in human genetics and have recently gained renewed popularity because of their relevance to the estimation of quantitative genetics parameters for disease traits using SNP data. In this review, we summarize the two early papers and put them into context. We show recent extensions of the theory for ascertained case-control data and review recent applications in human genetics. © 2015 Blackwell Verlag GmbH.

  3. [Genetics of congenital heart diseases].

    Science.gov (United States)

    Bonnet, Damien

    2017-06-01

    Developmental genetics of congenital heart diseases has evolved from analysis of serial slices in embryos towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Genetics of congenital heart diseases has also changed from formal genetic analysis of familial recurrences or population-based analysis to screening for mutations in candidates genes identified in animal models. Close cooperation between molecular embryologists, pathologists involved in heart development and pediatric cardiologists is crucial for further increase of knowledge in the field of cardiac morphogenesis and genetics of cardiac defects. The genetic model for congenital heart disease has to be revised to favor a polygenic origin rather than a monogenic one. The main mechanism is altered genic dosage that can account for heart diseases in chromosomal anomalies as well as in point mutations in syndromic and isolated congenital heart diseases. The use of big data grouping information from cardiac development, interactions between genes and proteins, epigenetic factors such as chromatin remodeling or DNA methylation is the current source for improving our knowledge in the field and to give clues for future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Genetic Evidence Highlights Potential Impacts of By-Catch to Cetaceans

    Science.gov (United States)

    Mendez, Martin; Rosenbaum, Howard C.; Wells, Randall S.; Stamper, Andrew; Bordino, Pablo

    2010-01-01

    Incidental entanglement in fishing gear is arguably the most serious threat to many populations of small cetaceans, judging by the alarming number of captured animals. However, other aspects of this threat, such as the potential capture of mother-offspring pairs or reproductive pairs, could be equally or even more significant but have rarely been evaluated. Using a combination of demographic and genetic data we provide evidence that i) Franciscana dolphin pairs that are potentially reproductive and mother-offspring pairs form temporal bonds, and ii) are entangled simultaneously. Our results highlight potential demographic and genetic impacts of by-catch to cetacean populations: the joint entanglement of mother-offspring or reproductive pairs, compared to random individuals, might exacerbate the demographic consequences of by-catch, and the loss of groups of relatives means that significant components of genetic diversity could be lost together. Given the social nature of many odontocetes (toothed cetaceans), we suggest that these potential impacts could be rather general to the group and therefore by-catch could be more detrimental than previously considered. PMID:21179542

  5. Genetics of Valvular Heart Disease

    Science.gov (United States)

    LaHaye, Stephanie; Lincoln, Joy

    2015-01-01

    Valvular heart disease is associated with significant morbidity and mortality and often the result of congenital malformations. However, the prevalence is increasing in adults not only because of the growing aging population, but also because of improvements in the medical and surgical care of children with congenital heart valve defects. The success of the Human Genome Project and major advances in genetic technologies, in combination with our increased understanding of heart valve development, has led to the discovery of numerous genetic contributors to heart valve disease. These have been uncovered using a variety of approaches including the examination of familial valve disease and genome-wide association studies to investigate sporadic cases. This review will discuss these findings and their implications in the treatment of valvular heart disease. PMID:24743897

  6. Genetic susceptibility to Grave's disease.

    Science.gov (United States)

    Li, Hong; Chen, Qiuying

    2013-06-01

    The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD.

  7. Genetic predisposition to Parkinson's disease

    DEFF Research Database (Denmark)

    Halling, Jónrit; Petersen, Maria Skaalum; Grandjean, Philippe

    2008-01-01

    OBJECTIVE: To investigate whether the genetic variants of CYP2D6 and HFE are more frequent in Parkinson's disease (PD) patients compared with controls in a population where the prevalence of these variants and PD are increased. METHODS: Blood samples were collected from 79 PD patients and 154...

  8. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

    DEFF Research Database (Denmark)

    Ellinghaus, David; Jostins, Luke; Spain, Sarah L

    2016-01-01

    We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more th...

  9. [Genetic diagnostics of cancer diseases].

    Science.gov (United States)

    Cobilanschi, Joana

    2013-11-27

    Cancer is caused by genetic alterations, but only 10% of the cancer diseases are inherited. The probability for an individual or a family of having inherited cancer, individual consequences of the respective results of genetic testing, as well as its costs and reimbursement by the health insurance must be addressed by expert genetic counseling which at-risk requires special expertise. Identification of a germline mutation which may predispose to a variety of different cancer types allows determination of an individual's specific life time risk in symptomatic as well as in a-symptomatic family members. Identification of the underlying defective gene in heritable cancer disorders also enables optimized preventive and novel therapeutic approaches specifically targeting the underlying molecular pathomechanisms.

  10. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

    NARCIS (Netherlands)

    Beaumont, R.N. (Robin N.); N.M. Warrington (Nicole); A. Cavadino (Alana); A.W.R. Tyrrell; M. Nodzenski (Michael); M. Horikoshi (Momoko); F. Geller (Frank); R. Myhre (Ronny); R.C. Richmond (Rebecca C.); Paternoster, L. (Lavinia); J.P. Bradfield (Jonathan); E. Kreiner-Møller (Eskil); V. Huikari (Ville); S. Metrustry (Sarah); K.L. Lunetta (Kathryn); J.N. Painter (Jodie N.); J.J. Hottenga (Jouke Jan); C. Allard (Catherine); S.J. Barton (Sheila J.); Espinosa, A. (Ana); J.A. Marsh (Julie); C. Potter (Catherine); Zhang, G. (Ge); W.Q. Ang (Wei); D. Berry (Diane); L. Bouchard (Luigi); S. Das (Shikta); H. Hakonarson (Hakon); J. Heikkinen (Jani); Helgeland, Ø. (Øyvind); B. Hocher (Berthold); A. Hofman (Albert); H.M. Inskip (Hazel); S.E. Jones (Samuel E.); M. Kogevinas (Manolis); P.A. Lind (Penelope); L. Marullo (Letizia); S.E. Medland (Sarah Elizabeth); Murray, A. (Anna); Murray, J.C. (Jeffrey C.); Njølstad, P.R. (Pa l R.); C. Nohr (Christian); C. Reichetzeder (Christoph); S.M. Ring (Susan); K.S. Ruth (Katherine S.); L. Santa-Marina (Loreto); D.M. Scholtens (Denise M.); Sebert, S. (Sylvain); V. Sengpiel (Verena); Tuke, M.A. (Marcus A.); Vaudel, M. (Marc); M.N. Weedon (Michael); G.A.H.M. Willemsen (Gonneke); Wood, A.R. (Andrew R.); Yaghootkar, H. (Hanieh); Muglia, L.J. (Louis J.); M. Bartels (Meike); C.L. Relton (Caroline); C.E. Pennell (Craig); L. Chatzi (Leda); Estivill, X. (Xavier); Holloway, J.W. (John W.); D.I. Boomsma (Dorret); Montgomery, G.W. (Grant W.); J. Murabito (Joanne); T.D. Spector (Timothy); Power, C. (Christine); Järvelin, M.-R. (Marjo-Ritta); Bisgaard, H. (Hans); Grant, S.F.A. (Struan F.A.); Sørensen, T.I.A. (Thorkild I.A.); Jaddoe, V.W. (Vincent W.); B. Jacobsson (Bo); Melbye, M. (Mads); McCarthy, M.I. (Mark I.); A.T. Hattersley (Andrew); Hayes, M.G. (M. Geoffrey); T.M. Frayling (Timothy); M.-F. Hivert (Marie-France); J.F. Felix (Janine); Hyppönen, E. (Elina); Lowe, W.L. (William L.); Evans, D.M. (David M.); Lawlor, D.A. (Debbie A.); B. Feenstra (Bjarke); R.M. Freathy (Rachel)

    2018-01-01

    textabstractGenome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal

  11. Nonmotor symptoms in genetic Parkinson disease

    DEFF Research Database (Denmark)

    Kasten, Meike; Kertelge, Lena; Brüggemann, Norbert

    2010-01-01

    To review current knowledge on nonmotor symptoms (NMS), particularly psychiatric features, in genetic Parkinson disease (PD) and to provide original data for genetic and idiopathic PD.......To review current knowledge on nonmotor symptoms (NMS), particularly psychiatric features, in genetic Parkinson disease (PD) and to provide original data for genetic and idiopathic PD....

  12. The genetics of Alzheimer's disease.

    Science.gov (United States)

    Bertram, Lars; Tanzi, Rudolph E

    2012-01-01

    Genetic factors play a major role in determining a person's risk to develop Alzheimer's disease (AD). Rare mutations transmitted in a Mendelian fashion within affected families, for example, APP, PSEN1, and PSEN2, cause AD. In the absence of mutations in these genes, disease risk is largely determined by common polymorphisms that, in concert with each other and nongenetic risk factors, modestly impact risk for AD (e.g., the ε4-allele in APOE). Recent genome-wide screening approaches have revealed several additional AD susceptibility loci and more are likely to be discovered over the coming years. In this chapter, we review the current state of AD genetics research with a particular focus on loci that now can be considered established disease genes. In addition to reviewing the potential pathogenic relevance of these genes, we provide an outlook into the future of AD genetics research based on recent advances in high-throughput sequencing technologies. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Celiac Disease Genetics : Past, Present and Future Challenges

    NARCIS (Netherlands)

    Wijmenga, Cisca; Gutierrez Achury, Javier

    In the past few years there has been enormous progress in unraveling the genetic basis of celiac disease (CD). Apart from the well-known association to HLA, there are currently 40 genomic loci associated to CD. Most of these loci show pleiotropic effects across many autoimmune diseases and highlight

  14. The genetics of Alzheimer disease.

    Science.gov (United States)

    Tanzi, Rudolph E

    2012-10-01

    Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD.

  15. Genetics of Coronary Artery Disease

    DEFF Research Database (Denmark)

    McPherson, Ruth; Tybjærg-Hansen, Anne

    2016-01-01

    Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200,000 individuals complemented by bioinformatic approaches, including...... identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (qgenetic risk scores that can improve risk prediction beyond conventional risk...... have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been...

  16. The genetics of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Bagyinszky E

    2014-04-01

    Full Text Available Eva Bagyinszky,1 Young Chul Youn,2 Seong Soo A An,1,* SangYun Kim3,*1Department of BioNano Technology Gachon University, Gyeonggi-do, 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, 3Department of Neurology, Seoul National University Budang Hospital, Gyeonggi-do, South Korea*These authors contributed equally to this workAbstract: Alzheimer's disease (AD is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age, or late onset (over 65 years of age. Three main genes are involved in early onset AD: amyloid precursor protein (APP, presenilin 1 (PSEN1, and presenilin 2 (PSEN2. The apolipoprotein E (APOE E4 allele has been found to be a main risk factor for late-onset Alzheimer's disease. Additionally, genome-wide association studies (GWASs have identified several genes that might be potential risk factors for AD, including clusterin (CLU, complement receptor 1 (CR1, phosphatidylinositol binding clathrin assembly protein (PICALM, and sortilin-related receptor (SORL1. Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2 and cluster of differentiation 33 (CD33. Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.Keywords: dementia, amyloid precursor protein, presenilin 1, presenilin 2, APOE, mutation, diagnosis, genetic testing

  17. Renal disease and mitochondrial genetics.

    Science.gov (United States)

    Rötig, Agnès

    2003-01-01

    Respiratory chain (RC) deficiencies have long been regarded as neuromuscular diseases mainly originating from mutations in the mitochondrial DNA. Oxidative phosphorylation, i.e. adenosine triphosphate (ATP) synthesis-coupled electron transfer from substrate to oxygen through the RC, does not occur only in the neuromuscular system. Therefore, a RC deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, owing to the dual genetic origin of RC enzymes (nuclear DNA and mitochondrial DNA). Mitochondrial diseases can give rise to various syndromes or association, namely, neurologic and neuromuscular diseases, cardiac, renal, hepatic, hematological and endocrin or dermatological presentations. The most frequent renal symptom is proximal tubular dysfunction with a more or less complete de Toni-Debre-Fanconi Syndrome. A few patients have been reported with tubular acidosis, Bartter Syndrome, chronic tubulointerstitial nephritis or nephrotic syndrome. The diagnosis of a RC deficiency is difficult when only renal symptoms are present, but should be easier when another, seemingly unrelated symptom is observed. Metabolic screening for abnormal oxidoreduction status in plasma, including lactate/pyruvate and ketone body molar ratios, can help to identify patients for further investigations. These include the measurement of oxygen consumption by mitochondria and the assessment of mitochondrial respiratory enzyme activities by spectrophotometric studies. Any mode of inheritance can be observed: sporadic, autosomal dominant or recessive, or maternal inheritance.

  18. Genetics Home Reference: Pelizaeus-Merzbacher disease

    Science.gov (United States)

    ... condition worsens, affected children develop spasticity leading to joint deformities (contractures) that restrict movement. Individuals with connatal ... Topic: Leukodystrophies Health Topic: Neurologic Diseases Health Topic: Neuromuscular Disorders Genetic and Rare Diseases Information Center (1 ...

  19. [Parkinson's disease(s): recent insight into genetic factors

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de; Scheffer, H.; Heutink, P.; Bloem, B.R.

    2007-01-01

    In recent years, 5 genes have been identified that are unambiguously associated with genetic forms of Parkinson's disease. These genes probably explain less than 10% of all cases of Parkinson's disease. Clinically, these genetic forms can closely resemble idiopathic Parkinson's disease. Mutation

  20. Genetic variants in periodontal health and disease

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-07-01

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

  1. Landscape genetics highlights the role of bank vole metapopulation dynamics in the epidemiology of Puumala hantavirus.

    Science.gov (United States)

    Guivier, E; Galan, M; Chaval, Y; Xuéreb, A; Ribas Salvador, A; Poulle, M-L; Voutilainen, L; Henttonen, H; Charbonnel, N; Cosson, J F

    2011-09-01

    Rodent host dynamics and dispersal are thought to be critical for hantavirus epidemiology as they determine pathogen persistence and transmission within and between host populations. We used landscape genetics to investigate how the population dynamics of the bank vole Myodes glareolus, the host of Puumala hantavirus (PUUV), vary with forest fragmentation and influence PUUV epidemiology. We sampled vole populations within the Ardennes, a French PUUV endemic area. We inferred demographic features such as population size, isolation and migration with regard to landscape configuration. We next analysed the influence of M. glareolus population dynamics on PUUV spatial distribution. Our results revealed that the global metapopulation dynamics of bank voles were strongly shaped by landscape features, including suitable patch size and connectivity. Large effective size in forest might therefore contribute to the higher observed levels of PUUV prevalence. By contrast, populations from hedge networks highly suffered from genetic drift and appeared strongly isolated from all other populations. This might result in high probabilities of local extinction for both M. glareolus and PUUV. Besides, we detected signatures of asymmetric bank vole migration from forests to hedges. These movements were likely to sustain PUUV in fragmented landscapes. In conclusion, our study provided arguments in favour of source-sink dynamics shaping PUUV persistence and spread in heterogeneous, Western European temperate landscapes. It illustrated the potential contribution of landscape genetics to the understanding of the epidemiological processes occurring at this local scale. © 2011 Blackwell Publishing Ltd.

  2. Genetics Home Reference: celiac disease

    Science.gov (United States)

    ... do not have celiac disease . On average, a diagnosis of celiac disease is not made until 6 to 10 years ... and tissues and leads to the signs and symptoms of celiac disease . Almost all people with celiac disease have specific ...

  3. Genetics Home Reference: Alzheimer disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Alzheimer disease Alzheimer disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Alzheimer disease is a degenerative disease of the brain ...

  4. Comparative "Omics" of the Fusarium fujikuroi Species Complex Highlights Differences in Genetic Potential and Metabolite Synthesis

    NARCIS (Netherlands)

    Niehaus, E.-M.; Münsterkötter, M.; Proctor, R.H.; Brown, D.W.; Sharon, A.; Idan, Y.; Oren-Young, L.; Sieber, C.M.; Novák, O.; Pěnčík, A.; Tarkowská, D.; Hromadová, K.; Freeman, S.; Maymon, M.; Elazar, M.; Youssef, S.A.; El-Shabrawy, E.S.M.; Shalaby, A.B.A.; Houterman, P.; Brock, N.L.; Burkhardt, I.; Tsavkelova, E.A.; Dickschat, J.S.; Galuszka, P.; Güldener, U.; Tudzynski, B.

    2016-01-01

    Species of the Fusarium fujikuroi species complex (FFC) cause a wide spectrum of often devastating diseases on diverse agricultural crops, including coffee, fig, mango, maize, rice, and sugarcane. Although species within the FFC are difficult to distinguish by morphology, and their genes often share

  5. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

    NARCIS (Netherlands)

    Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H; Johnson, Andrew D; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B; Nolte, Ilja M; van der Most, Peter J; Wright, Alan F; Shuldiner, Alan R; Morrison, Alanna C; Hofman, Albert; Smith, Albert V; Dreisbach, Albert W; Franke, Andre; Uitterlinden, Andre G; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I; Ponte, Belen; Oostra, Ben A; Paulweber, Bernhard; Krämer, Bernhard K; Mitchell, Braxton D; Buckley, Brendan M; Peralta, Carmen A; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N; Shaffer, Christian M; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J; Holliday, Elizabeth G; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B; Navis, Gerjan J; Curhan, Gary C; Ehret, George B; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K; Kramer, Holly; Lin, Honghuang; Leach, I Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M; Kolcic, Ivana; Persico, Ivana; Jukema, J Wouter; Wilson, James F; Felix, Janine F; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M; Gaspoz, Jean-Michel; Smith, Jennifer A; Faul, Jessica D; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N; Attia, John; Whitfield, John B; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C; Karjalainen, Juha; Fernandes, Jyotika K; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L; Lohman, Kurt; Portas, Laura; Launer, Lenore J; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K; Sale, Michele M; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B; Ridker, Paul M; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H; Kovacs, Peter; Wild, Philipp S; Froguel, Philippe; Rettig, Rainer; Mägi, Reedik; Biffar, Reiner; Schmidt, Reinhold; Middelberg, Rita P S; Carroll, Robert J; Penninx, Brenda W; Scott, Rodney J; Katz, Ronit; Sedaghat, Sanaz; Wild, Sarah H; Kardia, Sharon L R; Ulivi, Sheila; Hwang, Shih-Jen; Enroth, Stefan; Kloiber, Stefan; Trompet, Stella; Stengel, Benedicte; Hancock, Stephen J; Turner, Stephen T; Rosas, Sylvia E; Stracke, Sylvia; Harris, Tamara B; Zeller, Tanja; Zemunik, Tatijana; Lehtimäki, Terho; Illig, Thomas; Aspelund, Thor; Nikopensius, Tiit; Esko, Tonu; Tanaka, Toshiko; Gyllensten, Ulf; Völker, Uwe; Emilsson, Valur; Vitart, Veronique; Aalto, Ville; Gudnason, Vilmundur; Chouraki, Vincent; Chen, Wei-Min; Igl, Wilmar; März, Winfried; Koenig, Wolfgang; Lieb, Wolfgang; Loos, Ruth J F; Liu, Yongmei; Snieder, Harold; Pramstaller, Peter P; Parsa, Afshin; O'Connell, Jeffrey R; Susztak, Katalin; Hamet, Pavel; Tremblay, Johanne; de Boer, Ian H; Böger, Carsten A; Goessling, Wolfram; Chasman, Daniel I; Köttgen, Anna; Kao, W H Linda; Fox, Caroline S; van der Schouw, YT; Bots, Michael L; Grobbee, Diederick E; Moret, N. Charlotte

    2016-01-01

    Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication

  6. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    Science.gov (United States)

    Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W.H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; zu Schwabedissen, Henriette Meyer; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; consortium, HRGEN; den Hoed, Marcel; Loos, Ruth J.F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A.M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; Fabiola Del, Greco M.; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C.M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Leach, Irene Mateo; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C.M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R.P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I.W.; Newton-Cheh, Christopher

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD. PMID:24952745

  7. Genetics Home Reference: Parkinson disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Parkinson disease Parkinson disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Parkinson disease is a progressive disorder of the nervous ...

  8. Genetics Home Reference: Cole disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Cole disease Cole disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Cole disease is a disorder that affects the skin. People ...

  9. Genetics Home Reference: Fabry disease

    Science.gov (United States)

    ... Stroke: Fabry's Disease Information Page National Institute of Neurological Disorders and Stroke: Lipid Storage Diseases Fact Sheet Educational Resources (8 links) Children Living With Inherited Metabolic Diseases (CLIMB) (UK): Fabry ...

  10. Genetics Home Reference: Norrie disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Norrie disease Norrie disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Norrie disease is an inherited eye disorder that leads to ...

  11. Genetics Home Reference: Graves disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Graves disease Graves disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Graves disease is a condition that affects the function of ...

  12. Genetics Home Reference: Hirschsprung disease

    Science.gov (United States)

    ... occur in combination with other conditions, such as Waardenburg syndrome , type IV; Mowat-Wilson syndrome ; or congenital central ... Disease MalaCards: hirschsprung disease 1 Orphanet: Hirschsprung disease Patient Support and Advocacy Resources (4 links) Bowel Group ...

  13. Advances in genetic detection of kidney disease

    International Nuclear Information System (INIS)

    Dosekun, Akinsan K.; Foringer, John R.; Kone, Bruce C.

    2003-01-01

    The Human Genome Project has provided a vast amount of molecular genetic information for the analysis of normal and diseased genes. This new information provides new opportunities for precise diagnosis, assessment of predisposition and risk factors and novel therapeutic strategies. At the same time, this constantly expanding knowledge base represents on e of the most difficult challenges in molecular medicine. For monogenic disease nearly 2000 human disease genes have thus for been identified. Most of these conditions are characterized by large mutational variation and even greater phenotypic variation. In nephrology, several genetic diseases have been elucidated that provide new insight into the structure, function and developmental biology of the glomerulus, tubules and urogenital tracts, as well as renal cell tumors. Great improvements in the diagnostic resolution of genetic diseases have been achieved, such that single base pair mutations can be readily detected. Because of accurate diagnosis and risk assessment, genetic testing may be valuable in improving disease management and preventive care when genotype-specific therapies are available. Moreover, such testing may identify de novo mutations and potentially aid in understanding the disease process. This review summarizes recent advances in the renal genetic database and methods for genetic testing of renal diseases. (author)

  14. Current Evidence and Insights about Genetics in Thoracic Aorta Disease

    Science.gov (United States)

    Muneretto, Claudio

    2013-01-01

    Thoracic aortic aneurysms have been historically considered to be caused by etiologic factors similar to those implied in abdominal aortic aneurysms. However, during the past decade, there has been increasing evidence that almost 20% of thoracic aortic aneurysms may be associated with a genetic disease, often within a syndromic or familial disorder. Moreover, the presence of congenital anomalies, such as bicuspid aortic valve, may have a unique common genetic underlying cause. Finally, also sporadic forms have been found to be potentially associated with genetic disorders, as highlighted by the analysis of rare variants and expression of specific microRNAs. We therefore sought to perform a comprehensive review of the role of genetic causes in the development of thoracic aortic aneurysms, by analyzing in detail the current evidence of genetic alterations in syndromes such as Marfan, Loeys-Dietz, and Ehler-Danlos, familial or sporadic forms, or forms associated with bicuspid aortic valve. PMID:24453931

  15. [The genetics of collagen diseases].

    Science.gov (United States)

    Kaplan, J; Maroteaux, P; Frezal, J

    1986-01-01

    Heritable disorders of collagen include Ehler-Danlos syndromes (11 types are actually known), Larsen syndrome and osteogenesis imperfecta. Their clinical, genetic and biochemical features are reviewed. Marfan syndrome is closely related to heritable disorders of collagen.

  16. Preimplantation diagnosis of genetic diseases

    Directory of Open Access Journals (Sweden)

    Adiga S

    2010-01-01

    Full Text Available One of the landmarks in clinical genetics is prenatal diagnosis of genetic disorders. The recent advances in the field have made it possible to diagnose the genetic conditions in the embryos before implantation in a setting of in vitro fertilization. Polymerase chain reaction and fluorescence in situ hybridization are the two common techniques employed on a single or two cells obtained via embryo biopsy. The couple who seek in vitro fertilization may screen their embryos for aneuploidy and the couple at risk for a monogenic disorder but averse to abortion of the affected fetuses after prenatal diagnosis, are likely to be the best candidates to undergo this procedure. This article reviews the technique, indications, benefits, and limitations of pre-implantation genetic testing in clinical practice.

  17. Genetics, Disease Prevention and Treatment

    Science.gov (United States)

    ... Care Genomic Medicine Working Group New Horizons and Research Patient Management Policy and Ethics Issues Quick Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for ...

  18. Genetically Determined Height and Coronary Artery Disease

    NARCIS (Netherlands)

    Nelson, Christopher P.; Hamby, Stephen E.; Saleheen, Danish; Hopewell, Jenna C.; Zeng, Lingyao; Assimes, Themistocles L.; Kanoni, Stavroula; Willenborg, Christina; Burgess, Stephen; Amouyel, Phillipe; Anand, Sonia; Blankenberg, Stefan; Boehm, Bernhard O.; Clarke, Robert J.; Collins, Rory; Dedoussis, George; Farrall, Martin; Franks, Paul W.; Groop, Leif; Hall, Alistair S.; Hamsten, Anders; Hengstenberg, Christian; Hovingh, G. Kees; Ingelsson, Erik; Kathiresan, Sekar; Kee, Frank; König, Inke R.; Kooner, Jaspal; Lehtimäki, Terho; März, Winifred; McPherson, Ruth; Metspalu, Andres; Nieminen, Markku S.; O'Donnell, Christopher J.; Palmer, Colin N. A.; Peters, Annette; Perola, Markus; Reilly, Muredach P.; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Shah, Svati H.; Schreiber, Stefan; Siegbahn, Agneta; Thorsteinsdottir, Unnur; Veronesi, Giovani; Wareham, Nicholas; Willer, Cristen J.; Zalloua, Pierre A.; Erdmann, Jeanette

    2015-01-01

    BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested

  19. Genetics Home Reference: Paget disease of bone

    Science.gov (United States)

    ... is most common in people of western European heritage. Early-onset Paget disease of bone is much rarer. This form of the disorder has been reported in only a few families. Related Information What information about a genetic condition can statistics provide? Why are some genetic ...

  20. Genetics of Dyslipidemia and Ischemic Heart Disease.

    Science.gov (United States)

    Sharma, Kavita; Baliga, Ragavendra R

    2017-05-01

    Genetic dyslipidemias contribute to the prevalence of ischemic heart disease. The field of genetic dyslipidemias and their influence on atherosclerotic heart disease is rapidly developing and accumulating increasing evidence. The purpose of this review is to describe the current state of knowledge in regard to inherited atherogenic dyslipidemias. The disorders of familial hypercholesterolemia (FH) and elevated lipoprotein(a) will be detailed. Genetic technology has made rapid advancements, leading to new discoveries in inherited atherogenic dyslipidemias, which will be explored in this review, as well as a description of possible future developments. Increasing attention has come upon the genetic disorders of familial hypercholesterolemia and elevated lipoprotein(a). This review includes new knowledge of these disorders including description of these disorders, their method of diagnosis, their prevalence, their genetic underpinnings, and their effect on the development of cardiovascular disease. In addition, it discusses major advances in genetic technology, including the completion of the human genome sequence, next-generation sequencing, and genome-wide association studies. Also discussed are rare variant studies with specific genetic mechanisms involved in inherited dyslipidemias, such as in the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme. The field of genetics of dyslipidemia and cardiovascular disease is rapidly growing, which will result in a bright future of novel mechanisms of action and new therapeutics.

  1. The genetic basis of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    A. A. Tappakhov

    2017-01-01

    Full Text Available Parkinson's disease (PD is a multifactorial disease that develops in the presence of both genetic and environmental factors. In recent years, there has been sufficient information on the role of genetic predisposition in the development of not only familial cases, but also sporadic ones. A hereditary burden in PD may not be traced in cases of recessive inheritance with a low gene penetrance, as well as in a patient's death before the onset of the disease. Active introduction of molecular genetic methods, including next generation sequencing, can annually identify new gene mutations that underlie sporadic PD cases. This paper provides an overview of the current literature on the genetic aspects of PD with emphasis on the ethnic characteristics of the disease.

  2. Animal models for human genetic diseases

    African Journals Online (AJOL)

    Sharif Sons

    The study of human genetic diseases can be greatly aided by animal models because of their similarity .... and gene targeting in embryonic stem cells) has been a powerful tool in .... endonucleases that are designed to make a doublestrand.

  3. Congenital and Genetic Disease in Domestic Animals

    Science.gov (United States)

    Mulvihill, John J.

    1972-01-01

    Reviews observations on domestic animals that have led to the identification of environmental teratogens, and have provided insight into the pathogenesis of congenital defects and genetic diseases in man." (Author/AL)

  4. Advances in the genetically complex autoinflammatory diseases.

    Science.gov (United States)

    Ombrello, Michael J

    2015-07-01

    Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Behçet's disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases-namely, the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically complex autoinflammatory phenotypes.

  5. Genetics Home Reference: moyamoya disease

    Science.gov (United States)

    ... as neurofibromatosis type 1 , sickle cell disease , or Graves disease . These individuals are said to have moyamoya syndrome. ... altered gene in each cell is sufficient to cause the disorder. However, some people who have a ...

  6. Genetics Home Reference: prion disease

    Science.gov (United States)

    ... which have overlapping signs and symptoms, include familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal ... Sc . Sporadic forms of prion disease include sporadic Creutzfeldt-Jakob disease (sCJD), sporadic fatal insomnia (sFI), and variably protease- ...

  7. Genetic Modifiers of Sickle Cell Disease

    Science.gov (United States)

    Steinberg, Martin H.; Sebastiani, Paola

    2015-01-01

    Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ∝ thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new “druggable” pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease. PMID:22641398

  8. Role of genetic in periodontal disease

    Directory of Open Access Journals (Sweden)

    Anand Narayanrao Wankhede

    2017-01-01

    Full Text Available Genetics is the study and understanding of the phenomena of heredity and variation. A large number of genes are associated with many systemic conditions. Periodontitis is inflammatory condition of periodontium. Periodontium consists of gingiva, periodontal ligament, cementum, and alveolar bone. It is considered being a multifactorial disease. Studies of animals and humans support the concept that a large number of genes' factor may be associated with periodontitis and clearly play a role in the predisposition and progression of periodontal diseases. It has been proven that genetic factors impair inflammatory and immune responses during periodontal diseases. Research on identifying specific genes causing periodontitis may improve and prevent the disease progression. The aim of this article is to focus on genetic risk factors and its influence for the various forms of periodontal disease.

  9. Genetics Home Reference: Schindler disease

    Science.gov (United States)

    ... childhood, with some features of autism spectrum disorders. Autism spectrum disorders are characterized by impaired communication and socialization skills. Related Information What does it mean if a disorder seems to run in my family? What is the prognosis of a genetic condition? ...

  10. Genetics Home Reference: autoimmune Addison disease

    Science.gov (United States)

    ... common in particular ethnic groups? Genetic Changes The cause of autoimmune Addison disease is complex and not completely understood. A combination ... is not caused by an autoimmune reaction. Other causes include infections that ... adrenal glands. Addison disease can also be one of several features of ...

  11. Parkinson's disease: piecing together a genetic jigsaw.

    NARCIS (Netherlands)

    M.C.J. Dekker (Marieke); V. Bonifati (Vincenzo); C.M. van Duijn (Cornelia)

    2003-01-01

    textabstractThe role of genetics in the pathogenesis of Parkinson's disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important insight into its molecular aetiology. Some Parkinson's disease genes possibly cause

  12. Genetics Home Reference: Sandhoff disease

    Science.gov (United States)

    ... Cooper A, Ferrie CD. Juvenile Sandhoff disease--nine new cases and a review of the literature. J Inherit Metab Dis. 2004;27(2):241-9. Review. Citation on PubMed Tay SK, Low PS, Ong HT, Loke KY. Sandhoff disease--a case report of 3 siblings and a review of potential therapies. Ann Acad ...

  13. Genetics Home Reference: Tangier disease

    Science.gov (United States)

    ... Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature. 2005 Dec 1;438(7068):612-21. ... Hubácek JA. ATP-binding cassette (ABC) transporters in human metabolism and diseases. Physiol Res. 2004;53(3):235-43. Review. ...

  14. Genetics Home Reference: Dent disease

    Science.gov (United States)

    ... body effectively. Some people with Dent disease develop rickets , a bone disorder that results when the levels ... including calcium) in the blood become too low. Rickets can be associated with weakening and softening of ...

  15. Genetics Home Reference: Caffey disease

    Science.gov (United States)

    ... Mundlos S, Sillence D, Ala Kokko L, Seidman JG, Cole WG, Jüppner H. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J ...

  16. Genetics Home Reference: Refsum disease

    Science.gov (United States)

    ... disease is caused by an eye disorder called retinitis pigmentosa . This disorder affects the retina , the light-sensitive ... the retina gradually deteriorate. The first sign of retinitis pigmentosa is usually a loss of night vision, which ...

  17. Genetics Home Reference: Kawasaki disease

    Science.gov (United States)

    ... how do mutations occur? How can gene mutations affect health and development? More about ... but the inheritance pattern is unknown. Children of parents who have had Kawasaki disease have twice the ...

  18. Genetic risks for cardiovascular diseases

    NARCIS (Netherlands)

    Zafarmand, M.H.

    2008-01-01

    Atherosclerotic cardiovascular disease (CVD), which involves the heart, brain, and peripheral circulation, is a major health problem world-wide. The development of atherosclerosis is a complex process, and several established risk factors are involved. Nevertheless, these established risk factors

  19. Genetics Home Reference: Darier disease

    Science.gov (United States)

    ... when they are exposed to heat and humidity. UV light; minor injury or friction, such as rubbing or ... the social stigma experienced by people with numerous skin blemishes. A form of Darier disease known as ...

  20. Genetic influences in caries and periodontal diseases.

    Science.gov (United States)

    Hassell, T M; Harris, E L

    1995-01-01

    Deciphering the relative roles of heredity and environmental factors ("nature vs. nurture") in the pathogenesis of dental caries and diseases of the periodontium has occupied clinical and basic researchers for decades. Success in the endeavor has come more easily in the case of caries; the complex interactions that occur between host-response mechanisms and putative microbiologic pathogens in periodontal disease have made elucidation of genetic factors in disease susceptibility more difficult. In addition, during the 30-year period between 1958 and 1987, only meager resources were targeted toward the "nature" side of the nature/nurture dipole in periodontology. In this article, we present a brief history of the development of genetic epistemology, then describe the three main research mechanisms by which questions about the hereditary component of diseases in humans can be addressed. A critical discussion of the evidence for a hereditary component in caries susceptibility is next presented, also from a historical perspective. The evolution of knowledge concerning possible genetic ("endogenous", "idiotypic") factors in the pathogenesis of inflammatory periodontal disease is initiated with an analysis of some foreign-language (primarily German) literature that is likely to be unfamiliar to the reader. We identify a turning point at about 1960, when the periodontal research community turned away from genetics in favor of microbiology research. During the past five years, investigators have re-initiated the search for the hereditary component in susceptibility to common adult periodontal disease; this small but growing body of literature is reviewed. Recent applications of in vitro methods for genetic analyses in periodontal research are presented, with an eye toward a future in which persons who are at risk--genetically predisposed--to periodontal disease may be identified and targeted for interventive strategies. Critical is the realization that genes and environment

  1. The expanding universe of inflammatory bowel disease genetics.

    Science.gov (United States)

    Achkar, Jean-Paul; Duerr, Richard

    2008-07-01

    Genetic factors play an important role in the pathogenesis of inflammatory bowel disease. In this review, we will provide an update on the rapid advances in the discovery of inflammatory bowel disease, primarily Crohn's disease, associated genes. Seven recently published Crohn's disease genome-wide association studies have confirmed prior findings related to the nucleotide-binding oligomerization domain 2 (NOD2) gene and the IBD5 locus. In addition, 10 novel loci have been identified and well replicated. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal microflora in the pathogenesis of inflammatory bowel disease.

  2. The Molecular Genetics of von Willebrand Disease

    Directory of Open Access Journals (Sweden)

    Ergül Berber

    2012-12-01

    Full Text Available Quantitative and/or qualitative deficiency of von Willebrand factor (vWF is associated with the most common inherited bleeding disease von Willebrand disease (vWD. vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.

  3. The molecular genetics of von Willebrand disease.

    Science.gov (United States)

    Berber, Ergül

    2012-12-01

    Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

  4. Disease modeling in genetic kidney diseases: zebrafish.

    Science.gov (United States)

    Schenk, Heiko; Müller-Deile, Janina; Kinast, Mark; Schiffer, Mario

    2017-07-01

    Growing numbers of translational genomics studies are based on the highly efficient and versatile zebrafish (Danio rerio) vertebrate model. The increasing types of zebrafish models have improved our understanding of inherited kidney diseases, since they not only display pathophysiological changes but also give us the opportunity to develop and test novel treatment options in a high-throughput manner. New paradigms in inherited kidney diseases have been developed on the basis of the distinct genome conservation of approximately 70 % between zebrafish and humans in terms of existing gene orthologs. Several options are available to determine the functional role of a specific gene or gene sets. Permanent genome editing can be induced via complete gene knockout by using the CRISPR/Cas-system, among others, or via transient modification by using various morpholino techniques. Cross-species rescues succeeding knockdown techniques are employed to determine the functional significance of a target gene or a specific mutation. This article summarizes the current techniques and discusses their perspectives.

  5. Chronic obstructive pulmonary disease and genetics

    DEFF Research Database (Denmark)

    Ingebrigtsen, T.; Thomsen, S.F.; Vestbo, J.

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation and is associated with an inflammatory response of the lungs primarily caused by cigarette smoking. Cigarette smoking is by far the most important environmental risk factor for COPD, but less than half of all heavy...... smokers develop COPD. This indicates a genetic contribution to the individual disease susceptibility. Although many genes have been examined, the puzzle of COPD genetics seems still largely unsolved. It is therefore important to measure phenotypes and to perform genome-wide scans of COPD patients in order...

  6. Preimplantation Genetic Diagnosis for Stargardt Disease

    Science.gov (United States)

    Sohrab, Mahsa A.; Allikmets, Rando; Guarnaccia, Michael M.; Smith, R. Theodore

    2010-01-01

    Purpose To report the first use of in vitro fertilization (IVF) and preimplantation genetic diagnosis to achieve an unaffected pregnancy in an autosomal-recessive retinal dystrophy. Design Case report. Methods An affected male with Stargardt disease and his carrier wife underwent IVF. Embryos obtained by intracytoplasmic sperm injection underwent single-cell DNA testing via polymerase chain reaction and restriction enzyme analysis to detect the presence of ABCA4 mutant alleles. Embryos were diagnosed as being either affected by or carriers for Stargardt disease. A single carrier embryo was implanted. Results Chorionic villus sampling performed during the first trimester verified that the fetus possessed only one mutant paternal allele and one normal maternal allele, thus making her an unaffected carrier of the disease. A healthy, live-born female was delivered. Conclusion IVF and preimplantation genetic diagnosis can assist couples with an affected spouse and a carrier spouse with recessive retinal dystrophies to have an unaffected child. PMID:20149343

  7. Biomarkers and Genetics in Peripheral Artery Disease.

    Science.gov (United States)

    Hazarika, Surovi; Annex, Brian H

    2017-01-01

    Peripheral artery disease (PAD) is highly prevalent and there is considerable diversity in the initial clinical manifestation and disease progression among individuals. Currently, there is no ideal biomarker to screen for PAD, to risk stratify patients with PAD, or to monitor therapeutic response to revascularization procedures. Advances in human genetics have markedly enhanced the ability to develop novel diagnostic and therapeutic approaches across a host of human diseases, but such developments in the field of PAD are lagging. In this article, we will discuss the epidemiology, traditional risk factors for, and clinical presentations of PAD. We will discuss the possible role of genetic factors and gene-environment interactions in the development and/or progression of PAD. We will further explore future avenues through which genetic advances can be used to better our understanding of the pathophysiology of PAD and potentially find newer therapeutic targets. We will discuss the potential role of biomarkers in identifying patients at risk for PAD and for risk stratifying patients with PAD, and novel approaches to identification of reliable biomarkers in PAD. The exponential growth of genetic tools and newer technologies provides opportunities to investigate and identify newer pathways in the development and progression of PAD, and thereby in the identification of newer biomarkers and therapies. © 2016 American Association for Clinical Chemistry.

  8. Genetics Home Reference: non-alcoholic fatty liver disease

    Science.gov (United States)

    ... individual is considered to have a fatty liver (hepatic steatosis) if the liver contains more than 5 to ... Resources Genetic Testing (2 links) Genetic Testing Registry: Fatty liver disease, nonalcoholic 1 Genetic Testing Registry: Fatty liver ...

  9. Genetic dysbiosis: the role of microbial insults in chronic inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Luigi Nibali

    2014-02-01

    Full Text Available Thousands of bacterial phylotypes colonise the human body and the host response to this bacterial challenge greatly influences our state of health or disease. The concept of infectogenomics highlights the importance of host genetic factors in determining the composition of human microbial biofilms and the response to this microbial challenge. We hereby introduce the term ‘genetic dysbiosis’ to highlight the role of human genetic variants affecting microbial recognition and host response in creating an environment conducive to changes in the normal microbiota. Such changes can, in turn, predispose to, and influence, diseases such as: cancer, inflammatory bowel disease, rheumatoid arthritis, psoriasis, bacterial vaginosis and periodontitis. This review presents the state of the evidence on host genetic factors affecting dysbiosis and microbial misrecognition (i.e. an aberrant response to the normal microbiota and highlights the need for further research in this area.

  10. New Genetic Insights from Autoimmune Thyroid Disease

    Directory of Open Access Journals (Sweden)

    Terry F. Davies

    2012-01-01

    Full Text Available The autoimmune thyroid diseases (AITDs (Graves’ disease and Hashimoto’s thyroiditis are complex genetic diseases which most likely have more than 20 genes contributing to the clinical phenotypes. To date, the genes known to be contributing fall into two categories: immune regulatory genes (including HLA, CTLA4, PTPN22, CD40, CD25, and FCRL3 and thyroid-specific genes (TG and TSHR. However, none of these genes contribute more than a 4-fold increase in risk of developing one of these diseases, and none of the polymorphisms discovered is essential for disease development. Hence, it appears that a variety of different gene interactions can combine to cause the same clinical disease pattern, but the contributing genes may differ from patient to patient and from population to population. Furthermore, this possible mechanism leaves open the powerful influence of the environment and epigenetic modifications of gene expression. For the clinician, this means that genetic profiling of such patients is unlikely to be fruitful in the near future.

  11. Comparison of koala LPCoLN and human strains of Chlamydia pneumoniae highlights extended genetic diversity in the species

    Directory of Open Access Journals (Sweden)

    Carrasco Jose A

    2010-07-01

    Full Text Available Abstract Background Chlamydia pneumoniae is a widespread pathogen causing upper and lower respiratory tract infections in addition to a range of other diseases in humans and animals. Previous whole genome analyses have focused on four essentially clonal (> 99% identity C. pneumoniae human genomes (AR39, CWL029, J138 and TW183, providing relatively little insight into strain diversity and evolution of this species. Results We performed individual gene-by-gene comparisons of the recently sequenced C. pneumoniae koala genome and four C. pneumoniae human genomes to identify species-specific genes, and more importantly, to gain an insight into the genetic diversity and evolution of the species. We selected genes dispersed throughout the chromosome, representing genes that were specific to C. pneumoniae, genes with a demonstrated role in chlamydial biology and/or pathogenicity (n = 49, genes encoding nucleotide salvage or amino acid biosynthesis proteins (n = 6, and extrachromosomal elements (9 plasmid and 2 bacteriophage genes. Conclusions We have identified strain-specific differences and targets for detection of C. pneumoniae isolates from both human and animal origin. Such characterisation is necessary for an improved understanding of disease transmission and intervention.

  12. Comparison of koala LPCoLN and human strains of Chlamydia pneumoniae highlights extended genetic diversity in the species.

    Science.gov (United States)

    Mitchell, Candice M; Hovis, Kelley M; Bavoil, Patrik M; Myers, Garry S A; Carrasco, Jose A; Timms, Peter

    2010-07-21

    Chlamydia pneumoniae is a widespread pathogen causing upper and lower respiratory tract infections in addition to a range of other diseases in humans and animals. Previous whole genome analyses have focused on four essentially clonal (> 99% identity) C. pneumoniae human genomes (AR39, CWL029, J138 and TW183), providing relatively little insight into strain diversity and evolution of this species. We performed individual gene-by-gene comparisons of the recently sequenced C. pneumoniae koala genome and four C. pneumoniae human genomes to identify species-specific genes, and more importantly, to gain an insight into the genetic diversity and evolution of the species. We selected genes dispersed throughout the chromosome, representing genes that were specific to C. pneumoniae, genes with a demonstrated role in chlamydial biology and/or pathogenicity (n = 49), genes encoding nucleotide salvage or amino acid biosynthesis proteins (n = 6), and extrachromosomal elements (9 plasmid and 2 bacteriophage genes). We have identified strain-specific differences and targets for detection of C. pneumoniae isolates from both human and animal origin. Such characterisation is necessary for an improved understanding of disease transmission and intervention.

  13. Infectious diseases: Surveillance, genetic modification and simulation

    Science.gov (United States)

    Koh, H. L.; Teh, S.Y.; De Angelis, D. L.; Jiang, J.

    2011-01-01

    Infectious diseases such as influenza and dengue have the potential of becoming a worldwide pandemic that may exert immense pressures on existing medical infrastructures. Careful surveillance of these diseases, supported by consistent model simulations, provides a means for tracking the disease evolution. The integrated surveillance and simulation program is essential in devising effective early warning systems and in implementing efficient emergency preparedness and control measures. This paper presents a summary of simulation analysis on influenza A (H1N1) 2009 in Malaysia. This simulation analysis provides insightful lessons regarding how disease surveillance and simulation should be performed in the future. This paper briefly discusses the controversy over the experimental field release of genetically modified (GM) Aedes aegypti mosquito in Malaysia. Model simulations indicate that the proposed release of GM mosquitoes is neither a viable nor a sustainable control strategy. ?? 2011 WIT Press.

  14. Unifying diseases from a genetic point of view: the example of the genetic theory of infectious diseases.

    Science.gov (United States)

    Darrason, Marie

    2013-08-01

    In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call "a regional genetic theory." I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease.

  15. Interpreting predictive maps of disease: highlighting the pitfalls of distribution models in epidemiology

    Directory of Open Access Journals (Sweden)

    Nicola A. Wardrop

    2014-11-01

    Full Text Available The application of spatial modelling to epidemiology has increased significantly over the past decade, delivering enhanced understanding of the environmental and climatic factors affecting disease distributions and providing spatially continuous representations of disease risk (predictive maps. These outputs provide significant information for disease control programmes, allowing spatial targeting and tailored interventions. However, several factors (e.g. sampling protocols or temporal disease spread can influence predictive mapping outputs. This paper proposes a conceptual framework which defines several scenarios and their potential impact on resulting predictive outputs, using simulated data to provide an exemplar. It is vital that researchers recognise these scenarios and their influence on predictive models and their outputs, as a failure to do so may lead to inaccurate interpretation of predictive maps. As long as these considerations are kept in mind, predictive mapping will continue to contribute significantly to epidemiological research and disease control planning.

  16. Research highlights from the 2017 ERS International Congress: airway diseases in focus

    Directory of Open Access Journals (Sweden)

    Cecilia Andersson

    2018-03-01

    Full Text Available For another year, high-quality research studies from around the world transformed the annual ERS International Congress into a vivid platform to discuss trending research topics, to produce new research questions and to further push the boundaries of respiratory medicine and science. This article reviews only some of the high-quality research studies on asthma, chronic obstructive pulmonary disease (COPD, bronchiectasis and chronic cough that were presented during the congress through the Airway Diseases Assembly (ERS Assembly 5 and places them into the context of current knowledge and research challenges.

  17. [Coronary heart disease: epidemiologic-genetic aspects].

    Science.gov (United States)

    Epstein, F H

    1985-01-01

    Coronary heart disease and the risk factors which predispose to it aggregate in families. How much of this clustering of disease is "explained" by the familial resemblance in predisposing factors? The published reports which bear on this question fall into six distinct study designs: prospective studies, persons at high or low risk or persons with and without a positive family history as points of departure, case-control studies, studies of patients who had a coronary angiogram and studies in different ethnic groups. The findings of the 16 investigations reviewed suggest that there are as yet unidentified factors - genetic, environmental or both - which are responsible for familial clustering of coronary heart disease, apart from the three main risk factors (serum lipids, blood pressure, smoking) and diabetes. Future research must put greater emphasis on studies of families rather than individuals and on closer collaboration between epidemiologists and geneticists, in order to fill these gaps in knowledge. It is likely that the individual predisposition to coronary heart disease is due in part to genetic influences which remain to be discovered in the course of such studies. They would help in identifying susceptible person in the population with greater precision than is now possible. The "high-risk strategy" of coronary heart disease prevention will become more efficient as more specific and sensitive tests of disease prediction are developed. In the meantime, preventive programmes must be put into action on the basis of what is already known, on the level of both the high-risk and the community-wide mass strategy.

  18. Forum on Emerging Infectious Diseases Highlights Leading-Edge Research | Poster

    Science.gov (United States)

    Scientists and professionals from multiple governmental agencies recently gathered at NCI at Frederick for a forum on newly emerging infectious diseases, threats to public health, and ongoing efforts to study high-risk pathogens. During the one-day event, which was sponsored by the National Interagency Confederation for Biological Research’s Scientific Interaction

  19. Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer's disease.

    Science.gov (United States)

    Alkallas, Rached; Fish, Lisa; Goodarzi, Hani; Najafabadi, Hamed S

    2017-10-13

    The abundance of mRNA is mainly determined by the rates of RNA transcription and decay. Here, we present a method for unbiased estimation of differential mRNA decay rate from RNA-sequencing data by modeling the kinetics of mRNA metabolism. We show that in all primary human tissues tested, and particularly in the central nervous system, many pathways are regulated at the mRNA stability level. We present a parsimonious regulatory model consisting of two RNA-binding proteins and four microRNAs that modulate the mRNA stability landscape of the brain, which suggests a new link between RBFOX proteins and Alzheimer's disease. We show that downregulation of RBFOX1 leads to destabilization of mRNAs encoding for synaptic transmission proteins, which may contribute to the loss of synaptic function in Alzheimer's disease. RBFOX1 downregulation is more likely to occur in older and female individuals, consistent with the association of Alzheimer's disease with age and gender."mRNA abundance is determined by the rates of transcription and decay. Here, the authors propose a method for estimating the rate of differential mRNA decay from RNA-seq data and model mRNA stability in the brain, suggesting a link between mRNA stability and Alzheimer's disease."

  20. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

    DEFF Research Database (Denmark)

    Howson, Joanna M. M.; Zhao, Wei; Barnes, Daniel R

    2017-01-01

    Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy ...

  1. Endocrine autoimmune disease: genetics become complex.

    Science.gov (United States)

    Wiebolt, Janneke; Koeleman, Bobby P C; van Haeften, Timon W

    2010-12-01

    The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

  2. Shared genetic contribution to ischemic stroke and Alzheimer's disease

    Science.gov (United States)

    Adib‐Samii, Poneh; Harold, Denise; Dichgans, Martin; Williams, Julie; Lewis, Cathryn M.; Markus, Hugh S.; Fornage, Myriam; Holliday, Elizabeth G; Sharma, Pankaj; Bis, Joshua C; Psaty, Bruce M; Seshadri, Sudha; Nalls, Mike A; Devan, William J; Boncoraglio, Giorgio; Malik, Rainer; Mitchell, Braxton D; Kittner, Steven J; Ikram, M Arfan; Clarke, Robert; Rosand, Jonathan; Meschia, James F; Sudlow, Cathie; Rothwell, Peter M; Levi, Christopher; Bevan, Steve; Kilarski, Laura L; Walters, Matthew; Thijs, Vincent; Slowik, Agnieszka; Lindgren, Arne; de Bakker, Paul I W; Lambert, Jean‐Charles; Ibrahim‐Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier‐Boley, Benjamin; Russo, Giancarlo; Thornton‐Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao‐Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie‐Thçrèse; Choi, Seung‐Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiçvet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger‐Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George‐Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez‐Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton‐Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O'Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li‐San; Dartigues, Jean‐François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak‐Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

    2016-01-01

    Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747 PMID:26913989

  3. The Collaborative Cross Resource for Systems Genetics Research of Infectious Diseases.

    Science.gov (United States)

    Maurizio, Paul L; Ferris, Martin T

    2017-01-01

    An increasing body of evidence highlights the role of host genetic variation in driving susceptibility to severe disease following pathogen infection. In order to fully appreciate the importance of host genetics on infection susceptibility and resulting disease, genetically variable experimental model systems should be employed. These systems allow for the identification, characterization, and mechanistic dissection of genetic variants that cause differential disease responses. Herein we discuss application of the Collaborative Cross (CC) panel of recombinant inbred strains to study viral pathogenesis, focusing on practical considerations for experimental design, assessment and analysis of disease responses within the CC, as well as some of the resources developed for the CC. Although the focus of this chapter is on viral pathogenesis, many of the methods presented within are applicable to studies of other pathogens, as well as to case-control designs in genetically diverse populations.

  4. Fifteen new risk loci for coronary artery disease highlight arterial wall-specific mechanisms

    OpenAIRE

    Howson, Joanna M.M.; Zhao, Wei; Barnes, Daniel R.; Ho, Weang-Kee; Young, Robin; Paul, Dirk S.; Waite, Lindsay L.; Freitag, Daniel F.; Fauman, Eric B.; Salfati, Elias L.; Sun, Benjamin B.; Eicher, John D.; Johnson, Andrew D.; Sheu, Wayne H.H.; Nielsen, Sune F.

    2017-01-01

    Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier G...

  5. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

    OpenAIRE

    Howson, Joanna McCammond; Zhao, W; Barnes, Daniel Robert; Ho, W-K; Young, R; Paul, Dirk Stefan; Waite, LL; Freitag, DF; Fauman, EB; Salfati, EL; Sun, Benjamin; Eicher, JD; Johnson, AD; Sheu, WHH; Nielsen, SF

    2017-01-01

    Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier G...

  6. Forum on Emerging Infectious Diseases Highlights Leading-Edge Research | Poster

    Science.gov (United States)

    Scientists and professionals from multiple governmental agencies recently gathered at NCI at Frederick for a forum on newly emerging infectious diseases, threats to public health, and ongoing efforts to study high-risk pathogens. During the one-day event, which was sponsored by the National Interagency Confederation for Biological Research’s Scientific Interaction Subcommittee, nine speakers from four agencies shared their research and their agencies’ endeavors to address current and future biological threats.

  7. The rapid evolution of molecular genetic diagnostics in neuromuscular diseases.

    Science.gov (United States)

    Volk, Alexander E; Kubisch, Christian

    2017-10-01

    The development of massively parallel sequencing (MPS) has revolutionized molecular genetic diagnostics in monogenic disorders. The present review gives a brief overview of different MPS-based approaches used in clinical diagnostics of neuromuscular disorders (NMDs) and highlights their advantages and limitations. MPS-based approaches like gene panel sequencing, (whole) exome sequencing, (whole) genome sequencing, and RNA sequencing have been used to identify the genetic cause in NMDs. Although gene panel sequencing has evolved as a standard test for heterogeneous diseases, it is still debated, mainly because of financial issues and unsolved problems of variant interpretation, whether genome sequencing (and to a lesser extent also exome sequencing) of single patients can already be regarded as routine diagnostics. However, it has been shown that the inclusion of parents and additional family members often leads to a substantial increase in the diagnostic yield in exome-wide/genome-wide MPS approaches. In addition, MPS-based RNA sequencing just enters the research and diagnostic scene. Next-generation sequencing increasingly enables the detection of the genetic cause in highly heterogeneous diseases like NMDs in an efficient and affordable way. Gene panel sequencing and family-based exome sequencing have been proven as potent and cost-efficient diagnostic tools. Although clinical validation and interpretation of genome sequencing is still challenging, diagnostic RNA sequencing represents a promising tool to bypass some hurdles of diagnostics using genomic DNA.

  8. Periodontal disease associated to systemic genetic disorders.

    Science.gov (United States)

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-05-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role of bacterial plaque is subject to debate. In the presence of qualitative or quantitative cellular immune alterations, periodontal disease may manifest early on a severe localized or generalized basis--in some cases related to the presence of plaque and/or specific bacteria (severe congenital neutropenia or infantile genetic agranulocytosis, Chediak-Higiashi syndrome, Down syndrome and Papillon-Lefévre syndrome). In the presence of humoral immune alterations, periodontal damage may result indirectly as a consequence of alterations in other systems. In connective tissue disorders, bacterial plaque and alterations of the periodontal tissues increase patient susceptibility to gingival inflammation and alveolar resorption (Marfan syndrome and Ehler-Danlos syndrome). The management of periodontal disease focuses on the control of infection and bacterial plaque by means of mechanical and chemical methods. Periodontal surgery and even extraction of the most seriously affected teeth have also been suggested. There are variable degrees of consensus regarding the background systemic disorder, as in the case of Chediak-Higiashi syndrome, where antibiotic treatment proves ineffective; in severe congenital neutropenia or infantile genetic agranulocytosis, where antibiotic prophylaxis is suggested; and in Papillon-Lefévre syndrome, where an established treatment protocol is available.

  9. Basement Membrane Defects in Genetic Kidney Diseases

    Directory of Open Access Journals (Sweden)

    Christine Chew

    2018-01-01

    Full Text Available The glomerular basement membrane (GBM is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1 and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes COL4A3, COL4A4, or COL4A5. Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell–matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease.

  10. Shared genetic origins of allergy and autoimmune diseases

    DEFF Research Database (Denmark)

    Waage, J. E.; Kreiner-Møller, E.; Standl, M.

    2015-01-01

    Parallel increases in allergy and autoimmune disease prevalence in recent time suggest shared, but yet unknown, etiologies. Here, we investigated shared genetic loci and molecular pathways to identify possible shared disease mechanisms between allergy and autoimmune diseases.......Parallel increases in allergy and autoimmune disease prevalence in recent time suggest shared, but yet unknown, etiologies. Here, we investigated shared genetic loci and molecular pathways to identify possible shared disease mechanisms between allergy and autoimmune diseases....

  11. Genetic testing and counselling in inherited eye disease

    DEFF Research Database (Denmark)

    Brøndum-Nielsen, Karen; Jensen, Hanne; Timshel, Susanne

    2013-01-01

    Advances in genetics have made genetic testing in patients with inherited eye disease increasingly accessible, and the initiation of clinical intervention trials makes it increasingly clinically relevant. Based on a multidisciplinary collaboration between ophthalmologists and clinical geneticists...

  12. Hope and major strides for genetic diseases of the eye

    Indian Academy of Sciences (India)

    2009-12-31

    Dec 31, 2009 ... genetic etiology of inherited eye diseases and their underly- ing pathophysiology in the ... recent advances in the field of ophthalmic genetics. There have been .... sible or unlikely to be developed in the near future. Many of.

  13. An atlas of genetic correlations across human diseases and traits

    DEFF Research Database (Denmark)

    Bulik-Sullivan, Brendan; Finucane, Hilary K; Anttila, Verneri

    2015-01-01

    Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are t...

  14. Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

    Science.gov (United States)

    Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

    2008-01-01

    The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

  15. Genetic and cellular studies highlight that A Disintegrin and Metalloproteinase 19 is a protective biomarker in human prostate cancer

    International Nuclear Information System (INIS)

    Hoyne, Gerard; Rudnicka, Caroline; Sang, Qing-Xiang; Roycik, Mark; Howarth, Sarah; Leedman, Peter; Schlaich, Markus; Candy, Patrick; Matthews, Vance

    2016-01-01

    Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Current treatments include surgery, androgen ablation and radiation. Introduction of more targeted therapies in prostate cancer, based on a detailed knowledge of the signalling pathways, aims to reduce side effects, leading to better clinical outcomes for the patient. ADAM19 (A Disintegrin And Metalloproteinase 19) is a transmembrane and soluble protein which can regulate cell phenotype through cell adhesion and proteolysis. ADAM19 has been positively associated with numerous diseases, but has not been shown to be a tumor suppressor in the pathogenesis of any human cancers. Our group sought to investigate the role of ADAM19 in human prostate cancer. ADAM19 mRNA and protein levels were assessed in well characterised human prostate cancer cohorts. ADAM19 expression was assessed in normal prostate epithelial cells (RWPE-1) and prostate cancer cells (LNCaP, PC3) using western blotting and immunocytochemistry. Proliferation assays were conducted in LNCaP cells in which ADAM19 was over-expressed. In vitro scratch assays were performed in PC3 cells over-expressing ADAM19. Immunohistochemical studies highlighted that ADAM19 protein levels were elevated in normal prostate tissue compared to prostate cancer biopsies. Results from the clinical cohorts demonstrated that high levels of ADAM19 in microarrays are positively associated with lower stage (p = 0.02591) and reduced relapse (p = 0.00277) of human prostate cancer. In vitro, ADAM19 expression was higher in RWPE-1 cells compared to LNCaP cells. In addition, human ADAM19 over-expression reduced LNCaP cell proliferation and PC3 cell migration. Taken together, our immunohistochemical and microarray results and cellular studies have shown for the first time that ADAM19 is a protective factor for human prostate cancer. Further, this study suggests that upregulation of ADAM19 expression could be of therapeutic potential in human prostate cancer

  16. Eye and rare genetic diseases: Case series and literature review ...

    African Journals Online (AJOL)

    Genetic diseases are generally characterised by a multi visceral pathogenesis. Although orphan, these diseases interest many disciplines due to their clinical expression. Eye is sometimes part of the clinical polymorphism of some rare genetic diseases. Ocular signs are in some cases leading to the diagnosis of these ...

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

    NARCIS (Netherlands)

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

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

  18. Population Genetics and Natural Selection in Rheumatic Disease.

    Science.gov (United States)

    Ramos, Paula S

    2017-08-01

    Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Natural selection is an important influence on human genetic variation. Because immune and inflammatory function genes are enriched for signals of positive selection, the prevalence of rheumatic disease-risk alleles seen in different populations is partially the result of differing selective pressures (eg, due to pathogens). This review summarizes the genetic regions associated with susceptibility to different rheumatic diseases and concomitant evidence for natural selection, including known agents of selection exerting selective pressure in these regions. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Consumer preferences for the predictive genetic test for Alzheimer disease.

    Science.gov (United States)

    Huang, Ming-Yi; Huston, Sally A; Perri, Matthew

    2014-04-01

    The purpose of this study was to assess consumer preferences for predictive genetic testing for Alzheimer disease in the United States. A rating conjoint analysis was conducted using an anonymous online survey distributed by Qualtrics to a general population panel in April 2011 in the United States. The study design included three attributes: Accuracy (40%, 80%, and 100%), Treatment Availability (Cure is available/Drug for symptom relief but no cure), and Anonymity (Anonymous/Not anonymous). A total of 12 scenarios were used to elicit people's preference, assessed by an 11-point scale. The respondents also indicated their highest willingness-to-pay (WTP) for each scenario through open-ended questions. A total of 295 responses were collected over 4 days. The most important attribute for the aggregate model was Accuracy, contributing 64.73% to the preference rating. Treatment Availability and Anonymity contributed 20.72% and 14.59%, respectively, to the preference rating. The median WTP for the highest-rating scenario (Accuracy 100%, a cure is available, test result is anonymous) was $100 (mean = $276). The median WTP for the lowest-rating scenario (40% accuracy, no cure but drugs for symptom relief, not anonymous) was zero (mean = $34). The results of this study highlight attributes people find important when making the hypothetical decision to obtain an AD genetic test. These results should be of interests to policy makers, genetic test developers and health care providers.

  20. Analogs of human genetic skin disease in domesticated animals

    Directory of Open Access Journals (Sweden)

    Justin Finch, MD

    2017-09-01

    The genetic skin diseases we will review are pigmentary mosaicism, piebaldism, albinism, Griscelli syndrome, ectodermal dysplasias, Waardenburg syndrome, and mucinosis in both humans and domesticated animals.

  1. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease

    OpenAIRE

    Maury, Eleonore; Ramsey, Kathryn Moynihan; Bass, Joseph

    2010-01-01

    The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal ...

  2. Genetics of infectious diseases: hidden etiologies and common pathways.

    Science.gov (United States)

    Orlova, Marianna; Di Pietrantonio, Tania; Schurr, Erwin

    2011-09-01

    Since the completion of the human genome sequence, the study of common genetic polymorphisms in complex human diseases has become a main activity of human genetics. Employing genome-wide association studies, hundreds of modest genetic risk factors have been identified. In infectious diseases the identification of common risk factors has been varied and as in other common diseases it seems likely that important genetic risk factors remain to be discovered. Nevertheless, the identification of disease-specific genetic risk factors revealed an unexpected overlap in susceptibility genes of diverse inflammatory and infectious diseases. Analysis of the multi-disease susceptibility genes has allowed the definition of shared key pathways of inflammatory dysregulation and suggested unexpected infectious etiologies for other "non-infectious" common diseases.

  3. Genome-Wide Association Analyses Highlight the Potential for Different Genetic Mechanisms for Litter Size Among Sheep Breeds

    Science.gov (United States)

    Xu, Song-Song; Gao, Lei; Xie, Xing-Long; Ren, Yan-Ling; Shen, Zhi-Qiang; Wang, Feng; Shen, Min; Eyϸórsdóttir, Emma; Hallsson, Jón H.; Kiseleva, Tatyana; Kantanen, Juha; Li, Meng-Hua

    2018-01-01

    Reproduction is an important trait in sheep breeding as well as in other livestock. However, despite its importance the genetic mechanisms of litter size in domestic sheep (Ovis aries) are still poorly understood. To explore genetic mechanisms underlying the variation in litter size, we conducted multiple independent genome-wide association studies in five sheep breeds of high prolificacy (Wadi, Hu, Icelandic, Finnsheep, and Romanov) and one low prolificacy (Texel) using the Ovine Infinium HD BeadChip, respectively. We identified different sets of candidate genes associated with litter size in different breeds: BMPR1B, FBN1, and MMP2 in Wadi; GRIA2, SMAD1, and CTNNB1 in Hu; NCOA1 in Icelandic; INHBB, NF1, FLT1, PTGS2, and PLCB3 in Finnsheep; ESR2 in Romanov and ESR1, GHR, ETS1, MMP15, FLI1, and SPP1 in Texel. Further annotation of genes and bioinformatics analyses revealed that different biological pathways could be involved in the variation in litter size of females: hormone secretion (FSH and LH) in Wadi and Hu, placenta and embryonic lethality in Icelandic, folliculogenesis and LH signaling in Finnsheep, ovulation and preovulatory follicle maturation in Romanov, and estrogen and follicular growth in Texel. Taken together, our results provide new insights into the genetic mechanisms underlying the prolificacy trait in sheep and other mammals, suggesting targets for selection where the aim is to increase prolificacy in breeding projects.

  4. The Genetic Basis of Graves' Disease

    Science.gov (United States)

    Płoski, Rafał; Szymański, Konrad; Bednarczuk, Tomasz

    2011-01-01

    The presented comprehensive review of current knowledge about genetic factors predisposing to Graves’ disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLA-DPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus: Tenr–IL2–IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1), AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD. PMID:22654555

  5. Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil

    Science.gov (United States)

    Gibbon, Sahra

    2018-01-01

    ABSTRACT Within the context of a globalising agenda for genetic research where ‘global health’ is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases ‘rarenesss’ has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the ‘judicialisation’ of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities. PMID:29533091

  6. Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil.

    Science.gov (United States)

    Gibbon, Sahra; Aureliano, Waleska

    2018-04-01

    Within the context of a globalising agenda for genetic research where 'global health' is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases 'rarenesss' has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the 'judicialisation' of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities.

  7. Pervasive Sharing of Genetic Effects in Autoimmune Disease

    DEFF Research Database (Denmark)

    Cotsapas, Chris; Voight, Benjamin F.; Rossin, Elizabeth

    2011-01-01

    Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiologic...

  8. Genetics Home Reference: uromodulin-associated kidney disease

    Science.gov (United States)

    ... disease Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (3 links) Health Topic: Gout Health Topic: Kidney Diseases Health Topic: Kidney Failure ...

  9. Molecular Genetic Studies of Some Eye Diseases Affecting the ...

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Molecular Genetic Studies of Some Eye Diseases Affecting the Indian Population. Single gene disorders. Complex eye diseases. Genotype-phenotype correlation. Molecular diagnostics.

  10. Perceived genetic knowledge, attitudes towards genetic testing, and the relationship between these among patients with a chronic disease

    NARCIS (Netherlands)

    Morren, M.; Rijken, M.; Baanders, A.N.; Bensing, J.

    2007-01-01

    Objective: Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition,

  11. Perceived genetic knowledge, attitudes toward genetic testing, and the relationship between these among patients with a chronic disease.

    NARCIS (Netherlands)

    Morren, M.; Rijken, M.; Baanders, A.N.; Bensing, J.

    2007-01-01

    OBJECTIVE: Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition,

  12. Genetic Alterations in Intervertebral Disc Disease

    Directory of Open Access Journals (Sweden)

    Nikolay L. Martirosyan

    2016-11-01

    Full Text Available Background: Intervertebral disc degeneration (IVDD is considered a multifactorial disease. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single nucleotide polymorphisms (SNPs that are associated with IVDD.Aim: This review explores and presents updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD.Results: SNPs in the genes coding for structural proteins linked with IVDD or disc bulging include the Sp1 polymorphism of COL1A1, Trp3 polymorphism of COL9A3, several polymorphisms of COL11A1 and COL11A2, and a variable number tandem repeat polymorphism of ACAN. The rs4148941 SNP of CHST3 coding for an aggrecan sulfation enzyme is also associated with IVDD. The FokI, TaqI, and ApaI SNPs of the vitamin D receptor gene that is involved in chondrocyte functioning are also associated with IVDD. SNPs relevant to cytokine imbalance in IVDD include 889C/T of IL1a and 15T/A, as well as other SNPs (rs1800795, rs1800796, and rs1800797, of IL6, with effects limited to certain genders and populations. SNPs in collagenase genes include -1605G/D (guanine insertion/deletion of MMP1, -1306C/T of MMP2, -1562C/T and a 5-adenosine (5A variant (in the promotor region of MMP3, -1562C/T of MMP9, and -378T/C of MMP-14. SNPs in aggrecanase genes include 1877T/U of ADAMTS-4 and rs162509 of ADAMTS-5. Among the apoptosis-mediating genes, 1595T/C of the caspase 9 gene, 1525A/G and 1595T/C of the TRAIL gene, and 626C/G of the death receptor 4 gene (DR4 are SNPs associated with IVDD. Among the growth factors involved in disc homeostasis, the rs4871857 SNP of GDF5 was associated with IVDD. VEGF SNPs -2578C/A and -634G/C could foster neovascularization observed in IVDD.Conclusion: Improved understanding of the numerous genetic variants behind various

  13. AEB highlights

    International Nuclear Information System (INIS)

    1975-01-01

    AEB HIGHLIGHTS is a half-yearly report reflecting the most important recent achievements of the various Research and Technical Divisions of the Atomic Energy Board. It appears alternately in English and Afrikaans [af

  14. BBG Highlights

    Data.gov (United States)

    Broadcasting Board of Governors — BBG Highlights is a monthly summary of the BBG's accomplishments and news and developments affecting the Agency's work. Now, for the first time, this monthly update...

  15. AEB highlights

    International Nuclear Information System (INIS)

    1977-01-01

    AEB HIGHLIGHTS is a half yearly report reflecting the most important recent achievements of the various Research and Technical Divisions of the Atomic Energy Board. It appears alternately in English and Afrikaans [af

  16. Risk factors for Alzheimer's disease : a genetic-epidemiologic study

    NARCIS (Netherlands)

    C.M. van Duijn (Cornelia)

    1992-01-01

    textabstractThe work presented in this thesis has been motivated by the Jack of knowledge of risk factors for Alzheimer's disease. It has been long recognised that genetic factors are implicated, in particular in early-onset Alzheimer's disease.4 But to what extent are genetic factors involved?

  17. Exploration of genetic susceptibility factors for Parkinson's disease ...

    Indian Academy of Sciences (India)

    1Neurosciences Research Group, School of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá ... factors for Parkinson's disease in a South American sample. J. Genet. 89, ... In the current work, we report the results of a system- ..... Synaptic dysfunction and oxidative stress in Alzheimer's disease:.

  18. Genetic Variations and their Association with Diseases among ...

    African Journals Online (AJOL)

    genetics plays in disease, death and infections. The mode of study involved a combination of a retrospective study and the analysis of genetic variation among Kenyan ethnic populations using ABO blood group system. The results showed that there was association between allele frequencies of ABO system and disease ...

  19. Comparison of koala LPCoLN and human strains of Chlamydia pneumoniae highlights extended genetic diversity in the species

    OpenAIRE

    Mitchell, Candice M; Hovis, Kelley M; Bavoil, Patrik M; Myers, Garry SA; Carrasco, Jose A; Timms, Peter

    2010-01-01

    Abstract Background Chlamydia pneumoniae is a widespread pathogen causing upper and lower respiratory tract infections in addition to a range of other diseases in humans and animals. Previous whole genome analyses have focused on four essentially clonal (> 99% identity) C. pneumoniae human genomes (AR39, CWL029, J138 and TW183), providing relatively little insight into strain diversity and evolution of this species. Results We performed individual gene-by-gene comparisons of the recently sequ...

  20. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing.

    LENUS (Irish Health Repository)

    Murphy, Sinead M

    2012-07-01

    Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.

  1. Applying genetics in inflammatory disease drug discovery

    DEFF Research Database (Denmark)

    Folkersen, Lasse; Biswas, Shameek; Frederiksen, Klaus Stensgaard

    2015-01-01

    , with several notable exceptions, the journey from a small-effect genetic variant to a functional drug has proven arduous, and few examples of actual contributions to drug discovery exist. Here, we discuss novel approaches of overcoming this hurdle by using instead public genetics resources as a pragmatic guide...... alongside existing drug discovery methods. Our aim is to evaluate human genetic confidence as a rationale for drug target selection....

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

    OpenAIRE

    Yamada-Fowler, Naomi; Söderkvist, Peter

    2015-01-01

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

  3. Genetics of Common Endocrine Disease: The Present and the Future.

    Science.gov (United States)

    Goodarzi, Mark O

    2016-03-01

    In honor of the 75th issue of the Journal of Clinical Endocrinology and Metabolism, the author was invited to present his perspectives on genetics in human endocrinology. This paper reviews what the field has achieved in the genetics of common endocrine disease, and offers predictions on where the field will move in the future and its impact on endocrine clinical practice. The October 2015 data release of the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog of Published Genome-wide Association Studies was queried regarding endocrinologic diseases and traits. PubMed searches were focused on genetic prediction of disease, genetic findings and drug targets, functional interrogation of genetic loci, use of genetics to subtype disease, missing heritability, systems genomics, and higher order chromatin structures as regulators of gene function. Nearly a quarter of genome wide association study findings concern endocrinologic diseases and traits. While these findings have not yet dramatically altered clinical care, genetics will have a major impact by providing the drug targets of tomorrow, facilitated by experimental and bioinformatic advances that will shorten the time from gene discovery to drug development. Use of genetic findings to subtype common endocrine disease will allow more precise prevention and treatment efforts. Future advances will allow us to move away from the common view of DNA as a string of letters, allowing exploration of higher order structure that likely explains much "missing heritability." The future will see a greater role of genetics at the bedside, with genetic epidemiologic discoveries leading not only to new treatments of endocrine disease, but also helping us prescribe the right drug to the right patients by allowing subclassification of common heterogeneous endocrine conditions. Future technological breakthroughs will reveal the heritable mysteries hidden in chromatin structure, leading to a

  4. Genetics of animal health and disease in cattle

    Directory of Open Access Journals (Sweden)

    Berry Donagh P

    2011-03-01

    Full Text Available Abstract There have been considerable recent advancements in animal breeding and genetics relevant to disease control in cattle, which can now be utilised as part of an overall programme for improved cattle health. This review summarises the contribution of genetic makeup to differences in resistance to many diseases affecting cattle. Significant genetic variation in susceptibility to disease does exist among cattle suggesting that genetic selection for improved resistance to disease will be fruitful. Deficiencies in accurately recorded data on individual animal susceptibility to disease are, however, currently hindering the inclusion of health and disease resistance traits in national breeding goals. Developments in 'omics' technologies, such as genomic selection, may help overcome some of the limitations of traditional breeding programmes and will be especially beneficial in breeding for lowly heritable disease traits that only manifest themselves following exposure to pathogens or environmental stressors in adulthood. However, access to large databases of phenotypes on health and disease will still be necessary. This review clearly shows that genetics make a significant contribution to the overall health and resistance to disease in cattle. Therefore, breeding programmes for improved animal health and disease resistance should be seen as an integral part of any overall national disease control strategy.

  5. Brookhaven highlights

    International Nuclear Information System (INIS)

    Rowe, M.S.; Belford, M.; Cohen, A.; Greenberg, D.; Seubert, L.

    1993-01-01

    This report highlights the research activities of Brookhaven National Laboratory during the period dating from October 1, 1992 through September 30, 1993. There are contributions to the report from different programs and departments within the laboratory. These include technology transfer, RHIC, Alternating Gradient Synchrotron, physics, biology, national synchrotron light source, applied science, medical science, advanced technology, chemistry, reactor physics, safety and environmental protection, instrumentation, and computing and communications

  6. Comparative “Omics” of the Fusarium fujikuroi Species Complex Highlights Differences in Genetic Potential and Metabolite Synthesis

    Science.gov (United States)

    Niehaus, Eva-Maria; Münsterkötter, Martin; Proctor, Robert H.; Brown, Daren W.; Sharon, Amir; Idan, Yifat; Oren-Young, Liat; Sieber, Christian M.; Novák, Ondřej; Pěnčík, Aleš; Tarkowská, Danuše; Hromadová, Kristýna; Freeman, Stanley; Maymon, Marcel; Elazar, Meirav; Youssef, Sahar A.; El-Shabrawy, El Said M.; Shalaby, Abdel Baset A.; Houterman, Petra; Brock, Nelson L.; Burkhardt, Immo; Tsavkelova, Elena A.; Dickschat, Jeroen S.; Galuszka, Petr; Güldener, Ulrich; Tudzynski, Bettina

    2016-01-01

    Species of the Fusarium fujikuroi species complex (FFC) cause a wide spectrum of often devastating diseases on diverse agricultural crops, including coffee, fig, mango, maize, rice, and sugarcane. Although species within the FFC are difficult to distinguish by morphology, and their genes often share 90% sequence similarity, they can differ in host plant specificity and life style. FFC species can also produce structurally diverse secondary metabolites (SMs), including the mycotoxins fumonisins, fusarins, fusaric acid, and beauvericin, and the phytohormones gibberellins, auxins, and cytokinins. The spectrum of SMs produced can differ among closely related species, suggesting that SMs might be determinants of host specificity. To date, genomes of only a limited number of FFC species have been sequenced. Here, we provide draft genome sequences of three more members of the FFC: a single isolate of F. mangiferae, the cause of mango malformation, and two isolates of F. proliferatum, one a pathogen of maize and the other an orchid endophyte. We compared these genomes to publicly available genome sequences of three other FFC species. The comparisons revealed species-specific and isolate-specific differences in the composition and expression (in vitro and in planta) of genes involved in SM production including those for phytohormome biosynthesis. Such differences have the potential to impact host specificity and, as in the case of F. proliferatum, the pathogenic versus endophytic life style. PMID:28040774

  7. Genetic factors and molecular mechanisms in dry eye disease.

    Science.gov (United States)

    Lee, Ling; Garrett, Qian; Flanagan, Judith; Chakrabarti, Subhabrata; Papas, Eric

    2018-04-01

    Dry eye disease (DED) is a complex condition with a multifactorial etiology that can be difficult to manage successfully. While external factors are modifiable, treatment success is limited if genetic factors contribute to the disease. The purpose of this review is to compile research describing normal and abnormal ocular surface function on a molecular level, appraise genetic studies involving DED or DED-associated diseases, and introduce the basic methods used for conducting genetic epidemiology studies. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Genetics Home Reference: chylomicron retention disease

    Science.gov (United States)

    ... reflexes (hyporeflexia) and a decreased ability to feel vibrations. Related Information What does it mean if a ... Encyclopedia: Malabsorption General Information from MedlinePlus (5 links) Diagnostic Tests Drug Therapy Genetic Counseling Palliative Care Surgery ...

  9. Genetics Home Reference: critical congenital heart disease

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Critical congenital heart disease Critical congenital heart disease Printable PDF Open All Close All ... for Disease Control and Prevention: Congenital Heart Defects Disease InfoSearch: Congenital Heart Defects KidsHealth from Nemours Lucile Packard Children's ...

  10. Sleep disorders and Parkinson disease; lessons from genetics.

    Science.gov (United States)

    Gan-Or, Ziv; Alcalay, Roy N; Rouleau, Guy A; Postuma, Ronald B

    2018-01-31

    Parkinson disease is a common, age-related neurodegenerative disorder, projected to afflict millions of individuals in the near future. Understanding its etiology and identifying clinical, genetic or biological markers for Parkinson disease onset and progression is therefore of major importance. Various sleep-related disorders are the most common group of non-motor symptoms in advanced Parkinson disease, but they can also occur during its prodromal phase. However, with the exception of REM sleep behavior disorder, it is unclear whether they are part of the early pathological process of Parkinson disease, or if they develop as Parkinson disease advances because of treatments and neurodegeneration progression. The advancements in genetic studies in the past two decades have generated a wealth of information, and recent genetic studies offer new insight on the association of sleep-related disorders with Parkinson disease. More specifically, comparing genetic data between Parkinson disease and sleep-related disorders can clarify their association, which may assist in determining whether they can serve as clinical markers for Parkinson disease risk or progression. In this review, we discuss the current knowledge on the genetics of sleep-related disorders in Parkinson disease context, and the potential implications on research, diagnosis, counseling and treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Elucidating novel dysfunctional pathways in Alzheimer's disease by integrating loci identified in genetic and epigenetic studies

    Directory of Open Access Journals (Sweden)

    Adam R. Smith

    2016-06-01

    Full Text Available Alzheimer's disease is a complex neurodegenerative disorder. A large number of genome-wide association studies have been performed, which have been supplemented more recently by the first epigenome-wide association studies, leading to the identification of a number of novel loci altered in disease. Twin studies have shown monozygotic twin discordance for Alzheimer's disease (Gatz et al., 2006, leading to the conclusion that a combination of genetic and epigenetic mechanisms is likely to be involved in disease etiology (Lunnon & Mill, 2013. This review focuses on identifying overlapping pathways between published genome-wide association studies and epigenome-wide association studies, highlighting dysfunctional synaptic, lipid metabolism, plasma membrane/cytoskeleton, mitochondrial, and immune cell activation pathways. Identifying common pathways altered in genetic and epigenetic studies will aid our understanding of disease mechanisms and identify potential novel targets for pharmacological intervention.

  12. Symposium Highlights

    International Nuclear Information System (INIS)

    Owen-Whitred, K.

    2015-01-01

    Overview/Highlights: To begin, I'd like to take a moment to highlight some of the novel elements of this Symposium as compared to those that have been held in the past. For the first time ever, this Symposium was organized around five concurrent sessions, covering over 300 papers and presentations. These sessions were complemented by an active series of exhibits put on by vendors, universities, ESARDA, INMM, and Member State Support Programmes. We also had live demonstrations throughout the week on everything from software to destructive analysis to instrumentation, which provided the participants the opportunity to see recent developments that are ready for implementation. I'm sure you all had a chance to observe - and, more importantly, interact with - the electronic Poster, or ePoster format used this past week. This technology was used here for the first time ever by the IAEA, and I'm sure was a first for many of us as well. The ePoster format allowed participants to interact with the subject matter, and the subject matter experts, in a dynamic, engaging way. In addition to the novel technology used here, I have to say that having the posters strategically embedded in the sessions on the same topic, by having each poster author introduce his or her topic to the assembled group in order to lure us to the poster area during the breaks, was also a novel and highly effective technique. A final highlight I'd like to touch on in terms of the Symposium organization is the diversity of participation. This chart shows the breakdown by geographical distribution for the Symposium, in terms of participants. There are no labels, so don't try to read any, I simply wanted to demonstrate that we had great representation in terms of both the Symposium participants in general and the session chairs more specifically-and on that note, I would just mention here that 59 Member States participated in the Symposium. But what I find especially interesting and

  13. Genetic anaylsis of a disease resistance gene from loblolly pine

    Science.gov (United States)

    Yinghua Huang; Nili Jin; Alex Diner; Chuck Tauer; Yan Zhang; John Damicone

    2003-01-01

    Rapid advances in molecular genetics provide great opportunities for studies of host defense mechanisms. Examination of plant responses to disease at the cellular and molecular level permits both discovery of changes in gene expression in the tissues attacked by pathogens, and identification of genetic components involved in the interaction between host and pathogens....

  14. Animal models for human genetic diseases | Sharif | African Journal ...

    African Journals Online (AJOL)

    The study of human genetic diseases can be greatly aided by animal models because of their similarity to humans in terms of genetics. In addition to understand diverse aspects of basic biology, model organisms are extensively used in applied research in agriculture, industry, and also in medicine, where they are used to ...

  15. Exploration of genetic susceptibility factors for Parkinson's disease

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 89; Issue 2. Exploration of genetic susceptibility factors for Parkinson's disease in a South American sample. Bruno A. Benitez Diego A. Forero Gonzalo H. Arboleda Luis A. Granados Juan J. Yunis William Fernandez Humberto Arboleda. Research Note Volume 89 Issue 2 ...

  16. Genetics Home Reference: neutral lipid storage disease with myopathy

    Science.gov (United States)

    ... named? Additional Information & Resources MedlinePlus (6 links) Encyclopedia: Hypothyroidism Encyclopedia: Type 2 Diabetes Health Topic: Cardiomyopathy Health Topic: Lipid Metabolism Disorders Health Topic: Muscle Disorders Health Topic: Pancreatitis Genetic and Rare Diseases ...

  17. Genetics Home Reference: REN-related kidney disease

    Science.gov (United States)

    ... 2 Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (5 links) Encyclopedia: Hyperkalemia Encyclopedia: Renin Health Topic: Anemia Health Topic: Gout Health Topic: Kidney Diseases Additional NIH Resources (2 ...

  18. EDITORIAL Clinical issues in genetic testing for multifactorial diseases

    African Journals Online (AJOL)

    Given the importance of MDs, detection of genetic predisposition is potentially attractive ... burden for affected individuals and families: disease is often early onset and ... to detection of BRCA-related breast cancer in a local public health sector.

  19. Genetic influences on chronic obstructive pulmonary disease - a twin study

    DEFF Research Database (Denmark)

    Sylvan Ingebrigtsen, Truls; Thomsen, Simon Francis; Vestbo, Jørgen

    2010-01-01

    Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted.......Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted....

  20. Genetic Influences on the Development of Fibrosis in Crohn's Disease

    OpenAIRE

    Verstockt, Bram; Cleynen, Isabelle

    2016-01-01

    Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we revi...

  1. Genetics Home Reference: CLN3 disease

    Science.gov (United States)

    ... age, and people with CLN3 disease are often blind by late childhood or adolescence. Also around age 4 to 8, children with CLN3 disease start to fall behind in school. They have difficulty learning new information and lose ...

  2. Genetics Home Reference: adult polyglucosan body disease

    Science.gov (United States)

    ... Additional NIH Resources (1 link) National Institute of Neurological Disorders and Stroke: Spasticity Information Page Educational Resources (6 links) Boston Children's Hospital: Neurogenic Bladder Disease InfoSearch: Polyglucosan body disease, ...

  3. Genetics and ionizing radiations. 1. Genetics and hereditary diseases

    International Nuclear Information System (INIS)

    Dutrillaux, B.

    1980-01-01

    The desoxyribonucleic acid (DNA) is the chemical vehicle of heredity. Each hereditary character is determined by a short segment of the DNA molecule called gene. Gene operations are governed by regulating systems. The DNA is located in the chromosomes, easily analysed by light microscopy. The chromosome number and form are fairly characteristic of a species. Ours has 46 chromosomes, i.e. 23 pairs. Anomalies of the hereditary stock can be qualitative: affecting one gene they are expressed by diversely serious diseases. They can be quantitative and bear on the lack or excess of a chromosome or a segment of chromosome; most often, resulting diseases are very serious; Downs's syndrome is a well-known example. The various modes of transmission of these hereditary characters are analysed. The change of a chromosome or a gene from a normal to an abnormal form is called a mutation. It occurs scarcely, but the effects of mutations accumulate. At birth, nearly 10% of children should have one abnormal hereditary character at least, however most of these characters do not induce a true disease. Anomalies are more frequent at conception, many abnormal embryos or foetuses being aliminated by miscarriages [fr

  4. Progress in genetics of coronary artery disease

    African Journals Online (AJOL)

    Radwa Gamal

    To the Editor. Coronary Heart Disease (CHD) is the leading cause of mortality and morbidity worldwide [1] and it is a result of coronary artery disease (CAD). Coronary artery disease refers to the build-up of atherosclerotic plaque in the blood vessels that supply oxygen and nutrients to the heart. Progressive infiltration of the ...

  5. Invited review: Opportunities for genetic improvement of metabolic diseases.

    Science.gov (United States)

    Pryce, J E; Parker Gaddis, K L; Koeck, A; Bastin, C; Abdelsayed, M; Gengler, N; Miglior, F; Heringstad, B; Egger-Danner, C; Stock, K F; Bradley, A J; Cole, J B

    2016-09-01

    Metabolic disorders are disturbances to one or more of the metabolic processes in dairy cattle. Dysfunction of any of these processes is associated with the manifestation of metabolic diseases or disorders. In this review, data recording, incidences, genetic parameters, predictors, and status of genetic evaluations were examined for (1) ketosis, (2) displaced abomasum, (3) milk fever, and (4) tetany, as these are the most prevalent metabolic diseases where published genetic parameters are available. The reported incidences of clinical cases of metabolic disorders are generally low (less than 10% of cows are recorded as having a metabolic disease per herd per year or parity/lactation). Heritability estimates are also low and are typically less than 5%. Genetic correlations between metabolic traits are mainly positive, indicating that selection to improve one of these diseases is likely to have a positive effect on the others. Furthermore, there may also be opportunities to select for general disease resistance in terms of metabolic stability. Although there is inconsistency in published genetic correlation estimates between milk yield and metabolic traits, selection for milk yield may be expected to lead to a deterioration in metabolic disorders. Under-recording and difficulty in diagnosing subclinical cases are among the reasons why interest is growing in using easily measurable predictors of metabolic diseases, either recorded on-farm by using sensors and milk tests or off-farm using data collected from routine milk recording. Some countries have already initiated genetic evaluations of metabolic disease traits and currently most of these use clinical observations of disease. However, there are opportunities to use clinical diseases in addition to predictor traits and genomic information to strengthen genetic evaluations for metabolic health in the future. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  6. Genetics of Congenital Heart Disease: Past and Present.

    Science.gov (United States)

    Muntean, Iolanda; Togănel, Rodica; Benedek, Theodora

    2017-04-01

    Congenital heart disease is the most common congenital anomaly, representing an important cause of infant morbidity and mortality. Congenital heart disease represents a group of heart anomalies that include septal defects, valve defects, and outflow tract anomalies. The exact genetic, epigenetic, or environmental basis of congenital heart disease remains poorly understood, although the exact mechanism is likely multifactorial. However, the development of new technologies including copy number variants, single-nucleotide polymorphism, next-generation sequencing are accelerating the detection of genetic causes of heart anomalies. Recent studies suggest a role of small non-coding RNAs, micro RNA, in congenital heart disease. The recently described epigenetic factors have also been found to contribute to cardiac morphogenesis. In this review, we present past and recent genetic discoveries in congenital heart disease.

  7. Pervasive sharing of genetic effects in autoimmune disease.

    Directory of Open Access Journals (Sweden)

    Chris Cotsapas

    2011-08-01

    Full Text Available Genome-wide association (GWA studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs and risk of common autoimmune and inflammatory (immune-mediated diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44% immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA<0.01. We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.

  8. Genetics of intracranial aneurysms and related diseases

    NARCIS (Netherlands)

    van 't Hof, F.N.G.

    2017-01-01

    Intracranial aneurysms (IA) are dilatations of the vessel walls of cerebral arteries. Some can rupture and result in a subarachnoid hemorrhage (SAH), a severe subtype of stroke. This thesis is set out to elucidate the pathophysiology of IA from a genetic perspective. The main conclusions are: 1.

  9. ORIGINAL ARTICLES Huntington's disease: Genetic heterogeneity ...

    African Journals Online (AJOL)

    2008-03-01

    Mar 1, 2008 ... African origin.5 HD is considered rare among South African blacks, with an ... functions, syphilis, HIV and other tests in selected patients. We .... The discovery of a second genetic locus, resulting in HDL2,7 suggests the need ...

  10. Genetics of liver disease: From pathophysiology to clinical practice.

    Science.gov (United States)

    Karlsen, Tom H; Lammert, Frank; Thompson, Richard J

    2015-04-01

    Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. Maternal-Zygotic Epistasis and the Evolution of Genetic Diseases

    Directory of Open Access Journals (Sweden)

    Nicholas K. Priest

    2010-01-01

    Full Text Available Many birth defects and genetic diseases are expressed in individuals that do not carry the disease causing alleles. Genetic diseases observed in offspring can be caused by gene expression in mothers and by interactions between gene expression in mothers and offspring. It is not clear whether the underlying pattern of gene expression (maternal versus offspring affects the incidence of genetic disease. Here we develop a 2-locus population genetic model with epistatic interactions between a maternal gene and a zygotic gene to address this question. We show that maternal effect genes that affect disease susceptibility in offspring persist longer and at higher frequencies in a population than offspring genes with the same effects. We find that specific forms of maternal-zygotic epistasis can maintain disease causing alleles at high frequencies over a range of plausible values. Our findings suggest that the strength and form of epistasis and the underlying pattern of gene expression may greatly influence the prevalence of human genetic diseases.

  12. The genetic theory of infectious diseases: a brief history and selected illustrations.

    Science.gov (United States)

    Casanova, Jean-Laurent; Abel, Laurent

    2013-01-01

    Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.

  13. The Genetic Theory of Infectious Diseases: A Brief History and Selected Illustrations

    Science.gov (United States)

    Casanova, Jean-Laurent; Abel, Laurent

    2016-01-01

    Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases. PMID:23724903

  14. The genetics of Ménière’s disease

    Directory of Open Access Journals (Sweden)

    Chiarella G

    2015-01-01

    Full Text Available Giuseppe Chiarella,1 C Petrolo,1 E Cassandro2 1Department of Experimental and Clinical Medicine, Audiology and Phoniatrics Unit, Magna Graecia University of Catanzaro, Catanzaro, Italy; 2Department of Medicine and Surgery, University of Salerno, Salerno, Italy Abstract: Our understanding of the genetic basis of Ménière’s disease (MD is still limited. Although the familial clustering and the geographical and racial differences in incidence strongly suggest a certain role for genetic factors in the development of MD, no convincing evidence for an association with any gene exists, at present. In this review, starting from rational bases for a genetic approach to MD, we explored the numerous reports published in literature and summarize the recent advances in understanding of the genetic fundaments of the disease. Keywords: Mènière’s disease, gene, vertigo, etiology, pathogenesis

  15. Human genetics of infectious diseases: a unified theory

    Science.gov (United States)

    Casanova, Jean-Laurent; Abel, Laurent

    2007-01-01

    Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans. PMID:17255931

  16. Reduced serum myostatin concentrations associated with genetic muscle disease progression.

    Science.gov (United States)

    Burch, Peter M; Pogoryelova, Oksana; Palandra, Joe; Goldstein, Richard; Bennett, Donald; Fitz, Lori; Guglieri, Michela; Bettolo, Chiara Marini; Straub, Volker; Evangelista, Teresinha; Neubert, Hendrik; Lochmüller, Hanns; Morris, Carl

    2017-03-01

    Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

  17. The landscape genetics of infectious disease emergence and spread.

    Science.gov (United States)

    Biek, Roman; Real, Leslie A

    2010-09-01

    The spread of parasites is inherently a spatial process often embedded in physically complex landscapes. It is therefore not surprising that infectious disease researchers are increasingly taking a landscape genetics perspective to elucidate mechanisms underlying basic ecological processes driving infectious disease dynamics and to understand the linkage between spatially dependent population processes and the geographic distribution of genetic variation within both hosts and parasites. The increasing availability of genetic information on hosts and parasites when coupled to their ecological interactions can lead to insights for predicting patterns of disease emergence, spread and control. Here, we review research progress in this area based on four different motivations for the application of landscape genetics approaches: (i) assessing the spatial organization of genetic variation in parasites as a function of environmental variability, (ii) using host population genetic structure as a means to parameterize ecological dynamics that indirectly influence parasite populations, for example, gene flow and movement pathways across heterogeneous landscapes and the concurrent transport of infectious agents, (iii) elucidating the temporal and spatial scales of disease processes and (iv) reconstructing and understanding infectious disease invasion. Throughout this review, we emphasize that landscape genetic principles are relevant to infection dynamics across a range of scales from within host dynamics to global geographic patterns and that they can also be applied to unconventional 'landscapes' such as heterogeneous contact networks underlying the spread of human and livestock diseases. We conclude by discussing some general considerations and problems for inferring epidemiological processes from genetic data and try to identify possible future directions and applications for this rapidly expanding field.

  18. Investigation of the Genetics of Hematologic Diseases

    Science.gov (United States)

    2017-10-17

    Bone Marrow Failure Syndromes; Erythrocyte Disorder; Leukocyte Disorder; Hemostasis; Blood Coagulation Disorder; Sickle Cell Disease; Dyskeratosis Congenita; Diamond-Blackfan Anemia; Congenital Thrombocytopenia; Severe Congenital Neutropenia; Fanconi Anemia

  19. Genetics Home Reference: Tay-Sachs disease

    Science.gov (United States)

    ... NIH Resources (4 links) GeneEd National Human Genome Research Institute National Institute of Neurological Disorders and Stroke: Lipid Storage Diseases Fact Sheet National Institute of Neurological ...

  20. Genetic variation in lipid desaturases and its impact on the development of human disease.

    Science.gov (United States)

    Merino, Diana M; Ma, David W L; Mutch, David M

    2010-06-18

    Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management.

  1. Genetic analysis of infectious diseases: Estimating gene effects for susceptibility and infectivity

    NARCIS (Netherlands)

    Anche, M.T.; Bijma, P.; Jong, de M.C.M.

    2015-01-01

    Background: Genetic selection of livestock against infectious diseases can complement existing interventions to control infectious diseases. Most genetic approaches that aim at reducing disease prevalence assume that individual disease status (infected/not-infected) is solely a function of its

  2. Huntington\\'s disease: Genetic heterogeneity in black African patients

    African Journals Online (AJOL)

    Objective. Huntington's disease (HD) has been reported to occur rarely in black patients. A new genetic variant– Huntington's disease-like 2 (HDL2) – occurring more frequently in blacks, has recently been described. The absence of an expanded trinucleotide repeat at the chromosome 4 HD locus was previously regarded ...

  3. A genetic-epidemiologic study of Alzheimer’s disease

    NARCIS (Netherlands)

    A. Arias-Vásquez (Alejandro)

    2006-01-01

    textabstractAlzheimer's disease (AD) is the most frequent cause of dementia and thus is a major public-health problem. Age and genetic predisposition to the disease are the most important risk factors. In 2001 more than 24 million people in the western world had dementia. This number is expected to

  4. The household contact study design for genetic epidemiological studies of infectious diseases

    Directory of Open Access Journals (Sweden)

    Catherine eStein

    2013-04-01

    Full Text Available Most genetic epidemiological study designs fall into one of two categories: family-based and population-based (case-control. However, recent advances in statistical genetics call for study designs that combine these two approaches. We describe the household contact study design as we have applied it in our several years of study of the epidemiology of tuberculosis. Though we highlight its applicability for genetic epidemiological studies of infectious diseases, there are many facets of this design that are appealing for modern genetic studies, including the simultaneous enrollment of related and unrelated individuals, closely and distantly related individuals, collection of extensive epidemiologic and phenotypic data, and evaluation of effects of shared environment and gene by environment interaction. These study design characteristics are particularly appealing for current sequencing studies.

  5. Genetic Testing for Respiratory Disease: Are We There Yet?

    Directory of Open Access Journals (Sweden)

    Peter D Paré

    2012-01-01

    Full Text Available The human genome project promised a revolution in health care – the development of ‘personalized medicine’, where knowledge of an individual’s genetic code enables the prediction of risk for specific diseases and the potential to alter that risk based on preventive measures and lifestyle modification. The present brief review provides a report card on the progress toward that goal with respect to respiratory disease. Should generalized population screening for genetic risk factors for respiratory disease be instituted? Or not?

  6. Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease.

    Science.gov (United States)

    Chen, Xiaoying; Farrokhi, Vahid; Singh, Pratap; Ocana, Mireia Fernandez; Patel, Jenil; Lin, Lih-Ling; Neubert, Hendrik; Brodfuehrer, Joanne

    2018-01-01

    Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application. This model incorporates experimental biomeasures, including concentration of soluble Fn14 (sFn14) in human plasma and membrane Fn14 (mFn14) in human kidney tissue, and turnover rate of human sFn14. Pulse-chase studies using stable isotope-labeled amino acids and mass spectrometry indicated the sFn14 half-life to be approximately 5 hours in healthy volunteers. The biomeasures (concentration, turnover) of sFn14 in plasma reveals a significant hurdle in designing an antibody against Fn14 with desired characteristics. The projected dose (>1 mg/kg/wk for 90% target coverage) derived from the human PK/PD model revealed potential high and frequent dosing requirements under certain conditions. The PK/PD model suggested a unique bell-shaped relationship between target coverage and antibody affinity for anti-Fn14 mAb, which could be applied to direct the antibody engineering towards an optimized affinity. This investigation highlighted potential applications, including assessment of PK/PD risks during early target validation, human dose prediction and drug candidate optimization.

  7. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.

    Science.gov (United States)

    Bertram, Lars; Tanzi, Rudolph E

    2008-10-01

    The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

  8. Disease-Concordant Twins Empower Genetic Association Studies

    DEFF Research Database (Denmark)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

    and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient...... concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases...... population. Simulation was done by assigning various allele frequencies and allelic relative risks for different mode of genetic inheritance. In general, for achieving a power estimate of 80%, the sample sizes needed for dizygotic and monozygotic twin cases were one half and one fourth of the sample size...

  9. Prospect of Induced Pluripotent Stem Cell Genetic Repair to Cure Genetic Diseases

    Directory of Open Access Journals (Sweden)

    Jeanne Adiwinata Pawitan

    2012-01-01

    Full Text Available In genetic diseases, where the cells are already damaged, the damaged cells can be replaced by new normal cells, which can be differentiated from iPSC. To avoid immune rejection, iPSC from the patient’s own cell can be developed. However, iPSC from the patients’s cell harbors the same genetic aberration. Therefore, before differentiating the iPSCs into required cells, genetic repair should be done. This review discusses the various technologies to repair the genetic aberration in patient-derived iPSC, or to prevent the genetic aberration to cause further damage in the iPSC-derived cells, such as Zn finger and TALE nuclease genetic editing, RNA interference technology, exon skipping, and gene transfer method. In addition, the challenges in using the iPSC and the strategies to manage the hurdles are addressed.

  10. Genetics Home Reference: von Willebrand disease

    Science.gov (United States)

    ... mildest and most common of the three types, accounting for 75 percent of affected individuals. Type 3 ... diseases that affect bone marrow or immune cell function. This rare form of the condition is characterized ...

  11. Genetics Home Reference: Niemann-Pick disease

    Science.gov (United States)

    ... are compartments within cells that break down and recycle different types of molecules. Acid sphingomyelinase is responsible ... A, Brodie SE, Desnick RJ, Wasserstein MP. Natural history of Type A Niemann-Pick disease: possible endpoints ...

  12. Genetics Home Reference: CLN8 disease

    Science.gov (United States)

    ... about four to six times per year. By middle age, seizures become even less frequent. In addition to ... What is precision medicine? What is newborn screening? New Pages RAB18 deficiency Depression Pelizaeus-Merzbacher-like disease ...

  13. Genetics Home Reference: Dowling-Degos disease

    Science.gov (United States)

    ... can be triggered by UV light, sweating, or friction on the skin. The pigmentation changes characteristic of ... A, Ruzicka T, Betz RC, Hanneken S. The First Report of KRT5 Mutation Underlying Acantholytic Dowling-Degos Disease ...

  14. Genetic pathways to Neurodegeneration Neurodegenerative diseases

    Indian Academy of Sciences (India)

    SN Suresh

    much attention as it involves immediate turnover of proteins and, thus, affects synaptic transmission. Mutations in ...... disease phenotype such as impaired motor coordination, cognitive deficit, axonal swelling with ...... hyperactivity? Neurology.

  15. Genetics Home Reference: CLN10 disease

    Science.gov (United States)

    ... Foundation CLIMB: Children Living with Inherited Metabolic Diseases March of Dimes: Neonatal Death The ... Sources for This Page Anderson GW, Goebel HH, Simonati A. Human pathology in NCL. Biochim Biophys Acta. 2013 Nov;1832( ...

  16. Genetics Home Reference: CLN6 disease

    Science.gov (United States)

    ... the accumulation of proteins and other substances in lysosomes , which are cell structures that digest and recycle ... are involved in the buildup of substances in lysosomes in CLN6 disease . These accumulations occur in more ...

  17. Hypothesis: Cryptosporidium genetic diversity mirrors national disease notification rate

    OpenAIRE

    Takumi, Katsuhisa; Cacci?, Simone M.; van der Giessen, Joke; Xiao, Lihua; Sprong, Hein

    2015-01-01

    Background Cryptosporidiosis is a gastrointestinal disease affecting many people worldwide. Disease incidence is often unknown and surveillance of human cryptosporidiosis is installed in only a handful of developed countries. A genetic marker that mirrors disease incidence is potentially a powerful tool for monitoring the two primary human infected species of Cryptosporidium. Methods We used the molecular epidemiological database with Cryptosporidium isolates from ZoopNet, which currently con...

  18. RNA-Seq Analysis of Abdominal Fat in Genetically Fat and Lean Chickens Highlights a Divergence in Expression of Genes Controlling Adiposity, Hemostasis, and Lipid Metabolism

    Science.gov (United States)

    Resnyk, Christopher W.; Chen, Chuming; Huang, Hongzhan; Wu, Cathy H.; Simon, Jean; Le Bihan-Duval, Elisabeth; Duclos, Michel J.; Cogburn, Larry A.

    2015-01-01

    Genetic selection for enhanced growth rate in meat-type chickens (Gallus domesticus) is usually accompanied by excessive adiposity, which has negative impacts on both feed efficiency and carcass quality. Enhanced visceral fatness and several unique features of avian metabolism (i.e., fasting hyperglycemia and insulin insensitivity) mimic overt symptoms of obesity and related metabolic disorders in humans. Elucidation of the genetic and endocrine factors that contribute to excessive visceral fatness in chickens could also advance our understanding of human metabolic diseases. Here, RNA sequencing was used to examine differential gene expression in abdominal fat of genetically fat and lean chickens, which exhibit a 2.8-fold divergence in visceral fatness at 7 wk. Ingenuity Pathway Analysis revealed that many of 1687 differentially expressed genes are associated with hemostasis, endocrine function and metabolic syndrome in mammals. Among the highest expressed genes in abdominal fat, across both genotypes, were 25 differentially expressed genes associated with de novo synthesis and metabolism of lipids. Over-expression of numerous adipogenic and lipogenic genes in the FL chickens suggests that in situ lipogenesis in chickens could make a more substantial contribution to expansion of visceral fat mass than previously recognized. Distinguishing features of the abdominal fat transcriptome in lean chickens were high abundance of multiple hemostatic and vasoactive factors, transporters, and ectopic expression of several hormones/receptors, which could control local vasomotor tone and proteolytic processing of adipokines, hemostatic factors and novel endocrine factors. Over-expression of several thrombogenic genes in abdominal fat of lean chickens is quite opposite to the pro-thrombotic state found in obese humans. Clearly, divergent genetic selection for an extreme (2.5–2.8-fold) difference in visceral fatness provokes a number of novel regulatory responses that govern

  19. [Preimplantation genetic diagnosis and monogenic inherited eye diseases].

    Science.gov (United States)

    Hlavatá, L; Ďuďáková, Ľ; Trková, M; Soldátová, I; Skalická, P; Kousal, B; Lišková, P

    Preimplantation genetic diagnosis (PGD) is an established application of genetic testing in the context of in vitro fertilization. PGD is an alternative method to prenatal diagnosis which aims to prevent the transmission of an inherited disorder to the progeny by implanting only embryos that do not carry genetic predisposition for a particular disease. The aim of this study is to provide an overview of eye disorders for which PGD has been carried out. The European literature search focused on best practices, ethical issues, risks and results of PGD for inherited eye disorders. PGD is performed for a number of ocular disorders; a prerequisite for its application is however, the knowledge of a disease-causing mutation(s). The main advantage of this method is that the couple is not exposed to a decision of whether or not to undergo an abortion. Qualified counselling must be provided prior to the PGD in order to completely understand the risk of disability in any child conceived, consequences of disease manifestation, and advantages as well as limitations of this method. In the group of non-syndromic eye diseases and diseases in which ocular findings dominate, PGD has been performed in European countries for aniridia, choroideremia, congenital fibrosis of extraocular muscles, Leber congenital amaurosis, ocular albinism, retinitis pigmentosa, X-linked retinoschisis, Stargardt disease, blepharophimosis-ptosis-inverse epicanthus syndrome and retinoblastoma. Sexing for X-linked or mitochondrial diseases has been carried out for blue cone monochromatism, choroideremia, familial exudative vitreoretinopathy, Leber hereditary optic neuropathy, macular dystrophy (not further specified), Norrie disease, X-linked congenital stationary night blindness, X-linked retinoschisis and nystagmus (not further specified). In recent years, there has been an increase in potential to use PGD. The spectrum of diseases for this method has widened to include severe inherited eye diseases

  20. Genetics Home Reference: sickle cell disease

    Science.gov (United States)

    ... Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26;350( ...

  1. Genetics Home Reference: chronic granulomatous disease

    Science.gov (United States)

    ... Other common areas of infection in people with chronic granulomatous disease include the skin, liver , and lymph nodes . Inflammation can occur in ... Other common areas of inflammation in people with chronic granulomatous ... and skin. Additionally, granulomas within the gastrointestinal tract can lead ...

  2. Genetics Home Reference: Unverricht-Lundborg disease

    Science.gov (United States)

    ... disease is believed to be the most common cause of this type of epilepsy, but its worldwide prevalence is unknown. Unverricht-Lundborg ... V, Zerovnik E. Protein aggregation as a possible cause for pathology in a subset of familial ... progressive myoclonus epilepsy (EPM1). J Neurobiol. 2003 Sep 15;56(4): ...

  3. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease.

    Science.gov (United States)

    Maury, Eleonore; Ramsey, Kathryn Moynihan; Bass, Joseph

    2010-02-19

    The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.

  4. Genetic testing in congenital heart disease:A clinical approach

    Institute of Scientific and Technical Information of China (English)

    Marie A Chaix; Gregor Andelfinger; Paul Khairy

    2016-01-01

    Congenital heart disease(CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient followup. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.

  5. Genetic testing in congenital heart disease: A clinical approach

    Science.gov (United States)

    Chaix, Marie A; Andelfinger, Gregor; Khairy, Paul

    2016-01-01

    Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel. PMID:26981213

  6. Paradox of Genetic Diversity in the Case of Prionic Diseases in Sheep Breeds from Romania

    Directory of Open Access Journals (Sweden)

    Gheorghe Hrinca

    2016-05-01

    Full Text Available The main target of this debate is the revaluation of the biodiversity concept and especially of its significance in the animal husbandry field. The paper analyzes the genetic diversity at the determinant locus of scrapie (PrP in the sheep breeds from Romania: Palas Merino, Tsigai, Tsurcana, Botosani Karakul, Palas Meat Breed and Palas Milk Breed. The prionic genetic diversity (d has been quantified by means of informational energy (e. This study highlights the impact of increasing the genetic diversity from the PrP locus level on the health status of ovine species and especially on human food safety. The informational statistics processing shows that the resistance / susceptibility to scrapie is in relation to the degree of prionic genetic diversity. The limitation of genetic diversity by selecting the individuals possessing the ARR allele in both homozygous status and in combination with alleles ARQ, ARH AHQ confers to sheep herds certain levels of resistance to contamination with scrapie disease. Instead, promoting to reproduction also individuals possessing the VRQ allele in all possible genotypic combinations (including ARR allele increases genetic diversity but also has as effect increasing the susceptibility of sheep to prion disease onset. From the point of view of morbid phenomenon, the Botosani Karakul breed is clearly advantaged compared to all other indigenous sheep breeds from Romania. For methodological coherency in the interpretative context of this issue, the genetic diversity was analyzed in association with the heterozygosity degree of breeds and their Hardy-Weinberg genetic equilibrium at the PrP locus level. Finally, the paper refers to decisions that the improvers must take to achieve the genetic prophylaxis in the scrapie case taking into account the polymorphism degree of prion protein.

  7. [Genetic counseling and testing for families with Alzheimer's disease].

    Science.gov (United States)

    Kowalska, Anna

    2004-01-01

    With the identification of the genes responsible for autosomal dominant early-onset familial Alzheimer's disease (FAD genes), there is a considerable interest in the application of this genetic information in medical practice through genetic testing and counseling. Pathogenic mutations in the PSEN1 and PSEN2 genes encoding presenilin-1 and -2, and the APP gene encoding amyloid b precursor protein, account for 18-50% of familial EOAD cases with autosomal dominant pattern of inheritance. A clinical algorithm of genetic testing and counseling proposed for families with AD has been presented here. A screening for mutations in the APP, PSEN1, and PSEN2 genes is available to individuals with AD symptoms and at-risk children or siblings of patients with early-onset disease determined by a known mutation. In an early-onset family, a known mutation in an affected patient puts the siblings and children at a 50% risk of inheriting the same mutation. The goal of genetic testing is to identify at-risk individuals in order to facilitate early and effective treatments in the symptomatic person based on an individual's genotype and strategies to delay the onset of disease in the presymptomatic mutation carriers. However, there are several arguments against the use of genetic testing both presymptomatically (unpredictable psychological consequences of information about a genetic defect for family members) and as a diagnostic tool for the differential diagnosis of dementia in general practice (a risk of errors in an interpretation of mutation penetrance and its secondary effects on family members, especially for novel mutations; the possibility of coexistence of another form of dementia at the presence of a mutation). Currently, APOE genotyping for presymptomatic individuals with a family history of late-onset disease is not recommended. The APOE4 allele may only confer greater risk for disease, but its presence is not conclusive for the development of AD.

  8. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

    Science.gov (United States)

    Beaumont, Robin N; Warrington, Nicole M; Cavadino, Alana; Tyrrell, Jessica; Nodzenski, Michael; Horikoshi, Momoko; Geller, Frank; Myhre, Ronny; Richmond, Rebecca C; Paternoster, Lavinia; Bradfield, Jonathan P; Kreiner-Møller, Eskil; Huikari, Ville; Metrustry, Sarah; Lunetta, Kathryn L; Painter, Jodie N; Hottenga, Jouke-Jan; Allard, Catherine; Barton, Sheila J; Espinosa, Ana; Marsh, Julie A; Potter, Catherine; Zhang, Ge; Ang, Wei; Berry, Diane J; Bouchard, Luigi; Das, Shikta; Hakonarson, Hakon; Heikkinen, Jani; Helgeland, Øyvind; Hocher, Berthold; Hofman, Albert; Inskip, Hazel M; Jones, Samuel E; Kogevinas, Manolis; Lind, Penelope A; Marullo, Letizia; Medland, Sarah E; Murray, Anna; Murray, Jeffrey C; Njølstad, Pål R; Nohr, Ellen A; Reichetzeder, Christoph; Ring, Susan M; Ruth, Katherine S; Santa-Marina, Loreto; Scholtens, Denise M; Sebert, Sylvain; Sengpiel, Verena; Tuke, Marcus A; Vaudel, Marc; Weedon, Michael N; Willemsen, Gonneke; Wood, Andrew R; Yaghootkar, Hanieh; Muglia, Louis J; Bartels, Meike; Relton, Caroline L; Pennell, Craig E; Chatzi, Leda; Estivill, Xavier; Holloway, John W; Boomsma, Dorret I; Montgomery, Grant W; Murabito, Joanne M; Spector, Tim D; Power, Christine; Järvelin, Marjo-Ritta; Bisgaard, Hans; Grant, Struan F A; Sørensen, Thorkild I A; Jaddoe, Vincent W; Jacobsson, Bo; Melbye, Mads; McCarthy, Mark I; Hattersley, Andrew T; Hayes, M Geoffrey; Frayling, Timothy M; Hivert, Marie-France; Felix, Janine F; Hyppönen, Elina; Lowe, William L; Evans, David M; Lawlor, Debbie A; Feenstra, Bjarke

    2018-01-01

    Abstract Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights. PMID:29309628

  9. Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin.

    Directory of Open Access Journals (Sweden)

    Anke Tönjes

    2014-12-01

    Full Text Available Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791. In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2/Leucine Rich Repeat Containing (LRRC61 locus reached genome-wide significance (p<5.0×10-8 in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8×10-14, beta = -0.067, explained variance 2.0%. All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort. The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index. In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.

  10. Rare genetic diseases: update on diagnosis, treatment and online resources.

    Science.gov (United States)

    Pogue, Robert E; Cavalcanti, Denise P; Shanker, Shreya; Andrade, Rosangela V; Aguiar, Lana R; de Carvalho, Juliana L; Costa, Fabrício F

    2018-01-01

    Rare genetic diseases collectively impact a significant portion of the world's population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how the collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Genetic engineering in nonhuman primates for human disease modeling.

    Science.gov (United States)

    Sato, Kenya; Sasaki, Erika

    2018-02-01

    Nonhuman primate (NHP) experimental models have contributed greatly to human health research by assessing the safety and efficacy of newly developed drugs, due to their physiological and anatomical similarities to humans. To generate NHP disease models, drug-inducible methods, and surgical treatment methods have been employed. Recent developments in genetic and developmental engineering in NHPs offer new options for producing genetically modified disease models. Moreover, in recent years, genome-editing technology has emerged to further promote this trend and the generation of disease model NHPs has entered a new era. In this review, we summarize the generation of conventional disease model NHPs and discuss new solutions to the problem of mosaicism in genome-editing technology.

  12. Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases.

    Science.gov (United States)

    Ejlerskov, Patrick; Ashkenazi, Avraham; Rubinsztein, David C

    2018-04-03

    Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Miguel eCalero

    2015-04-01

    Full Text Available Familial Alzheimer's disease (AD, mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1 and PSEN2 involved in the production of the amyloid  peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies (GWAS there is a mounting list of genetic risk factors associated to common genetic variants that have been associated to sporadic AD. Besides APOE, that presents a strong association with the disease (OR~4, the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated to AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways and networks rather than the contribution of specific genes.

  14. Modern vitiligo genetics sheds new light on an ancient disease

    Science.gov (United States)

    SPRITZ, Richard A.

    2013-01-01

    Vitiligo is a complex disorder in which autoimmune destruction of melanocytes results in white patches of skin and overlying hair. Over the past several years, extensive genetic studies have outlined a biological framework of vitiligo pathobiology that underscores its relationship to other autoimmune diseases. This biological framework offers insight into both vitiligo pathogenesis and perhaps avenues towards more effective approaches to treatment and even disease prevention. PMID:23668538

  15. Human genetics of infectious diseases: a unified theory

    OpenAIRE

    Casanova, Jean-Laurent; Abel, Laurent

    2007-01-01

    Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predispos...

  16. Genetics of Parkinson’s Disease - A Clinical Perspective

    Directory of Open Access Journals (Sweden)

    Sang-Myung Cheon

    2012-10-01

    Full Text Available Discovering genes following Medelian inheritance, such as autosomal dominant-synuclein and leucine-rich repeat kinase 2 gene, or autosomal recessive Parkin, P-TEN-induced putative kinase 1 gene and Daisuke-Junko 1 gene, has provided great insights into the pathogenesis of Parkinson’s disease (PD. Genes found to be associated with PD through investigating genetic polymorphisms or via the whole genome association studies suggest that such genes could also contribute to an increased risk of PD in the general population. Some environmental factors have been found to be associated with genetic factors in at-risk patients, further implicating the role of gene-environment interactions in sporadic PD. There may be confusion for clinicians facing rapid progresses of genetic understanding in PD. After a brief review of PD genetics, we will discuss the insight of new genetic discoveries to clinicians, the implications of ethnic differences in PD genetics and the role of genetic testing for general clinicians managing PD patients.

  17. Human Genetic Variation and Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Sun Ju Chung

    2010-05-01

    Full Text Available Parkinson’s disease (PD is a chronic neurodegenerative disorder with multifactorial etiology. In the past decade, the genetic causes of monogenic forms of familial PD have been defined. However, the etiology and pathogenesis of the majority of sporadic PD cases that occur in outbred populations have yet to be clarified. The recent development of resources such as the International HapMap Project and technological advances in high-throughput genotyping have provided new basis for genetic association studies of common complex diseases, including PD. A new generation of genome-wide association studies will soon offer a potentially powerful approach for mapping causal genes and will likely change treatment and alter our perception of the genetic determinants of PD. However, the execution and analysis of such studies will require great care.

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

    African Journals Online (AJOL)

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

  19. 1 S.I. : Genetic pathways to Neurodegeneration Parkinson's Disease ...

    Indian Academy of Sciences (India)

    Dorit Trudler

    Parkinson's Disease: What the Model Systems Have Taught Us So Far? .... triggered by the finding that the protein α-synuclein (encoded by the SNCA gene) is a ... lower dopamine levels in the GI tract in severely constipated PD patients ..... related genetic defects even in healthy carriers, as well as the variable age of onset ...

  20. genetic variability for tuber yield, quality, and virus disease complex

    African Journals Online (AJOL)

    Administrator

    have not been fully exploited due to limited breeding efforts and poor ... Flowering ability was low in some cultivars and a few did not flower at all. ... tion with other genes in different genetic backgrounds that can modify flesh ... sweetpotato production and utilisation, thus .... expressed as a percentage of diseased plants.

  1. Clinical and genetic data of Huntington disease in Moroccan patients

    African Journals Online (AJOL)

    Background: Huntington's disease (HD) occurs worldwide with prevalence varying from 0.1 to 10 /100,000 depending of the ethnic origin. Since no data is available in the Maghreb population, the aim of this study is to describe clinical and genetic characteristics of Huntington patients of Moroccan origin. Methods: Clinical ...

  2. Genetic epidemiology of coronary artery disease: an Asian Indian ...

    Indian Academy of Sciences (India)

    Coronary artery disease (CAD) has emerged as a major cause of morbidity and mortality worldwide. Recent findings on the role of genetic factors in the aetiopathology of CAD have implicated novel genes and variants in addition to those involved in lipid and lipoprotein metabolism. However, our present knowledge is ...

  3. Genetics Home Reference: glycogen storage disease type I

    Science.gov (United States)

    ... resulting from uric acid crystals in the joints (gout), kidney disease, and high blood pressure in the ... particular ethnic groups? Genetic Changes Mutations in two genes, G6PC and SLC37A4 , cause GSDI. G6PC gene mutations ...

  4. Predictive genetic testing for cardiovascular diseases: Impact on carrier children

    NARCIS (Netherlands)

    Meulenkamp, Tineke M.; Tibben, Aad; Mollema, Eline D.; Van Langen, Irene M.; Wiegman, Albert; De Wert, Guido M.; De Beaufort, Inez D.; Wilde, Arthur A. M.; Smets, Ellen M. A.

    2008-01-01

    We studied the experiences of children identified by family screening who were found to be a mutation carrier for a genetic cardiovascular disease (Long QT Syndrome (LQTS), Hypertrophic Cardiomyopathy (HCM), Familial Hypercholesterolemia (FH)). We addressed the (a) manner in which they perceive

  5. Partial status epilepticus - rapid genetic diagnosis of Alpers' disease.

    LENUS (Irish Health Repository)

    McCoy, Bláthnaid

    2011-11-01

    We describe four children with a devastating encephalopathy characterised by refractory focal seizures and variable liver dysfunction. We describe their electroencephalographic, radiologic, genetic and pathologic findings. The correct diagnosis was established by rapid gene sequencing. POLG1 based Alpers\\' disease should be considered in any child presenting with partial status epilepticus.

  6. Drug Repositioning in Inflammatory Bowel Disease Based on Genetic Information

    NARCIS (Netherlands)

    Collij, Valerie; Festen, Eleonora A. M.; Alberts, Rudi; Weersma, Rinse K.

    2016-01-01

    Background:Currently, 200 genetic risk loci have been identified for inflammatory bowel disease (IBD). Although these findings have significantly advanced our insight into IBD biology, there has been little progress in translating this knowledge toward clinical practice, like more cost-efficient

  7. Is there a Common Genetic Basis for Autoimmune Diseases?

    Directory of Open Access Journals (Sweden)

    Juan-Manuel Anaya

    2006-01-01

    Full Text Available Autoimmune diseases (ADs represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the “common genetic origin” theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sjögren's (pSS syndrome or type 1 diabetes mellitus (T1D. A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22 influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.

  8. CD209 genetic polymorphism and tuberculosis disease.

    Directory of Open Access Journals (Sweden)

    Fredrik O Vannberg

    2008-01-01

    Full Text Available Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded by CD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans. The present study investigates the role of the CD209 -336A/G variant in susceptibility to tuberculosis in a large sample of individuals from sub-Saharan Africa.A total of 2,176 individuals enrolled in tuberculosis case-control studies from four sub-Saharan Africa countries were genotyped for the CD209 -336A/G SNP (rs4804803. Significant overall protection against pulmonary tuberculosis was observed with the -336G allele when the study groups were combined (n = 914 controls vs. 1262 cases, Mantel-Haenszel 2 x 2 chi(2 = 7.47, P = 0.006, odds ratio = 0.86, 95%CI 0.77-0.96. In addition, the patients with -336GG were associated with a decreased risk of cavitory tuberculosis, a severe form of tuberculosis disease (n = 557, Pearson's 2x2 chi(2 = 17.34, P = 0.00003, odds ratio = 0.42, 95%CI 0.27-0.65. This direction of association is opposite to a previously observed result in a smaller study of susceptibility to tuberculosis in a South African Coloured population, but entirely in keeping with the previously observed protective effect of the -336G allele.This study finds that the CD209 -336G variant allele is associated with significant protection against tuberculosis in individuals from sub-Saharan Africa and, furthermore, cases with -336GG were significantly less likely to develop tuberculosis-induced lung cavitation. Previous in vitro work demonstrated that the promoter variant -336G allele causes down-regulation of CD209 mRNA expression. Our present work suggests that decreased levels of the DC-SIGN receptor may therefore be

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  10. Demographic, genetic, and environmental factors that modify disease course.

    Science.gov (United States)

    Marrie, Ruth Ann

    2011-05-01

    As with susceptibility to disease, it is likely that multiple factors interact to influence the phenotype of multiple sclerosis and long-term disease outcomes. Such factors may include genetic factors, socioeconomic status, comorbid diseases, and health behaviors, as well as environmental exposures. An improved understanding of the influence of these factors on disease course may reap several benefits, such as improved prognostication, allowing us to tailor disease management with respect to intensity of disease-modifying therapies and changes in specific health behaviors, in the broad context of coexisting health issues. Such information can facilitate appropriately adjusted comparisons within and between populations. Elucidation of these factors will require careful study of well-characterized populations in which the roles of multiple factors are considered simultaneously. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Genotator: A disease-agnostic tool for genetic annotation of disease

    Directory of Open Access Journals (Sweden)

    Jung Jae-Yoon

    2010-10-01

    Full Text Available Abstract Background Disease-specific genetic information has been increasing at rapid rates as a consequence of recent improvements and massive cost reductions in sequencing technologies. Numerous systems designed to capture and organize this mounting sea of genetic data have emerged, but these resources differ dramatically in their disease coverage and genetic depth. With few exceptions, researchers must manually search a variety of sites to assemble a complete set of genetic evidence for a particular disease of interest, a process that is both time-consuming and error-prone. Methods We designed a real-time aggregation tool that provides both comprehensive coverage and reliable gene-to-disease rankings for any disease. Our tool, called Genotator, automatically integrates data from 11 externally accessible clinical genetics resources and uses these data in a straightforward formula to rank genes in order of disease relevance. We tested the accuracy of coverage of Genotator in three separate diseases for which there exist specialty curated databases, Autism Spectrum Disorder, Parkinson's Disease, and Alzheimer Disease. Genotator is freely available at http://genotator.hms.harvard.edu. Results Genotator demonstrated that most of the 11 selected databases contain unique information about the genetic composition of disease, with 2514 genes found in only one of the 11 databases. These findings confirm that the integration of these databases provides a more complete picture than would be possible from any one database alone. Genotator successfully identified at least 75% of the top ranked genes for all three of our use cases, including a 90% concordance with the top 40 ranked candidates for Alzheimer Disease. Conclusions As a meta-query engine, Genotator provides high coverage of both historical genetic research as well as recent advances in the genetic understanding of specific diseases. As such, Genotator provides a real-time aggregation of ranked

  12. Genotator: a disease-agnostic tool for genetic annotation of disease.

    Science.gov (United States)

    Wall, Dennis P; Pivovarov, Rimma; Tong, Mark; Jung, Jae-Yoon; Fusaro, Vincent A; DeLuca, Todd F; Tonellato, Peter J

    2010-10-29

    Disease-specific genetic information has been increasing at rapid rates as a consequence of recent improvements and massive cost reductions in sequencing technologies. Numerous systems designed to capture and organize this mounting sea of genetic data have emerged, but these resources differ dramatically in their disease coverage and genetic depth. With few exceptions, researchers must manually search a variety of sites to assemble a complete set of genetic evidence for a particular disease of interest, a process that is both time-consuming and error-prone. We designed a real-time aggregation tool that provides both comprehensive coverage and reliable gene-to-disease rankings for any disease. Our tool, called Genotator, automatically integrates data from 11 externally accessible clinical genetics resources and uses these data in a straightforward formula to rank genes in order of disease relevance. We tested the accuracy of coverage of Genotator in three separate diseases for which there exist specialty curated databases, Autism Spectrum Disorder, Parkinson's Disease, and Alzheimer Disease. Genotator is freely available at http://genotator.hms.harvard.edu. Genotator demonstrated that most of the 11 selected databases contain unique information about the genetic composition of disease, with 2514 genes found in only one of the 11 databases. These findings confirm that the integration of these databases provides a more complete picture than would be possible from any one database alone. Genotator successfully identified at least 75% of the top ranked genes for all three of our use cases, including a 90% concordance with the top 40 ranked candidates for Alzheimer Disease. As a meta-query engine, Genotator provides high coverage of both historical genetic research as well as recent advances in the genetic understanding of specific diseases. As such, Genotator provides a real-time aggregation of ranked data that remains current with the pace of research in the disease

  13. Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease.

    Science.gov (United States)

    Murphy, Erin L; Droher, Madeline L; DiMaio, Miriam S; Dahl, Neera K

    2018-03-30

    Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  14. [Leprosy, a pillar of human genetics of infectious diseases].

    Science.gov (United States)

    Gaschignard, J; Scurr, E; Alcaïs, A

    2013-06-01

    Despite a natural reservoir of Mycobacterium leprae limited to humans and free availability of an effective antibiotic treatment, more than 200,000 people develop leprosy each year. This disease remains a major cause of disability and social stigma worldwide. The cause of this constant incidence is currently unknown and indicates that important aspects of the complex relationship between the pathogen and its human host remain to be discovered. An important contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability between individuals sustainably exposed to M. leprae. Given the inability to cultivate M. leprae in vitro and in the absence of relevant animal model, genetic epidemiology is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. Recent genome-wide studies have identified new pathophysiological pathways which importance is only beginning to be understood. In addition, the prism of human genetics placed leprosy at the crossroads of other common diseases such as Crohn's disease, asthma or myocardial infarction. Therefore, novel lights on the pathogenesis of many common diseases could eventually emerge from the detailed understanding of a disease of the shadows. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease.

    Science.gov (United States)

    Losekoot, Monique; van Belzen, Martine J; Seneca, Sara; Bauer, Peter; Stenhouse, Susan A R; Barton, David E

    2013-05-01

    Huntington disease (HD) is caused by the expansion of an unstable polymorphic trinucleotide (CAG)n repeat in exon 1 of the HTT gene, which translates into an extended polyglutamine tract in the protein. Laboratory diagnosis of HD involves estimation of the number of CAG repeats. Molecular genetic testing for HD is offered in a wide range of laboratories both within and outside the European community. In order to measure the quality and raise the standard of molecular genetic testing in these laboratories, the European Molecular Genetics Quality Network has organized a yearly external quality assessment (EQA) scheme for molecular genetic testing of HD for over 10 years. EQA compares a laboratory's output with a fixed standard both for genotyping and reporting of the results to the referring physicians. In general, the standard of genotyping is very high but the clarity of interpretation and reporting of the test result varies more widely. This emphasizes the need for best practice guidelines for this disorder. We have therefore developed these best practice guidelines for genetic testing for HD to assist in testing and reporting of results. The analytical methods and the potential pitfalls of molecular genetic testing are highlighted and the implications of the different test outcomes for the consultand and his or her family members are discussed.

  16. Combination of genetics and spatial modelling highlights the sensitivity of cod (Gadus morhua) population diversity in the North Sea to distributions of fishing

    DEFF Research Database (Denmark)

    Heath, Michael R.; Culling, Mark A.; Crozier, Walter W.

    2014-01-01

    Conserving genetic diversity in animal populations is important for sustaining their ability to respond to environmental change. However, the “between-population” component of genetic diversity (biocomplexity) is threatened in many exploited populations, particularly marine fish, where harvest ma...

  17. Genetic background in nonalcoholic fatty liver disease: A comprehensive review

    Science.gov (United States)

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-01-01

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

  18. Multi-taxa integrated landscape genetics for zoonotic infectious diseases: deciphering variables influencing disease emergence.

    Science.gov (United States)

    Leo, Sarah S T; Gonzalez, Andrew; Millien, Virginie

    2016-05-01

    Zoonotic disease transmission systems involve sets of species interacting with each other and their environment. This complexity impedes development of disease monitoring and control programs that require reliable identification of spatial and biotic variables and mechanisms facilitating disease emergence. To overcome this difficulty, we propose a framework that simultaneously examines all species involved in disease emergence by integrating concepts and methods from population genetics, landscape ecology, and spatial statistics. Multi-taxa integrated landscape genetics (MTILG) can reveal how interspecific interactions and landscape variables influence disease emergence patterns. We test the potential of our MTILG-based framework by modelling the emergence of a disease system across multiple species dispersal, interspecific interaction, and landscape scenarios. Our simulations showed that both interspecific-dependent dispersal patterns and landscape characteristics significantly influenced disease spread. Using our framework, we were able to detect statistically similar inter-population genetic differences and highly correlated spatial genetic patterns that imply species-dependent dispersal. Additionally, species that were assigned coupled-dispersal patterns were affected to the same degree by similar landscape variables. This study underlines the importance of an integrated approach to investigating emergence of disease systems. MTILG is a robust approach for such studies and can identify potential avenues for targeted disease management strategies.

  19. Exploring Genetic Factors Involved in Huntington Disease Age of Onset

    DEFF Research Database (Denmark)

    Valcárcel-Ocete, Leire; Alkorta-Aranburu, Gorka; Iriondo, Mikel

    2015-01-01

    age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample......Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim...... of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms...

  20. Shared genetics in coeliac disease and other immune-mediated diseases

    NARCIS (Netherlands)

    Gutierrez-Achury, J.; Coutinho de Almeida, R.; Wijmenga, C.

    Gutierrez-Achury J, Coutinho de Almeida R, Wijmenga C (University Medical Centre Groningen and University of Groningen, Groningen, the Netherlands; University of Brasilia School of Health Sciences, Brasilia, DF, Brazil). Shared genetics in coeliac disease and other immune-mediated diseases

  1. Genetic biomarkers for brain hemisphere differentiation in Parkinson's Disease

    Science.gov (United States)

    Hourani, Mou'ath; Mendes, Alexandre; Berretta, Regina; Moscato, Pablo

    2007-11-01

    This work presents a study on the genetic profile of the left and right hemispheres of the brain of a mouse model of Parkinson's disease (PD). The goal is to characterize, in a genetic basis, PD as a disease that affects these two brain regions in different ways. Using the same whole-genome microarray expression data introduced by Brown et al. (2002) [1], we could find significant differences in the expression of some key genes, well-known to be involved in the mechanisms of dopamine production control and PD. The problem of selecting such genes was modeled as the MIN (α,β)—FEATURE SET problem [2]; a similar approach to that employed previously to find biomarkers for different types of cancer using gene expression microarray data [3]. The Feature Selection method produced a series of genetic signatures for PD, with distinct expression profiles in the Parkinson's model and control mice experiments. In addition, a close examination of the genes composing those signatures shows that many of them belong to genetic pathways or have ontology annotations considered to be involved in the onset and development of PD. Such elements could provide new clues on which mechanisms are implicated in hemisphere differentiation in PD.

  2. Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario.

    Science.gov (United States)

    Ali, Muhammad Umar; Rahman, Muhammad Saif Ur; Cao, Jiang; Yuan, Ping Xi

    2017-08-01

    Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies.

  3. Splicing modulation therapy in the treatment of genetic diseases

    Directory of Open Access Journals (Sweden)

    Arechavala-Gomeza V

    2014-12-01

    Full Text Available Virginia Arechavala-Gomeza,1 Bernard Khoo,2 Annemieke Aartsma-Rus3 1Neuromuscular Disorders Group, BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain; 2Endocrinology, Division of Medicine, University College London, London, UK; 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands All authors contributed equally to this manuscript Abstract: Antisense-mediated splicing modulation is a tool that can be exploited in several ways to provide a potential therapy for rare genetic diseases. This approach is currently being tested in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy. The present review outlines the versatility of the approach to correct cryptic splicing, modulate alternative splicing, restore the open reading frame, and induce protein knockdown, providing examples of each. Finally, we outline a possible path forward toward the clinical application of this approach for a wide variety of inherited rare diseases. Keywords: splicing, therapy, antisense oligonucleotides, cryptic splicing, alternative splicing

  4. Genetic diversity of disease-associated loci in Turkish population.

    Science.gov (United States)

    Karaca, Sefayet; Cesuroglu, Tomris; Karaca, Mehmet; Erge, Sema; Polimanti, Renato

    2015-04-01

    Many consortia and international projects have investigated the human genetic variation of a large number of ethno-geographic groups. However, populations with peculiar genetic features, such as the Turkish population, are still absent in publically available datasets. To explore the genetic predisposition to health-related traits of the Turkish population, we analyzed 34 genes associated with different health-related traits (for example, lipid metabolism, cardio-vascular diseases, hormone metabolism, cellular detoxification, aging and energy metabolism). We observed relevant differences between the Turkish population and populations with non-European ancestries (that is, Africa and East Asia) in some of the investigated genes (that is, AGT, APOE, CYP1B1, GNB3, IL10, IL6, LIPC and PON1). As most complex traits are highly polygenic, we developed polygenic scores associated with different health-related traits to explore the genetic diversity of the Turkish population with respect to other human groups. This approach showed significant differences between the Turkish population and populations with non-European ancestries, as well as between Turkish and Northern European individuals. This last finding is in agreement with the genetic structure of European and Middle East populations, and may also agree with epidemiological evidences about the health disparities of Turkish communities in Northern European countries.

  5. Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases

    Science.gov (United States)

    Gaschignard, Jean; Grant, Audrey Virginia; Thuc, Nguyen Van; Orlova, Marianna; Cobat, Aurélie; Huong, Nguyen Thu; Ba, Nguyen Ngoc; Thai, Vu Hong; Abel, Laurent; Schurr, Erwin; Alcaïs, Alexandre

    2016-01-01

    After sustained exposure to Mycobacterium leprae, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This “polarization” of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes. Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy. PMID:27219008

  6. A case report highlighting the growing trend of Internet-based self-diagnosis of "Morgellon's disease".

    Science.gov (United States)

    Mortillaro, Gino; Rodgman, Christopher; Kinzie, Erik; Ryals, Sarah

    2013-01-01

    "Morgellon's Disease" is a term used to describe a bizarre condition characterized by the belief that strange sensations in the skin are due to filaments called "Morgellon's Bodies."' The focus of this case report is to inform readers of the growing incidence of this psychosomatic condition. Unfortunately, self-diagnosis has become increasingly common because of the widespread coverage on the Internet. While the validity of the diagnosis is in question, the impact on patient's lives is real, often debilitating, and bears more examination.

  7. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

    DEFF Research Database (Denmark)

    Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana

    2017-01-01

    BACKGROUND: Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between...

  8. G protein-coupled receptor mutations and human genetic disease.

    Science.gov (United States)

    Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

    2014-01-01

    Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common

  9. Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.

    Directory of Open Access Journals (Sweden)

    Ole A Andreassen

    Full Text Available Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS to investigate shared single nucleotide polymorphisms (SNPs between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals, applying new False Discovery Rate (FDR methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG, low density lipoproteins (LDL, high density lipoproteins (HDL] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis. We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88, LDL (n = 87 and HDL (n = 52. Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2 and intestinal host-microbe interactions (e.g. ATG16L1. We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

  10. Disease-threat model explains acceptance of genetically modified products

    Directory of Open Access Journals (Sweden)

    Prokop Pavol

    2013-01-01

    Full Text Available Natural selection favoured survival of individuals who were able to avoid disease. The behavioural immune system is activated especially when our sensory system comes into contact with disease-connoting cues and/or when these cues resemble disease threat. We investigated whether or not perception of modern risky technologies, risky behaviour, expected reproductive goals and food neophobia are associated with the behavioural immune system related to specific attitudes toward genetically modified (GM products. We found that respondents who felt themselves more vulnerable to infectious diseases had significantly more negative attitudes toward GM products. Females had less positive attitudes toward GM products, but engaging in risky behaviours, the expected reproductive goals of females and food neophobia did not predict attitudes toward GM products. Our results suggest that evolved psychological mechanisms primarily designed to protect us against pathogen threat are activated by modern technologies possessing potential health risks.

  11. Understanding Celiac Disease From Genetics to the Future Diagnostic Strategies

    Directory of Open Access Journals (Sweden)

    Carolina Salazar

    2017-07-01

    Full Text Available Celiac disease (CD is an autoimmune disorder characterized by the permanent inflammation of the small bowel, triggered by the ingestion of gluten. It is associated with a number of symptoms, the most common being gastrointestinal. The prevalence of this illness worldwide is 1%. One of the main problems of CD is its difficulty to be diagnosed due to the various presentations of the disease. Besides, in many cases, CD is asymptomatic. Celiac disease is a multifactorial disease, HLA-DQ2 and HLA-DQ8 haplotypes are predisposition factors. Nowadays, molecular markers are being studied as diagnostic tools. In this review, we explore CD from its basic concept, manifestations, types, current and future methods of diagnosis, and associated disorders. Before addressing the therapeutic approaches, we also provide a brief overview of CD genetics and treatment.

  12. Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease

    NARCIS (Netherlands)

    van der Harst, Pim; Verweij, Niek

    2018-01-01

    Rationale: Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic

  13. Neglected Tropical Diseases among Two Indigenous Subtribes in Peninsular Malaysia: Highlighting Differences and Co-Infection of Helminthiasis and Sarcocystosis

    Science.gov (United States)

    Lee, Soo Ching; Ngui, Romano; Tan, Tiong Kai; Muhammad Aidil, Roslan; Lim, Yvonne Ai Lian

    2014-01-01

    Soil-transmitted helminth (STH) infections have been documented among these minority groups since 1938. However the prevalence of STH is still high among these communities. Most studies tend to consider the Orang Asli (indigenous) as a homogenous group. In contrary, different subtribes have their own cultural practices. To understand this variation better, we studied the prevalence and associated factors of STH and other gut parasitic infections among two common subtribes (i.e. Temuan and Temiar). Results showed that the prevalence of the overall STH infections was higher in the Temuan subtribe (53.2% of 171) compared to the Temiar subtribe (52.7% of 98). Trichuris trichiura (46.2%) was the most prevalent parasite in the Temuan subtribe, followed by Ascaris spp. (25.7%) and hookworm (4.1%). In contrast, Ascaris spp. (39.8%) was more prevalent among the Temiar subtribe, preceded by T. trichiura (35.7%) and finally hookworm (8.3%). There were also co-infections of helminthiasis and intestinal protozoa among both Temuan and Temiar subtribes with rates being three times higher among the Temiar compared to Temuan. The most common co-infection was with Entamoeba histolytica/dispar/moshkovskii (n = 24; 24.5%, 16.0–33.0), followed by Giardia spp. (n = 3; 3.1%, −0.3–6.5). In Temuan, STH infection individuals were also infected with Entamoeba histolytica/dispar/moshkovskii (n = 11; 6.4%, 5.0–13.8), Cryptosporidium spp. (n = 3, 1.8%, −0.2–3.8) and Giardia spp. (n = 2, 1.2%, −0.4–2.8). In comparison, there was no Cryptosporidium spp. detected among the Temiar. However, it was interesting to note that there was an occurrence of co-infection of intestinal helminthiasis and sarcocystosis (intestinal) in a Temiar individual. The last report of sarcocystosis (muscular) among the Orang Asli was in 1978. The present study highlighted the importance of understanding the variation of infections amongst the different Orang Asli subtribes. It is vital

  14. Neglected tropical diseases among two indigenous subtribes in peninsular Malaysia: highlighting differences and co-infection of helminthiasis and sarcocystosis.

    Directory of Open Access Journals (Sweden)

    Soo Ching Lee

    Full Text Available Soil-transmitted helminth (STH infections have been documented among these minority groups since 1938. However the prevalence of STH is still high among these communities. Most studies tend to consider the Orang Asli (indigenous as a homogenous group. In contrary, different subtribes have their own cultural practices. To understand this variation better, we studied the prevalence and associated factors of STH and other gut parasitic infections among two common subtribes (i.e. Temuan and Temiar. Results showed that the prevalence of the overall STH infections was higher in the Temuan subtribe (53.2% of 171 compared to the Temiar subtribe (52.7% of 98. Trichuris trichiura (46.2% was the most prevalent parasite in the Temuan subtribe, followed by Ascaris spp. (25.7% and hookworm (4.1%. In contrast, Ascaris spp. (39.8% was more prevalent among the Temiar subtribe, preceded by T. trichiura (35.7% and finally hookworm (8.3%. There were also co-infections of helminthiasis and intestinal protozoa among both Temuan and Temiar subtribes with rates being three times higher among the Temiar compared to Temuan. The most common co-infection was with Entamoeba histolytica/dispar/moshkovskii (n = 24; 24.5%, 16.0-33.0, followed by Giardia spp. (n = 3; 3.1%, -0.3-6.5. In Temuan, STH infection individuals were also infected with Entamoeba histolytica/dispar/moshkovskii (n = 11; 6.4%, 5.0-13.8, Cryptosporidium spp. (n = 3, 1.8%, -0.2-3.8 and Giardia spp. (n = 2, 1.2%, -0.4-2.8. In comparison, there was no Cryptosporidium spp. detected among the Temiar. However, it was interesting to note that there was an occurrence of co-infection of intestinal helminthiasis and sarcocystosis (intestinal in a Temiar individual. The last report of sarcocystosis (muscular among the Orang Asli was in 1978. The present study highlighted the importance of understanding the variation of infections amongst the different Orang Asli subtribes. It is vital to note these

  15. Neglected tropical diseases among two indigenous subtribes in peninsular Malaysia: highlighting differences and co-infection of helminthiasis and sarcocystosis.

    Science.gov (United States)

    Lee, Soo Ching; Ngui, Romano; Tan, Tiong Kai; Muhammad Aidil, Roslan; Lim, Yvonne Ai Lian

    2014-01-01

    Soil-transmitted helminth (STH) infections have been documented among these minority groups since 1938. However the prevalence of STH is still high among these communities. Most studies tend to consider the Orang Asli (indigenous) as a homogenous group. In contrary, different subtribes have their own cultural practices. To understand this variation better, we studied the prevalence and associated factors of STH and other gut parasitic infections among two common subtribes (i.e. Temuan and Temiar). Results showed that the prevalence of the overall STH infections was higher in the Temuan subtribe (53.2% of 171) compared to the Temiar subtribe (52.7% of 98). Trichuris trichiura (46.2%) was the most prevalent parasite in the Temuan subtribe, followed by Ascaris spp. (25.7%) and hookworm (4.1%). In contrast, Ascaris spp. (39.8%) was more prevalent among the Temiar subtribe, preceded by T. trichiura (35.7%) and finally hookworm (8.3%). There were also co-infections of helminthiasis and intestinal protozoa among both Temuan and Temiar subtribes with rates being three times higher among the Temiar compared to Temuan. The most common co-infection was with Entamoeba histolytica/dispar/moshkovskii (n = 24; 24.5%, 16.0-33.0), followed by Giardia spp. (n = 3; 3.1%, -0.3-6.5). In Temuan, STH infection individuals were also infected with Entamoeba histolytica/dispar/moshkovskii (n = 11; 6.4%, 5.0-13.8), Cryptosporidium spp. (n = 3, 1.8%, -0.2-3.8) and Giardia spp. (n = 2, 1.2%, -0.4-2.8). In comparison, there was no Cryptosporidium spp. detected among the Temiar. However, it was interesting to note that there was an occurrence of co-infection of intestinal helminthiasis and sarcocystosis (intestinal) in a Temiar individual. The last report of sarcocystosis (muscular) among the Orang Asli was in 1978. The present study highlighted the importance of understanding the variation of infections amongst the different Orang Asli subtribes. It is vital to note these

  16. Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease.

    Science.gov (United States)

    Jammoul, Adham; Lederman, Richard J; Tavee, Jinny; Li, Yuebing

    2014-06-05

    Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is the rare instance when a positive VGKC complex antibody titre occurs in a definite case of prion disease. We present a pathologically and genetically confirmed case of CJD with elevated serum VGKC complex antibody titres. This case highlights the importance of interpreting the result of a positive VGKC complex antibody with caution and in the context of the overall clinical manifestation. 2014 BMJ Publishing Group Ltd.

  17. Genetic mouse models of brain ageing and Alzheimer's disease.

    Science.gov (United States)

    Bilkei-Gorzo, Andras

    2014-05-01

    Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression

    DEFF Research Database (Denmark)

    Ren, Shancheng; Wei, Gong-Hong; Liu, Dongbing

    2018-01-01

    BACKGROUND: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. OBJECTIVE: To systematically explore the genomic complexity and define disease-driven genetic......-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment....... alterations in PCa. DESIGN, SETTING, AND PARTICIPANTS: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. OUTCOME...

  19. Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.

    Science.gov (United States)

    Ringman, John M; Goate, Alison; Masters, Colin L; Cairns, Nigel J; Danek, Adrian; Graff-Radford, Neill; Ghetti, Bernardino; Morris, John C

    2014-11-01

    Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.

  20. The genetics of Alzheimer disease: back to the future.

    Science.gov (United States)

    Bertram, Lars; Lill, Christina M; Tanzi, Rudolph E

    2010-10-21

    Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Clinical highlights from Amsterdam

    Directory of Open Access Journals (Sweden)

    Jouke T. Annema

    2016-07-01

    Full Text Available This article contains highlights and a selection of the scientific advances from the Clinical Assembly that were presented at the 2015 European Respiratory Society International Congress in Amsterdam, the Netherlands. The most relevant topics for clinicians will be discussed, covering a wide range of areas including interventional pulmonology, rehabilitation and chronic care, thoracic imaging, diffuse and parenchymal lung diseases, and general practice and primary care. In this comprehensive review, exciting novel data will be discussed and put into perspective.

  2. Genetic Manipulations of PPARs: Effects on Obesity and Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Yaacov Barak

    2007-01-01

    Full Text Available The interest in genetic manipulations of PPARs is as old as their discovery as receptors of ligands with beneficial clinical activities. Considering the effects of PPAR ligands on critical aspects of systemic physiology, including obesity, lipid metabolism, insulin resistance, and diabetes, gene knockout (KO in mice is the ideal platform for both hypothesis testing and discovery of new PPAR functions in vivo. With the fervent pursuit of the magic bullet to eradicate the obesity epidemic, special emphasis has been placed on the impacts of PPARs on obesity and its associated diseases. As detailed in this review, understanding how PPARs regulate gene expression and basic metabolic pathways is a necessary intermediate en route to deciphering their effects on obesity. Over a decade and dozens of genetic modifications of PPARs into this effort, valuable lessons have been learned, but we are left with more questions to be answered. These lessons and future prospects are the subject of this review.

  3. The Congenital Heart Disease Genetic Network Study: Cohort description.

    Directory of Open Access Journals (Sweden)

    Thanh T Hoang

    Full Text Available The Pediatric Cardiac Genomics Consortium (PCGC designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome. Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727 and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40% or left ventricular outflow tract obstruction (21%. Across CHD types, there were significant differences (p<0.05 in the distribution of all four case characteristics (e.g., sex, four parental characteristics (e.g., maternal pregestational diabetes, and five neurodevelopmental outcomes (e.g., learning disabilities. Several characteristics (e.g., sex were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

  4. Recent advances in antisense oligonucleotide therapy in genetic neuromuscular diseases

    Directory of Open Access Journals (Sweden)

    Ashok Verma

    2018-01-01

    Full Text Available Genetic neuromuscular diseases are caused by defective expression of nuclear or mitochondrial genes. Mutant genes may reduce expression of wild-type proteins, and strategies to activate expression of the wild-type proteins might provide therapeutic benefits. Also, a toxic mutant protein may cause cell death, and strategies that reduce mutant gene expression may provide therapeutic benefit. Synthetic antisense oligonucleotide (ASO can recognize cellular RNA and control gene expression. In recent years, advances in ASO chemistry, creation of designer ASO molecules to enhance their safety and target delivery, and scientific controlled clinical trials to ascertain their therapeutic safety and efficacy have led to an era of plausible application of ASO technology to treat currently incurable neuromuscular diseases. Over the past 1 year, for the first time, the United States Food and Drug Administration has approved two ASO therapies in genetic neuromuscular diseases. This overview summarizes the recent advances in ASO technology, evolution and use of synthetic ASOs as a therapeutic platform, and the mechanism of ASO action by exon-skipping in Duchenne muscular dystrophy and exon-inclusion in spinal muscular atrophy, with comments on their advantages and limitations.

  5. Genetics of sputum gene expression in chronic obstructive pulmonary disease.

    Directory of Open Access Journals (Sweden)

    Weiliang Qiu

    Full Text Available Previous expression quantitative trait loci (eQTL studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs. The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5, the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.

  6. Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease

    Science.gov (United States)

    Qiu, Weiliang; Cho, Michael H.; Riley, John H.; Anderson, Wayne H.; Singh, Dave; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A.; Lomas, David A.; Crapo, James D.; Beaty, Terri H.; Celli, Bartolome R.; Rennard, Stephen; Tal-Singer, Ruth; Fox, Steven M.; Silverman, Edwin K.; Hersh, Craig P.

    2011-01-01

    Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus. PMID:21949713

  7. Molecular identification of GAPDHs in cassava highlights the antagonism of MeGAPCs and MeATG8s in plant disease resistance against cassava bacterial blight.

    Science.gov (United States)

    Zeng, Hongqiu; Xie, Yanwei; Liu, Guoyin; Lin, Daozhe; He, Chaozu; Shi, Haitao

    2018-06-01

    MeGAPCs were identified as negative regulators of plant disease resistance, and the interaction of MeGAPCs and MeATG8s was highlighted in plant defense response. As an important enzyme of glycolysis metabolic pathway, glyceraldehyde-3-P dehydrogenase (GAPDH) plays important roles in plant development, abiotic stress and immune responses. Cassava (Manihot esculenta) is most important tropical crop and one of the major food crops, however, no information is available about GAPDH gene family in cassava. In this study, 14 MeGAPDHs including 6 cytosol GAPDHs (MeGAPCs) were identified from cassava, and the transcripts of 14 MeGAPDHs in response to Xanthomonas axonopodis pv manihotis (Xam) indicated their possible involvement in immune responses. Further investigation showed that MeGAPCs are negative regulators of disease resistance against Xam. Through transient expression in Nicotiana benthamiana, we found that overexpression of MeGAPCs led to decreased disease resistance against Xam. On the contrary, MeGAPCs-silenced cassava plants through virus-induced gene silencing (VIGS) conferred improved disease resistance. Notably, MeGAPCs physically interacted with autophagy-related protein 8b (MeATG8b) and MeATG8e and inhibited autophagic activity. Moreover, MeATG8b and MeATG8e negatively regulated the activities of NAD-dependent MeGAPDHs, and are involved in MeGAPCs-mediated disease resistance. Taken together, this study highlights the involvement of MeGAPCs in plant disease resistance, through interacting with MeATG8b and MeATG8e.

  8. Genetic prion disease: no role for the immune system in disease pathogenesis?

    Science.gov (United States)

    Friedman-Levi, Yael; Binyamin, Orli; Frid, Kati; Ovadia, Haim; Gabizon, Ruth

    2014-08-01

    Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Co-circulation of two extremely divergent serotype SAT 2 lineages in Kenya highlights challenges to foot-and-mouth disease control

    DEFF Research Database (Denmark)

    Sangula, Abraham; Belsham, Graham; Muwanika, Vincent

    2010-01-01

    Amongst the SAT serotypes of foot-and-mouth disease virus (FMDV), the SAT 2 serotype is the most widely distributed throughout sub-Saharan Africa. Kenyan serotype SAT 2 viruses have been reported to display the highest genetic diversity for the serotype globally. This complicates diagnosis...... and control, and it is essential that patterns of virus circulation are known in order to overcome these difficulties. This study was undertaken to establish patterns of evolution of FMDV serotype SAT 2 in Kenya using complete VP1 coding sequences in a dataset of 65 sequences from Africa, collected over...

  10. A Multi-Marker Genetic Association Test Based on the Rasch Model Applied to Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Wenjia Wang

    Full Text Available Results from Genome-Wide Association Studies (GWAS have shown that the genetic basis of complex traits often include many genetic variants with small to moderate effects whose identification remains a challenging problem. In this context multi-marker analysis at the gene and pathway level can complement traditional point-wise approaches that treat the genetic markers individually. In this paper we propose a novel statistical approach for multi-marker analysis based on the Rasch model. The method summarizes the categorical genotypes of SNPs by a generalized logistic function into a genetic score that can be used for association analysis. Through different sets of simulations, the false-positive rate and power of the proposed approach are compared to a set of existing methods, and shows good performances. The application of the Rasch model on Alzheimer's Disease (AD ADNI GWAS dataset also allows a coherent interpretation of the results. Our analysis supports the idea that APOE is a major susceptibility gene for AD. In the top genes selected by proposed method, several could be functionally linked to AD. In particular, a pathway analysis of these genes also highlights the metabolism of cholesterol, that is known to play a key role in AD pathogenesis. Interestingly, many of these top genes can be integrated in a hypothetic signalling network.

  11. Beyond the patient: the broader impact of genetic discrimination among individuals at risk of Huntington disease.

    Science.gov (United States)

    Bombard, Yvonne; Palin, JoAnne; Friedman, Jan M; Veenstra, Gerry; Creighton, Susan; Bottorff, Joan L; Hayden, Michael R

    2012-03-01

    We aimed to address gaps in current understanding of the scope and impact of discrimination, by examining a cohort of individuals at-risk for Huntington disease (HD), to describe the prevalence of concern for oneself and one's family in multiple domains; strategies used to mitigate discrimination; and the extent to which concerns relate to experiences. We conducted a cross-sectional survey of 293 individuals at-risk for HD (80% response rate); 167 respondents were genetically tested and 66 were not. Fear of discrimination was widespread (86%), particularly in the insurance, family and social settings. Approximately half of concerned individuals experienced discrimination (40-62%, depending on genetic status). Concern was associated with "keeping quiet" about one's risk of HD or "taking action to avoid" discrimination. Importantly, concern was highly distressing for some respondents (21% for oneself; 32% for relatives). Overall, concerned respondents with high education levels, who discovered their family history at a younger age, and those who were mutation-positive were more likely to report experiences of discrimination than others who were concerned. Concerns were rarely attributed to genetic test results alone. Concern about genetic discrimination is frequent among individuals at-risk of HD and spans many settings. It influences behavioral patterns and can result in high levels of self-rated distress, highlighting the need for practice and policy interventions. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

  12. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease.

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    Sanjeev Rajakulendran

    Full Text Available Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA. Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS, one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO. All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.

  13. Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula

    Directory of Open Access Journals (Sweden)

    Giraldo Pilar

    2012-03-01

    Full Text Available Abstract Background Gaucher disease (GD is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics. Methods We evaluated the distribution, and clinical and genetic characteristics of GD patients in the Iberian Peninsula (IP. We analysed geographical distribution, demographic, genetic and clinical data, age at diagnosis, type, and years of therapy in 436 GD patients from the IP. Results The prevalence of GD was 1/149,000 inhabitants; 88.3% were type 1, 6.7% type 2, and 5.0% type 3. The mean age at diagnosis in type 1 was 28.7 years. A total of 72.7% were classified as having mild forms, 25.5% moderate, and 1.7% severe. Anemia and thrombocytopenia were present in 56% and 55%, respectively. Bone disease and hepatomegaly were reported in 62% and 68%, respectively, and were more likely in asplenic than in non-splenectomized patients. Sixty-nine mutant alleles were identified, and five mutations accounted for 75% of the GBA alleles. Several patients described in our series had interesting phenotypes. A total of 58.7% of patients had received enzyme replacement therapy and 12.6% were treated with miglustat. Conclusions A broad spectrum of GBA mutations is present in the IP, with 98.2% of type 1 GD being mild and 23.0% never treated. These data highlight genetic and phenotypic heterogeneities among geographic populations.

  14. Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula

    Science.gov (United States)

    2012-01-01

    Background Gaucher disease (GD) is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics. Methods We evaluated the distribution, and clinical and genetic characteristics of GD patients in the Iberian Peninsula (IP). We analysed geographical distribution, demographic, genetic and clinical data, age at diagnosis, type, and years of therapy in 436 GD patients from the IP. Results The prevalence of GD was 1/149,000 inhabitants; 88.3% were type 1, 6.7% type 2, and 5.0% type 3. The mean age at diagnosis in type 1 was 28.7 years. A total of 72.7% were classified as having mild forms, 25.5% moderate, and 1.7% severe. Anemia and thrombocytopenia were present in 56% and 55%, respectively. Bone disease and hepatomegaly were reported in 62% and 68%, respectively, and were more likely in asplenic than in non-splenectomized patients. Sixty-nine mutant alleles were identified, and five mutations accounted for 75% of the GBA alleles. Several patients described in our series had interesting phenotypes. A total of 58.7% of patients had received enzyme replacement therapy and 12.6% were treated with miglustat. Conclusions A broad spectrum of GBA mutations is present in the IP, with 98.2% of type 1 GD being mild and 23.0% never treated. These data highlight genetic and phenotypic heterogeneities among geographic populations. PMID:22429443

  15. The importance of genetics in the diagnosis of animal diseases - A ...

    African Journals Online (AJOL)

    The use of recombinant DNA techniques in conjunction with conventional genetic methods have led to a rapid increase in knowledge of the genetic map. Many animal genes have been mapped to chromosomes. A detailed genetic map has become of great value in the diagnosis of genetic diseases and in the development ...

  16. Comparative analysis of spatial genetic structure in an ant-plant symbiosis reveals a tension zone and highlights speciation processes in tropical Africa

    NARCIS (Netherlands)

    Blatrix, Rumsaïs; Peccoud, Jean; Born, Céline; Piatscheck, Finn; Benoit, Laure; Sauve, Mathieu; Djiéto-Lordon, Champlain; Atteke, Christiane; Wieringa, Jan J.; Harris, David J.; Mckey, Doyle

    2017-01-01

    Aim: Pleistocene climatic oscillations induced range fluctuations in African rain forest organisms and may have shaped species diversification through allopatric speciation events. We compared the spatial genetic structure of two forest species that live in obligate symbiosis and thus must have

  17. Genetic characteristics of inflammatory bowel disease in a Japanese population.

    Science.gov (United States)

    Fuyuno, Yuta; Yamazaki, Keiko; Takahashi, Atsushi; Esaki, Motohiro; Kawaguchi, Takaaki; Takazoe, Masakazu; Matsumoto, Takayuki; Matsui, Toshiyuki; Tanaka, Hiroki; Motoya, Satoshi; Suzuki, Yasuo; Kiyohara, Yutaka; Kitazono, Takanari; Kubo, Michiaki

    2016-07-01

    Crohn's disease (CD) and ulcerative colitis (UC) are two major forms of inflammatory bowel disease (IBD). Meta-analyses of genome-wide association studies (GWAS) have identified 163 susceptibility loci for IBD among European populations; however, there is limited information for IBD susceptibility in a Japanese population. We performed a GWAS using imputed genotypes of 743 IBD patients (372 with CD and 371 with UC) and 3321 controls. Using 100 tag single-nucleotide polymorphisms (SNPs) (P Japanese and European populations. In the IBD GWAS, two East Asia-specific IBD susceptibility loci were identified in the Japanese population: ATG16L2-FCHSD2 and SLC25A15-ELF1-WBP4. Among 163 reported SNPs in European IBD patients, significant associations were confirmed in 18 (8 CD-specific, 4 UC-specific, and 6 IBD-shared). In Japanese CD patients, genes in the Th17-IL23 pathway showed stronger genetic effects, whereas the association of genes in the autophagy pathway was limited. The association of genes in the epithelial barrier and the Th17-IL23R pathways were similar in the Japanese and European UC populations. We confirmed two IBD susceptibility loci as common for CD and UC, and East Asian-specific. The genetic architecture in UC appeared to be similar between Europeans and East Asians, but may have some differences in CD.

  18. Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

    Directory of Open Access Journals (Sweden)

    Agostino Di Ciaula

    2013-01-01

    Full Text Available Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.

  19. Molecular genetics of early-onset Alzheimer's disease revisited.

    Science.gov (United States)

    Cacace, Rita; Sleegers, Kristel; Van Broeckhoven, Christine

    2016-06-01

    As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Perceptions of genetic discrimination among people at risk for Huntington's disease: a cross sectional survey.

    Science.gov (United States)

    Bombard, Yvonne; Veenstra, Gerry; Friedman, Jan M; Creighton, Susan; Currie, Lauren; Paulsen, Jane S; Bottorff, Joan L; Hayden, Michael R

    2009-06-09

    To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington's disease who had undergone genetic testing or remained untested. Cross sectional, self reported survey. Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. 233 genetically tested and untested asymptomatic people at risk for Huntington's disease (response rate 80%): 167 underwent testing (83 had the Huntington's disease mutation, 84 did not) and 66 chose not to be tested. Self reported experiences of genetic discrimination and related psychological distress based on family history or genetic test results. Discrimination was reported by 93 respondents (39.9%). Reported experiences occurred most often in insurance (29.2%), family (15.5%), and social (12.4%) settings. There were few reports of discrimination in employment (6.9%), health care (8.6%), or public sector settings (3.9%). Although respondents who were aware that they carried the Huntington's disease mutation reported the highest levels of discrimination, participation in genetic testing was not associated with increased levels of genetic discrimination. Family history of Huntington's disease, rather than the result of genetic testing, was the main reason given for experiences of genetic discrimination. Psychological distress was associated with genetic discrimination (PGenetic discrimination was commonly reported by people at risk for Huntington's disease and was a source of psychological distress. Family history, and not genetic testing, was the major reason for genetic discrimination.

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

    Science.gov (United States)

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

    2016-07-01

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

  2. The National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a national genetics data repository facilitating access to genotypic...

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

    Science.gov (United States)

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

    2012-08-01

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

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

    Science.gov (United States)

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

    2012-01-01

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

  5. Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

    Science.gov (United States)

    Friedman-Levi, Yael; Meiner, Zeev; Canello, Tamar; Frid, Kati; Kovacs, Gabor G.; Budka, Herbert; Avrahami, Dana; Gabizon, Ruth

    2011-01-01

    Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments. PMID:22072968

  6. Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease.

    Directory of Open Access Journals (Sweden)

    Yael Friedman-Levi

    2011-11-01

    Full Text Available Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K, causing genetic Creutzfeldt-Jakob disease (gCJD in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5-6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

  7. Genetics

    DEFF Research Database (Denmark)

    Christensen, Kaare; McGue, Matt

    2016-01-01

    The sequenced genomes of individuals aged ≥80 years, who were highly educated, self-referred volunteers and with no self-reported chronic diseases were compared to young controls. In these data, healthy ageing is a distinct phenotype from exceptional longevity and genetic factors that protect...

  8. Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

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    Jingyu Liu

    2018-03-01

    Full Text Available Huntington’s disease (HD is a neurodegenerative disorder caused by an expansion mutation of the cytosine–adenine–guanine (CAG trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715, we extracted gray matter (GM components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age. Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.

  9. Considerations for subgroups and phenocopies in complex disease genetics.

    Directory of Open Access Journals (Sweden)

    Ryan Ramanujam

    Full Text Available The number of identified genetic variants associated to complex disease cannot fully explain heritability. This may be partially due to more complicated patterns of predisposition than previously suspected. Diseases such as multiple sclerosis (MS may consist of multiple disease causing mechanisms, each comprised of several elements. We describe how the effect of subgroups can be calculated using the standard association measurement odds ratio, which is then manipulated to provide a formula for the true underlying association present within the subgroup. This is sensitive to the initial minor allele frequencies present in both cases and the subgroup of patients. The methodology is then extended to the χ(2 statistic, for two related scenarios. First, to determine the true χ(2 when phenocopies or disease subtypes reduce association and are reclassified as controls when calculating statistics. Here, the χ(2 is given by (1 + σ * (a + b/(c + d/(1 - σ, or (1 + σ/(1 - σ for equal numbers of cases and controls. Second, when subgroups corresponding to heterogeneity mask the true effect size, but no reclassification is made. Here, the proportion increase in total sample size required to attain the same χ(2 statistic as the subgroup is given as γ = (1 - σ/2/((1 - σ(1 - σc/(a + c(1 - σd/(b + d, and a python script to calculate and plot this value is provided at kirc.se. Practical examples show how in a study of modest size (1000 cases and 1000 controls, a non-significant SNP may exceed genome-wide significance when corresponding to a subgroup of 20% of cases, and may occur in heterozygous form in all cases. This methodology may explain the modest association found in diseases such as MS wherein heterogeneity confounds straightforward measurement of association.

  10. Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Qiongshi Lu

    2017-07-01

    Full Text Available Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD. Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.

  11. Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer's disease.

    Science.gov (United States)

    Lu, Qiongshi; Powles, Ryan L; Abdallah, Sarah; Ou, Derek; Wang, Qian; Hu, Yiming; Lu, Yisi; Liu, Wei; Li, Boyang; Mukherjee, Shubhabrata; Crane, Paul K; Zhao, Hongyu

    2017-07-01

    Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.

  12. Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer’s disease

    Science.gov (United States)

    Abdallah, Sarah; Ou, Derek; Wang, Qian; Hu, Yiming; Lu, Yisi; Liu, Wei; Li, Boyang; Mukherjee, Shubhabrata; Crane, Paul K.; Zhao, Hongyu

    2017-01-01

    Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer’s disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson’s disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline. PMID:28742084

  13. Functional modules, mutational load and human genetic disease.

    Science.gov (United States)

    Zaghloul, Norann A; Katsanis, Nicholas

    2010-04-01

    The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals. Copyright 2010 Elsevier Ltd. All rights reserved.

  14. Human lipodystrophies: genetic and acquired diseases of adipose tissue

    Science.gov (United States)

    Capeau, Jacqueline; Magré, Jocelyne; Caron-Debarle, Martine; Lagathu, Claire; Antoine, Bénédicte; Béréziat, Véronique; Lascols, Olivier; Bastard, Jean-Philippe; Vigouroux, Corinne

    2010-01-01

    Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2 (AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARγ. Importantly, lamin A/C mutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their aetiology is generally unknown, they could be associated with signs of auto-immunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardio-vascular and hepatic complications. PMID:20551664

  15. Genetic dissection of Sharka disease tolerance in peach (P. persica L. Batsch).

    Science.gov (United States)

    Cirilli, Marco; Rossini, Laura; Geuna, Filippo; Palmisano, Francesco; Minafra, Angelantonio; Castrignanò, Tiziana; Gattolin, Stefano; Ciacciulli, Angelo; Babini, Anna Rosa; Liverani, Alessandro; Bassi, Daniele

    2017-11-03

    Plum pox virus (PPV), agent of Sharka disease, is the most important quarantine pathogen of peach (P. persica L. Batsch). Extensive evaluation of peach germplasm has highlighted the lack of resistant sources, while suggesting the presence of a quantitative disease resistance, expressed as reduction in the intensity of symptoms. Unravelling the genetic architecture of peach response to PPV infection is essential for pyramiding resistant genes and for developing more tolerant varieties. For this purpose, a genome-wide association (GWA) approach was applied in a panel of accessions phenotyped for virus susceptibility and genotyped with the IPSC peach 9 K SNP Array, and coupled with an high-coverage resequencing of the tolerant accession 'Kamarat'. Genome-wide association identified three highly significant associated loci on chromosome 2 and 3, accounting for most of the reduction in PPV-M susceptibility within the analysed peach population. The exploration of associated intervals through whole-genome comparison of the tolerant accession 'Kamarat' and other susceptible accessions, including the PPV-resistant wild-related species P. davidiana, allow the identification of allelic variants in promising candidate genes, including an RTM2-like gene already characterized in A. thaliana. The present study is the first effort to identify genetic factors involved in Sharka disease in peach germplasm through a GWA approach. We provide evidence of the presence of quantitative resistant loci in a collection of peach accessions, identifying major loci and highly informative SNPs that could be useful for marker assisted selection. These results could serve as reference bases for future research aimed at the comprehension of genetic mechanism regulating the complex peach-PPV interaction.

  16. Convergent genetic and expression data implicate immunity in Alzheimer's disease.

    Science.gov (United States)

    2015-06-01

    Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10(-11)), cholesterol transport (P = 2.96 × 10(-9)), and proteasome-ubiquitin activity (P = 1.34 × 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics. Copyright © 2015. Published by Elsevier Inc.

  17. CTLA-4 as a genetic determinant in autoimmune Addison's disease.

    Science.gov (United States)

    Wolff, A S B; Mitchell, A L; Cordell, H J; Short, A; Skinningsrud, B; Ollier, W; Badenhoop, K; Meyer, G; Falorni, A; Kampe, O; Undlien, D; Pearce, S H S; Husebye, E S

    2015-09-01

    In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

  18. Human diseases with genetically altered DNA repair processes

    International Nuclear Information System (INIS)

    Cleaver, J.E.; Bootsma, D.; Friedberg, E.

    1975-01-01

    DNA repair of single-strand breaks (produced by ionizing radiation) and of base damage (produced by ultraviolet (uv) light) are two repair mechanisms that most mammalian cells possess. Genetic defects in these repair mechanisms are exemplified by cells from the human premature-aging disease, progeria, which fail to rejoin single-strand breaks, and the skin disease, xeroderma pigmentosum (XP), which exhibits high actinic carcinogenesis and involves failure to repair base damage. In terms of the response of XP cells, many chemical carcinogens can be classified as either x-ray-like (i.e., they cause damage that XP cells can repair) or uv-like (i.e., they cause damage that XP cells cannot repair). The first group contains some of the more strongly carcinogenic chemicals (e.g., alkylating agents). XP occurs in at least two clinical forms, and somatic cell hybridization indicates at least three complementation groups. In order to identify cell lines from various different laboratories unambiguously, a modified nomenclature of XP lines is proposed. (U.S.)

  19. Human diseases with genetically altered DNA repair processes

    International Nuclear Information System (INIS)

    Cleaver, J.E.; Bootsma, D.; Friedberg, E.

    1975-01-01

    DNA repair of single-strand breaks (produced by ionizing radiation) and of base damage (produced by ultraviolet (UV) light) are two repair mechanisms that most mammalian cells possess. Genetic defects in these repair mechanisms are exemplified by cells from the human premature-aging disease, progeria, which fail to rejoin single-strand breaks, and the skin disease, xeroderma pigmentosum (XP), which exhibits high actinic carcinogenesis and involves failure to repair base damage. In terms of the response of XP cells, many chemical carcinogens can be classified as either X-ray-like (i.e., they cause damage that XP cells can repair) or UV-like (i.e., they cause damage that XP cells cannot repair). The first group contains some of the more strongly carcinogenic chemicals (e.g., alkylating agents). XP occurs in at least two clinical forms, and somatic cell hybridization indicates at least three complementation groups. In order to identify cell lines from various different laboratories unambiguously, a modified nomenclature of XP lines is proposed

  20. Periodontal disease in individuals with Down Syndrome: genetic focus

    Directory of Open Access Journals (Sweden)

    Lícia Bezerra Cavalcante

    2009-12-01

    Full Text Available Fundamental concepts of etiology, inheritance and clinical characteristics of Down syndrome are used in this review as a basis for submission of studies that focus on periodontal disease in individuals with Down syndrome, since almost 100% of them develop the disease in adult life. It is believed that in association with environmental and cultural factors related to hygiene and disabilities of coordination, the immunological characteristics that are found altered in individuals with Down syndrome, such as deficient neutrophil chemotaxis and reduced number of mature T lymphocytes, may contribute to the greater prevalence and severity of periodontal involvement in patients with Down syndrome. Moreover, the pattern of periodontal destruction observed in individuals with Down syndrome is consistent with aggressive periodontitis, with a predominance of periodontopathogens such as Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Tannerella forsythensis during childhood and adolescence of Down’s syndrome patients. It is possible to note a relationship between the development of molecular techniques and the evolution of knowledge about Down syndrome, for example: identification of the trisomy syndrome by observing only part of chromosome 21 (distal long arm; identification of genes in this trisomic region and the pattern of superexpression (or not of these genes. Moreover, in this review future perspectives are presented with regard to better understanding Down syndrome in the genetic context, which will reflect in more individualized and effective clinical treatments that will provide these patients with a better quality of life.

  1. Chemical and genetic defenses against disease in insect societies.

    Science.gov (United States)

    Stow, Adam; Beattie, Andrew

    2008-10-01

    The colonies of ants, bees, wasps and termites, the social insects, consist of large numbers of closely related individuals; circumstances ideal for contagious diseases. Antimicrobial assays of these animals have demonstrated a wide variety of chemical defenses against both bacteria and fungi that can be broadly classified as either external antiseptic compounds or internal immune molecules. Reducing the disease risks inherent in colonies of social insects is also achieved by behaviors, such as multiple mating or dispersal, that lower genetic relatedness both within- and among colonies. The interactions between social insects and their pathogens are complex, as illustrated by some ants that require antimicrobial and behavioral defenses against highly specialized fungi, such as those in the genus Cordyceps that attack larvae and adults and species in the genus Escovopsis that attack their food supplies. Studies of these defenses, especially in ants, have revealed remarkably sophisticated immune systems, including peptides induced by, and specific to, individual bacterial strains. The latter may be the result of the recruitment by the ants of antibiotic-producing bacteria but the extent of such three-way interactions remains unknown. There is strong experimental evidence that the evolution of sociality required dramatic increases in antimicrobial defenses and that microbes have been powerful selective agents. The antimicrobial chemicals and the insect-killing fungi may be useful in medicine and agriculture, respectively.

  2. Genetic Modification of Oncolytic Newcastle Disease Virus for Cancer Therapy.

    Science.gov (United States)

    Cheng, Xing; Wang, Weijia; Xu, Qi; Harper, James; Carroll, Danielle; Galinski, Mark S; Suzich, JoAnn; Jin, Hong

    2016-06-01

    Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has a modification at the fusion protein (F) cleavage site to reduce the efficiency of F protein cleavage and an insertion of a 198-nucleotide sequence into the HN-L intergenic region, resulting in reduced viral gene expression and replication in avian cells but not in mammalian cells. In mammalian cells, except for viral polymerase (L) gene expression, viral gene expression is not negatively impacted or increased by the HN-L intergenic insertion. Furthermore, the virus can be engineered to express a foreign gene while still retaining the ability to grow to high titers in cell culture. The recombinant NDV selectively replicates in and kills tumor cells and is able to drive potent tumor growth inhibition following intratumoral or intravenous administration in a mouse tumor model. The candidate is well positioned for clinical development as an oncolytic virus. Avian paramyxovirus type 1, NDV, has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step toward moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide without impacting viral production in

  3. Moyamoya disease and syndromes: from genetics to clinical management

    Directory of Open Access Journals (Sweden)

    Guey S

    2015-02-01

    . Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unraveled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies. Keywords: moyamoya disease, moyamoya syndrome, stroke, surgical revascularization, genetics

  4. Genetics and Treatment Response in Parkinson's Disease: An Update on Pharmacogenetic Studies.

    Science.gov (United States)

    Politi, Cristina; Ciccacci, Cinzia; Novelli, Giuseppe; Borgiani, Paola

    2018-03-01

    Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients' quality of life.

  5. Infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases.

    Science.gov (United States)

    Tarín, Juan J; García-Pérez, Miguel A; Hamatani, Toshio; Cano, Antonio

    2015-04-15

    The present review aims to ascertain whether different infertility etiologies share particular genes and/or molecular pathways with other pathologies and are associated with distinct and particular risks of later-life morbidity and mortality. In order to reach this aim, we use two different sources of information: (1) a public web server named DiseaseConnect ( http://disease-connect.org ) focused on the analysis of common genes and molecular mechanisms shared by diseases by integrating comprehensive omics and literature data; and (2) a literature search directed to find clinical comorbid relationships of infertility etiologies with only those diseases appearing after infertility is manifested. This literature search is performed because DiseaseConnect web server does not discriminate between pathologies emerging before, concomitantly or after infertility is manifested. Data show that different infertility etiologies not only share particular genes and/or molecular pathways with other pathologies but they have distinct clinical relationships with other diseases appearing after infertility is manifested. In particular, (1) testicular and high-grade prostate cancer in male infertility; (2) non-fatal stroke and endometrial cancer, and likely non-fatal coronary heart disease and ovarian cancer in polycystic ovary syndrome; (3) osteoporosis, psychosexual dysfunction, mood disorders and dementia in premature ovarian failure; (4) breast and ovarian cancer in carriers of BRCA1/2 mutations in diminished ovarian reserve; (5) clear cell and endometrioid histologic subtypes of invasive ovarian cancer, and likely low-grade serous invasive ovarian cancer, melanoma and non-Hodgkin lymphoma in endometriosis; and (6) endometrial and ovarian cancer in idiopathic infertility. The present data endorse the principle that the occurrence of a disease (in our case infertility) is non-random in the population and suggest that different infertility etiologies are genetically and clinically

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

    Science.gov (United States)

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

    2016-01-01

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

  7. Genetic determinants and stroke in children with sickle cell disease,

    Directory of Open Access Journals (Sweden)

    Daniela O.W. Rodrigues

    Full Text Available Abstract Objective: To verify genetic determinants associated with stroke in children with sickle cell disease (SCD. Methods: Prospective cohort with 110 children submitted to neonatal screening by the Neonatal Screening Program, between 1998 and 2007, with SCD diagnosis, followed at a regional reference public service for hemoglobinopathies. The analyzed variables were type of hemoglobinopathy, gender, coexistence with alpha thalassemia (α-thal, haplotypes of the beta globin chain cluster, and stroke. The final analysis was conducted with 66 children with sickle cell anemia (SCA, using the chi-squared test in the program SPSS® version 14.0. Results: Among children with SCD, 60% had SCA. The prevalence of coexistence with α-thal was 30.3% and the Bantu haplotype (CAR was identified in 89.2%. The incidence of stroke was significantly higher in those with SCA (27.3% vs. 2.3%; p = 0.001 and males (24.1% vs. 9.6%; p = 0.044. The presence of α-thal (p = 0.196, the CAR haplotype (p = 0.543, and socioeconomic factors were not statistically significant in association with the occurrence of stroke. Conclusion: There is a high incidence of stroke in male children and in children with SCA. Coexistence with α-thal and haplotypes of the beta globin chain cluster did not show any significant association with stroke. The heterogeneity between previously evaluated populations, the non-reproducibility between studies, and the need to identify factors associated with stroke in patients with SCA indicate the necessity of conducting further research to demonstrate the relevance of genetic factors in stroke related to SCD.

  8. Genetic determinants and stroke in children with sickle cell disease.

    Science.gov (United States)

    Rodrigues, Daniela O W; Ribeiro, Luiz C; Sudário, Lysla C; Teixeira, Maria T B; Martins, Marina L; Pittella, Anuska M O L; Junior, Irtis de O Fernandes

    To verify genetic determinants associated with stroke in children with sickle cell disease (SCD). Prospective cohort with 110 children submitted to neonatal screening by the Neonatal Screening Program, between 1998 and 2007, with SCD diagnosis, followed at a regional reference public service for hemoglobinopathies. The analyzed variables were type of hemoglobinopathy, gender, coexistence with alpha thalassemia (α-thal), haplotypes of the beta globin chain cluster, and stroke. The final analysis was conducted with 66 children with sickle cell anemia (SCA), using the chi-squared test in the program SPSS ® version 14.0. Among children with SCD, 60% had SCA. The prevalence of coexistence with α-thal was 30.3% and the Bantu haplotype (CAR) was identified in 89.2%. The incidence of stroke was significantly higher in those with SCA (27.3% vs. 2.3%; p=0.001) and males (24.1% vs. 9.6%; p=0.044). The presence of α-thal (p=0.196), the CAR haplotype (p=0.543), and socioeconomic factors were not statistically significant in association with the occurrence of stroke. There is a high incidence of stroke in male children and in children with SCA. Coexistence with α-thal and haplotypes of the beta globin chain cluster did not show any significant association with stroke. The heterogeneity between previously evaluated populations, the non-reproducibility between studies, and the need to identify factors associated with stroke in patients with SCA indicate the necessity of conducting further research to demonstrate the relevance of genetic factors in stroke related to SCD. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  9. Analysis of the genetic basis of disease in the context of worldwide human relationships and migration.

    Directory of Open Access Journals (Sweden)

    Erik Corona

    2013-05-01

    Full Text Available Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation.

  10. Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene

    DEFF Research Database (Denmark)

    Amano, Mariane T; Ferriani, Virgínia P L; Florido, Marlene P C

    2008-01-01

    Deficiencies of complement proteins of the classical pathway are strongly associated with the development of autoimmune diseases. Deficiency of C1r has been observed to occur concomitantly with deficiency in C1s and 9 out of 15 reported cases presented systemic lupus erythematosus (SLE). Here, we...... describe a family in which all four children are deficient in C1s but only two of them developed SLE. Hemolytic activity mediated by the alternative and the lectin pathways were normal, but classical pathway activation was absent in all children's sera. C1s was undetectable, while in the parents' sera...

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

    Science.gov (United States)

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

    2017-07-01

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

  12. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

    NARCIS (Netherlands)

    Alvarenga Fernandes Sin, Olga; Michels, Helen; Nollen, Ellen A. A.

    2014-01-01

    Caenorhabditis elegans comprises unique features that make it an attractive model organism in diverse fields of biology. Genetic screens are powerful to identify genes and C. elegans can be customized to forward or reverse genetic screens and to establish gene function. These genetic screens can be

  13. Clinical Considerations of Preimplantation Genetic Diagnosis for Monogenic Diseases.

    Directory of Open Access Journals (Sweden)

    Xiaokun Hu

    Full Text Available The aim of this study was to explore factors contribute to the success of PGD cycles for monogenic diseases.During a 3-year period (January 2009 to December 2012, 184 consecutive ICSI-PGD cycles for monogenic diseases reaching the ovum pick-up and fresh embryo-transfer stage performed at the Reproductive Medicine Center of The First Affiliated Hospital Of Sun Yat-sen University were evaluated.ICSI was performed on 2206 metaphase II oocytes, and normal fertilization and cleavage rates were 83.4% (1840/2206 and 96.2% (1770/1840, respectively. In the present study, 60.5% (181/299 of day 3 good-quality embryos developed into good-quality embryos on day 4 after biopsy. Collectively, 42.9% clinical pregnancy rate (79/184 and 28.5% implantation rate (111/389 were presented. In the adjusted linear regression model, the only two significant factors affecting the number of genetically unaffected embryos were the number of biopsied embryos (coefficient: 0.390, 95%CI 0.317-0.463, P = 0.000 and basal FSH level (coefficient: 0.198, 95%CI 0.031-0.365, P = 0.021. In the adjusted binary logistic regression model, the only two significant factors affecting pregnancy outcome were the number of genetically available transferable embryos after PGD (adjusted OR 1.345, 95% CI 1.148-1.575, P = 0.000 and number of oocyte retrieved (adjusted OR 0.934, 95% CI 0.877-0.994, P = 0.031.There should be at least four biopsied embryos to obtain at least one unaffected embryos in a PGD system for patients with single gene disorder and under the condition of basal FSH level smaller than 8.0mmol/L. Moreover, if only a low number (< 4 of biopsied embryos are available on day 3, the chance of unaffected embryos for transfer was small, with poor outcome.

  14. The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease

    NARCIS (Netherlands)

    Janssens, A. C. J. W.; Wilde, A. A. M.; van Langen, I. M.

    2011-01-01

    Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine-to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are

  15. [Advance in the methods of preimplantation genetic diagnosis for single gene diseases].

    Science.gov (United States)

    Ren, Yixin; Qiao, Jie; Yan, Liying

    2017-06-10

    More than 7000 single gene diseases have been identified and most of them lack effective treatment. As an early form of prenatal diagnosis, preimplantation genetic diagnosis (PGD) is a combination of in vitro fertilization and genetic diagnosis. PGD has been applied in clinics for more than 20 years to avoid the transmission of genetic defects through analysis of embryos at early stages of development. In this paper, a review for the recent advances in PGD for single gene diseases is provided.

  16. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

    OpenAIRE

    Gan-Or, Ziv; Dion, Patrick A; Rouleau, Guy A

    2015-01-01

    Parkinson disease (PD), once considered as a prototype of a sporadic disease, is now known to be considerably affected by various genetic factors, which interact with environmental factors and the normal process of aging, leading to PD. Large studies determined that the hereditary component of PD is at least 27%, and in some populations, single genetic factors are responsible for more than 33% of PD patients. Interestingly, many of these genetic factors, such as LRRK2, GBA, SMPD1, SNCA, PARK2...

  17. The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach

    Directory of Open Access Journals (Sweden)

    Amr T. M. Saeb

    2016-01-01

    Full Text Available Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases.

  18. Genetic management strategies for controlling infectious diseases in livestock populations

    Directory of Open Access Journals (Sweden)

    Bishop Stephen C

    2003-06-01

    Full Text Available Abstract This paper considers the use of disease resistance genes to control the transmission of infection through an animal population. Transmission is summarised by R0, the basic reproductive ratio of a pathogen. If R0 > 1.0 a major epidemic can occur, thus a disease control strategy should aim to reduce R0 below 1.0, e.g. by mixing resistant with susceptible wild-type animals. Suppose there is a resistance allele, such that transmission of infection through a population homozygous for this allele will be R02 01, where R01 describes transmission in the wildtype population. For an otherwise homogeneous population comprising animals of these two groups, R0 is the weighted average of the two sub-populations: R0 = R01ρ + R02 (1 - ρ, where ρ is the proportion of wildtype animals. If R01 > 1 and R02 0 ≤ 1, i.e. ρ ≤ (R0 - R02/(R01 - R02. If R02 = 0, the proportion of resistant animals must be at least 1 - 1/R01. For an n genotype model the requirement is still to have R0 ≤ 1.0. Probabilities of epidemics in genetically mixed populations conditional upon the presence of a single infected animal were derived. The probability of no epidemic is always 1/(R0 + 1. When R0 ≤ 1 the probability of a minor epidemic, which dies out without intervention, is R0/(R0 + 1. When R0 > 1 the probability of a minor and major epidemics are 1/(R0 + 1 and (R0 - 1/(R0 + 1. Wherever possible a combination of genotypes should be used to minimise the invasion possibilities of pathogens that have mutated to overcome the effects of specific resistance alleles.

  19. Joint modeling of genetically correlated diseases and functional annotations increases accuracy of polygenic risk prediction.

    Directory of Open Access Journals (Sweden)

    Yiming Hu

    2017-06-01

    Full Text Available Accurate prediction of disease risk based on genetic factors is an important goal in human genetics research and precision medicine. Advanced prediction models will lead to more effective disease prevention and treatment strategies. Despite the identification of thousands of disease-associated genetic variants through genome-wide association studies (GWAS in the past decade, accuracy of genetic risk prediction remains moderate for most diseases, which is largely due to the challenges in both identifying all the functionally relevant variants and accurately estimating their effect sizes. In this work, we introduce PleioPred, a principled framework that leverages pleiotropy and functional annotations in genetic risk prediction for complex diseases. PleioPred uses GWAS summary statistics as its input, and jointly models multiple genetically correlated diseases and a variety of external information including linkage disequilibrium and diverse functional annotations to increase the accuracy of risk prediction. Through comprehensive simulations and real data analyses on Crohn's disease, celiac disease and type-II diabetes, we demonstrate that our approach can substantially increase the accuracy of polygenic risk prediction and risk population stratification, i.e. PleioPred can significantly better separate type-II diabetes patients with early and late onset ages, illustrating its potential clinical application. Furthermore, we show that the increment in prediction accuracy is significantly correlated with the genetic correlation between the predicted and jointly modeled diseases.

  20. Genetically decreased vitamin D and risk of Alzheimer disease.

    Science.gov (United States)

    Mokry, Lauren E; Ross, Stephanie; Morris, John A; Manousaki, Despoina; Forgetta, Vincenzo; Richards, J Brent

    2016-12-13

    To test whether genetically decreased vitamin D levels are associated with Alzheimer disease (AD) using mendelian randomization (MR), a method that minimizes bias due to confounding or reverse causation. We selected single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels (p risk from the International Genomics of Alzheimer's Project (N = 17,008 AD cases and 37,154 controls). To produce MR estimates, we weighted the effect of each SNP on AD by its effect on 25OHD and meta-analyzed these estimates using a fixed-effects model to provide a summary effect estimate. The SUNLIGHT Consortium identified 4 SNPs to be genome-wide significant for 25OHD, which described 2.44% of the variance in 25OHD in CaMos. All 4 SNPs map to genes within the vitamin D metabolic pathway. MR analyses demonstrated that a 1-SD decrease in natural log-transformed 25OHD increased AD risk by 25% (odds ratio 1.25, 95% confidence interval 1.03-1.51, p = 0.021). After sensitivity analysis in which we removed SNPs possibly influenced by pleiotropy and population stratification, the results were largely unchanged. Our results provide evidence supporting 25OHD as a causal risk factor for AD. These findings provide further rationale to understand the effect of vitamin D supplementation on cognition and AD risk in randomized controlled trials. © 2016 American Academy of Neurology.

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

    Directory of Open Access Journals (Sweden)

    Ho-Chang Kuo

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

  2. Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

    Science.gov (United States)

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

    2014-01-01

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

  3. Towards the genetic manipulation of mosquito disease vectors

    International Nuclear Information System (INIS)

    Crampton, J.M.; Lycett, G.J.; Warren, A.

    1998-01-01

    Our research is aimed at developing the technologies necessary to undertake the genetic manipulation of insect vector genomes. In the longer term, we wish to explore the potential that this technology may have for developing novel strategies for the control of vector-borne diseases. The focus of our current research has been to: i) identify and characterise endogenous transposable elements in the genomes of mosquito vectors -research has focussed on identifying both Class I and Class 11 elements and determining their structure and distribution within mosquito genomes; ii) develop and use transfection systems for mosquito cells in culture as a test bed for transformation vectors and promoters - transfection techniques, vector constructs and different promoters driving reporter genes have been utilised to optimise the transformation of both Aedes aegypti and Anopheles gambiae cells in culture; iii) identify putative promoter sequences which are induced in the female mosquito midgut when it takes a blood meal - the Anopheles gambiae trypsin gene locus has been cloned and sequenced and the intergenic regions assessed for their ability to induce reporter gene expression in mosquito gut cells. The progress we have made in each of these areas will be described and discussed in the context of our longer term aim which is to introduce genes coding for antiparasitic agents into mosquito genomes in such a way that they are expressed in the mosquito midgut and disrupt transmission of the malaria parasite. (author)

  4. Towards the genetic manipulation of mosquito disease vectors

    Energy Technology Data Exchange (ETDEWEB)

    Crampton, J M; Lycett, G J; Warren, A [Division of Molecular Biology and Immunology, Liverpool School of Tropical Medicine, Liverpool (United Kingdom)

    1998-01-01

    Our research is aimed at developing the technologies necessary to undertake the genetic manipulation of insect vector genomes. In the longer term, we wish to explore the potential that this technology may have for developing novel strategies for the control of vector-borne diseases. The focus of our current research has been to: i) identify and characterise endogenous transposable elements in the genomes of mosquito vectors -research has focussed on identifying both Class I and Class 11 elements and determining their structure and distribution within mosquito genomes; ii) develop and use transfection systems for mosquito cells in culture as a test bed for transformation vectors and promoters - transfection techniques, vector constructs and different promoters driving reporter genes have been utilised to optimise the transformation of both Aedes aegypti and Anopheles gambiae cells in culture; iii) identify putative promoter sequences which are induced in the female mosquito midgut when it takes a blood meal - the Anopheles gambiae trypsin gene locus has been cloned and sequenced and the intergenic regions assessed for their ability to induce reporter gene expression in mosquito gut cells. The progress we have made in each of these areas will be described and discussed in the context of our longer term aim which is to introduce genes coding for antiparasitic agents into mosquito genomes in such a way that they are expressed in the mosquito midgut and disrupt transmission of the malaria parasite. (author). 41 refs, 2 figs.

  5. Indirect Genetic Effects and the Spread of Infectious Disease: Are We Capturing the Full Heritable Variation Underlying Disease Prevalence?

    Science.gov (United States)

    Lipschutz-Powell, Debby; Woolliams, John A.; Bijma, Piter; Doeschl-Wilson, Andrea B.

    2012-01-01

    Reducing disease prevalence through selection for host resistance offers a desirable alternative to chemical treatment. Selection for host resistance has proven difficult, however, due to low heritability estimates. These low estimates may be caused by a failure to capture all the relevant genetic variance in disease resistance, as genetic analysis currently is not taylored to estimate genetic variation in infectivity. Host infectivity is the propensity of transmitting infection upon contact with a susceptible individual, and can be regarded as an indirect effect to disease status. It may be caused by a combination of physiological and behavioural traits. Though genetic variation in infectivity is difficult to measure directly, Indirect Genetic Effect (IGE) models, also referred to as associative effects or social interaction models, allow the estimation of this variance from more readily available binary disease data (infected/non-infected). We therefore generated binary disease data from simulated populations with known amounts of variation in susceptibility and infectivity to test the adequacy of traditional and IGE models. Our results show that a conventional model fails to capture the genetic variation in infectivity inherent in populations with simulated infectivity. An IGE model, on the other hand, does capture some of the variation in infectivity. Comparison with expected genetic variance suggests that there is scope for further methodological improvement, and that potential responses to selection may be greater than values presented here. Nonetheless, selection using an index of estimated direct and indirect breeding values was shown to have a greater genetic selection differential and reduced future disease risk than traditional selection for resistance only. These findings suggest that if genetic variation in infectivity substantially contributes to disease transmission, then breeding designs which explicitly incorporate IGEs might help reduce disease

  6. How will insights from genetics translate to clinical practice in inflammatory bowel disease?

    NARCIS (Netherlands)

    Festen, E. A. M.; Weersma, R. K.

    Inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its

  7. The challenge for genetic epidemiologists: how to analyze large numbers of SNPs in relation to complex diseases.

    Science.gov (United States)

    Heidema, A Geert; Boer, Jolanda M A; Nagelkerke, Nico; Mariman, Edwin C M; van der A, Daphne L; Feskens, Edith J M

    2006-04-21

    Genetic epidemiologists have taken the challenge to identify genetic polymorphisms involved in the development of diseases. Many have collected data on large numbers of genetic markers but are not familiar with available methods to assess their association with complex diseases. Statistical methods have been developed for analyzing the relation between large numbers of genetic and environmental predictors to disease or disease-related variables in genetic association studies. In this commentary we discuss logistic regression analysis, neural networks, including the parameter decreasing method (PDM) and genetic programming optimized neural networks (GPNN) and several non-parametric methods, which include the set association approach, combinatorial partitioning method (CPM), restricted partitioning method (RPM), multifactor dimensionality reduction (MDR) method and the random forests approach. The relative strengths and weaknesses of these methods are highlighted. Logistic regression and neural networks can handle only a limited number of predictor variables, depending on the number of observations in the dataset. Therefore, they are less useful than the non-parametric methods to approach association studies with large numbers of predictor variables. GPNN on the other hand may be a useful approach to select and model important predictors, but its performance to select the important effects in the presence of large numbers of predictors needs to be examined. Both the set association approach and random forests approach are able to handle a large number of predictors and are useful in reducing these predictors to a subset of predictors with an important contribution to disease. The combinatorial methods give more insight in combination patterns for sets of genetic and/or environmental predictor variables that may be related to the outcome variable. As the non-parametric methods have different strengths and weaknesses we conclude that to approach genetic association

  8. Mucosal Interactions Between Genetics, Diet And Microbiome In Inflammatory Bowel Diseases

    Directory of Open Access Journals (Sweden)

    Abigail Basson

    2016-08-01

    Full Text Available Numerous reviews have discussed gut microbiota composition changes during inflammatory bowel diseases (IBD, particularly Crohn’s disease (CD. However, most studies address the observed effects by focusing on studying the univariate connection between disease and dietary-induced alterations to gut microbiota composition. The possibility that these effects may reflect a number of other interconnected (i.e. pantropic mechanisms, activated in parallel, particularly concerning various bacterial metabolites, is in the process of been elucidated. Progress seems however hampered by various difficult-to-study factors interacting at the mucosal level. Here we highlight some of such factors that merit consideration, namely; 1 the contribution of host genetics and diet in altering gut microbiome, and in turn, the crosstalk among secondary metabolic pathways; 2 the interdependence between the amount of dietary fat, the fatty acid composition, the effects of timing and route of administration on gut microbiota community, and the impact of microbiota-derived fatty acids; 3 the effect of diet on bile acid composition, and the modulator role of bile acids on the gut microbiota; 4 the impact of endogenous and exogenous intestinal micronutrients and metabolites, and 5 the need to consider food associated toxins and chemicals which can introduce confounding immune modulating elements (e.g., antioxidant and phytochemicals in oils and proteins. These concepts, which are not mutually exclusive, are herein illustrated paying special emphasis on physiologically inter-related processes.

  9. Clinical implications of shared genetics and pathogenesis in autoimmune diseases

    NARCIS (Netherlands)

    Zhernakova, Alexandra; Withoff, Sebo; Wijmenga, Cisca

    2013-01-01

    Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the

  10. Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease.

    Science.gov (United States)

    Specht, Andrew; Fiske, Laurie; Erger, Kirsten; Cossette, Travis; Verstegen, John; Campbell-Thompson, Martha; Struck, Maggie B; Lee, Young Mok; Chou, Janice Y; Byrne, Barry J; Correia, Catherine E; Mah, Cathryn S; Weinstein, David A; Conlon, Thomas J

    2011-01-01

    A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including "lactic acidosis", larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

  11. Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

    Directory of Open Access Journals (Sweden)

    Andrew Specht

    2011-01-01

    Full Text Available A canine model of Glycogen storage disease type Ia (GSDIa is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

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

    OpenAIRE

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

    2017-01-01

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

  13. Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children

    Institute of Scientific and Technical Information of China (English)

    Theresa A Mikhailov; Sylvia E Furner

    2009-01-01

    Inflammatory bowel disease is a chronic, debilitating disorder of the gastrointestinal tract. The etiology of inflammatory bowel disease has not been elucidated, but is thought to be multifactorial with both environmental and genetic influences. A large body of research has been conducted to elucidate the etiology of inflammatory bowel disease. This article reviews this literature, emphasizing the studies of breastfeeding and the studies of genetic factors, particularly NOD2 polymorphisms.

  14. Tourette syndrome research highlights 2015

    Science.gov (United States)

    Richards, Cheryl A.; Black, Kevin J.

    2016-01-01

    We present selected highlights from research that appeared during 2015 on Tourette syndrome and other tic disorders. Topics include phenomenology, comorbidities, developmental course, genetics, animal models, neuroimaging, electrophysiology, pharmacology, and treatment. We briefly summarize articles whose results we believe may lead to new treatments, additional research or modifications in current models of TS. PMID:27429744

  15. Genetic variability for tuber yield, quality, and virus disease complex ...

    African Journals Online (AJOL)

    Some cultivars e.g. Munyeera, New Kawogo, Silk and Sowola which showed high flowering ability failed to fertilise and set seed when crossed to specific cultivars. Preliminary genetic analysis for yield and quality following crossing elite 7 female and 6 male cultivars in a North Carolina 2 mating design showed wide genetic ...

  16. Ethical issues of genetic susceptibility testing for occupational diseases: opinions of trainees in a high-risk job

    NARCIS (Netherlands)

    Visser, M. J.; Rhebergen, M. D. F.; Kezic, S.; van Dijk, F. J. H.; Willems, D. L.; Verberk, M. M.

    2013-01-01

    Genetic research has opened up possibilities for identification of persons with an increased susceptibility for occupational disease. However, regulations considering the ethical issues that are inevitably associated with the use of genetic tests for susceptibility for occupational diseases are

  17. Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

    DEFF Research Database (Denmark)

    Beaumont, Robin N; Warrington, Nicole M; Cavadino, Alana

    2018-01-01

    determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal...

  18. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

    Science.gov (United States)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-09

    Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with

  19. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    Science.gov (United States)

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  20. Genetics Home Reference: glycogen storage disease type VII

    Science.gov (United States)

    ... Home Health Conditions Glycogen storage disease type VII Glycogen storage disease type VII Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Glycogen storage disease type VII (GSDVII) is an inherited ...

  1. Genetics Home Reference: glycogen storage disease type IV

    Science.gov (United States)

    ... Home Health Conditions Glycogen storage disease type IV Glycogen storage disease type IV Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Glycogen storage disease type IV (GSD IV) is an ...

  2. Palaeopathology and genes: investigating the genetics of infectious diseases in excavated human skeletal remains and mummies from past populations.

    Science.gov (United States)

    Anastasiou, Evilena; Mitchell, Piers D

    2013-10-01

    The aim of this paper is to review the use of genetics in palaeomicrobiology, and to highlight the importance of understanding past diseases. Palaeomicrobiology is the study of disease pathogens in skeletal and mummified remains from archaeological contexts. It has revolutionarised our understanding of health in the past by enabling a deeper knowledge of the origins and evolution of many diseases that have shaped us as a species. Bacterial diseases explored include tuberculosis, leprosy, bubonic plague, typhoid, syphilis, endemic and epidemic typhus, trench fever, and Helicobacter pylori. Viral diseases discussed include influenza, hepatitis B, human papilloma virus (HPV), human T-cell lymphotrophic virus (HTLV-1) and human immunodeficiency virus (HIV). Parasitic diseases investigated include malaria, leishmaniasis, Chagas' disease, roundworm, whipworm, pinworm, Chinese liver fluke, fleas and lice. Through a better understanding of disease origins and their evolution, we can place into context how many infectious diseases are changing over time, and so help us estimate how they may change in the future. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Can an Internet-based health risk assessment highlight problems of heart disease risk factor awareness? A cross-sectional analysis.

    Science.gov (United States)

    Dickerson, Justin B; McNeal, Catherine J; Tsai, Ginger; Rivera, Cathleen M; Smith, Matthew Lee; Ohsfeldt, Robert L; Ory, Marcia G

    2014-04-18

    Health risk assessments are becoming more popular as a tool to conveniently and effectively reach community-dwelling adults who may be at risk for serious chronic conditions such as coronary heart disease (CHD). The use of such instruments to improve adults' risk factor awareness and concordance with clinically measured risk factor values could be an opportunity to advance public health knowledge and build effective interventions. The objective of this study was to determine if an Internet-based health risk assessment can highlight important aspects of agreement between respondents' self-reported and clinically measured CHD risk factors for community-dwelling adults who may be at risk for CHD. Data from an Internet-based cardiovascular health risk assessment (Heart Aware) administered to community-dwelling adults at 127 clinical sites were analyzed. Respondents were recruited through individual hospital marketing campaigns, such as media advertising and print media, found throughout inpatient and outpatient facilities. CHD risk factors from the Framingham Heart Study were examined. Weighted kappa statistics were calculated to measure interrater agreement between respondents' self-reported and clinically measured CHD risk factors. Weighted kappa statistics were then calculated for each sample by strata of overall 10-year CHD risk. Three samples were drawn based on strategies for treating missing data: a listwise deleted sample, a pairwise deleted sample, and a multiple imputation (MI) sample. The MI sample (n=16,879) was most appropriate for addressing missing data. No CHD risk factor had better than marginal interrater agreement (κ>.60). High-density lipoprotein cholesterol (HDL-C) exhibited suboptimal interrater agreement that deteriorated (eg, κInternet-based health risk assessments such as Heart Aware may contribute to public health surveillance, but they must address selection bias of Internet-based recruitment methods.

  4. Surveillance Data Highlights Feed Form, Biosecurity, and Disease Control as Significant Factors Associated with Salmonella Infection on Farrow-to-Finish Pig Farms

    Directory of Open Access Journals (Sweden)

    Hector Argüello

    2018-02-01

    Full Text Available Among the zoonotic pathogens affecting pigs, Salmonella stands out due to the high number of human cases linked to pork consumption. In the last two decades many countries have put considerable effort into the control of the infection by surveillance and control strategies on farm. Despite this effort, many herds still have a high Salmonella prevalence and they require guidance to address this problem. The present study, using the serological surveillance data of finishing pigs from the Irish National pig Salmonella Control Programme, aimed to highlight factors associated with increased risk or that might mitigate Salmonella occurrence on farm. A questionnaire with 33 questions regarding herd characteristics, management, feeding, biosecurity, and health was completed for 61 individual herds. After the multivariate analysis by linear regression, nine variables were retained in the final model and linked to herd seroprevalence. Home produced-feed linked to the use of meal showed an eight points reduction in Salmonella prevalence compared to purchased feed (p = 0.042. Different biosecurity measures were associated to lower seroprevalence. Changing of footwear from outside to inside the farm decreased seroprevalence nearly 20 units (p = 0.014 and policies not permitting access to the farmyard to feed trucks (p = 0.048 or avoiding the presence of cats on the farm (p = 0.05 were estimated in 10 units less of seroprevalence. In contrast, the lack of perimeter fence increased the chance to have higher seroprevalence in five units (p = 0.05. Finally, intestinal diseases such as swine dysentery (p = 0.044 and E. coli diarrhea (p = 0.1 were estimated to increase Salmonella prevalence in ~20 and 10 units, respectively, demonstrating the importance of controlling other enteric pathogens in an on-farm Salmonella control programme. These results show the usefulness of surveillance data to improve on-farm control and confirm that Salmonella infection in pigs is

  5. Impact of genetic variations in C-C chemokine receptors and ligands on infectious diseases.

    Science.gov (United States)

    Qidwai, Tabish; Khan, M Y

    2016-10-01

    Chemokine receptors and ligands are crucial for extensive immune response against infectious diseases such as malaria, leishmaniasis, HIV and tuberculosis and a wide variety of other diseases. Role of chemokines are evidenced in the activation and regulation of immune cell migration which is important for immune response against diseases. Outcome of disease is determined by complex interaction among pathogen, host genetic variability and surrounding milieu. Variation in expression or function of chemokines caused by genetic polymorphisms could be associated with attenuated immune responses. Exploration of chemokine genetic polymorphisms in therapeutic response, gene regulation and disease outcome is important. Infectious agents in human host alter the expression of chemokines via epigenetic alterations and thus contribute to disease pathogenesis. Although some fragmentary data are available on chemokine genetic variations and their contribution in diseases, no unequivocal conclusion has been arrived as yet. We therefore, aim to investigate the association of CCR5-CCL5 and CCR2-CCL2 genetic polymorphisms with different infectious diseases, transcriptional regulation of gene, disease severity and response to therapy. Furthermore, the role of epigenetics in genes related to chemokines and infectious disease are also discussed. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  6. A genetic risk score combining ten psoriasis risk loci improves disease prediction.

    Directory of Open Access Journals (Sweden)

    Haoyan Chen

    2011-04-01

    Full Text Available Psoriasis is a chronic, immune-mediated skin disease affecting 2-3% of Caucasians. Recent genetic association studies have identified multiple psoriasis risk loci; however, most of these loci contribute only modestly to disease risk. In this study, we investigated whether a genetic risk score (GRS combining multiple loci could improve psoriasis prediction. Two approaches were used: a simple risk alleles count (cGRS and a weighted (wGRS approach. Ten psoriasis risk SNPs were genotyped in 2815 case-control samples and 858 family samples. We found that the total number of risk alleles in the cases was significantly higher than in controls, mean 13.16 (SD 1.7 versus 12.09 (SD 1.8, p = 4.577×10(-40. The wGRS captured considerably more risk than any SNP considered alone, with a psoriasis OR for high-low wGRS quartiles of 10.55 (95% CI 7.63-14.57, p = 2.010×10(-65. To compare the discriminatory ability of the GRS models, receiver operating characteristic curves were used to calculate the area under the curve (AUC. The AUC for wGRS was significantly greater than for cGRS (72.0% versus 66.5%, p = 2.13×10(-8. Additionally, the AUC for HLA-C alone (rs10484554 was equivalent to the AUC for all nine other risk loci combined (66.2% versus 63.8%, p = 0.18, highlighting the dominance of HLA-C as a risk locus. Logistic regression revealed that the wGRS was significantly associated with two subphenotypes of psoriasis, age of onset (p = 4.91×10(-6 and family history (p = 0.020. Using a liability threshold model, we estimated that the 10 risk loci account for only 11.6% of the genetic variance in psoriasis. In summary, we found that a GRS combining 10 psoriasis risk loci captured significantly more risk than any individual SNP and was associated with early onset of disease and a positive family history. Notably, only a small fraction of psoriasis heritability is captured by the common risk variants identified to date.

  7. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

    Science.gov (United States)

    Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Terranova Barberio, Manuela; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D; Nestle, Frank O

    2015-04-09

    Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Genetics Home Reference: hepatic veno-occlusive disease with immunodeficiency

    Science.gov (United States)

    ... Donald JA, Kirk EP, Ziegler JB, Salzer U, McDonald GB, Wong M, Lindeman R, Buckley MF. Mutations ... 10 All Bulletins Features What is direct-to-consumer genetic testing? What are genome editing and CRISPR- ...

  9. Genetics Home Reference: biotin-thiamine-responsive basal ganglia disease

    Science.gov (United States)

    ... BTBGD thiamine metabolism dysfunction syndrome 2 thiamine-responsive encephalopathy thiamine transporter-2 deficiency THMD2 Related Information How ... genetic testing? What is precision medicine? What is newborn screening? New Pages LMNA-related congenital muscular dystrophy ...

  10. Genetic control of yellow vein mosaic virus disease tolerance in ...

    Indian Academy of Sciences (India)

    PUSHPARANI SENJAM

    2018-01-29

    Jan 29, 2018 ... 2All India Coordinated Research Project on Vegetable Crops, Directorate of Research, ... Qualitative genetic analysis was done on the basis of segregation pattern of ...... effective and useful method to utilize all the three types.

  11. Progress in genetics of coronary artery disease | Shawky | Egyptian ...

    African Journals Online (AJOL)

    Egyptian Journal of Medical Human Genetics. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 19, No 1 (2018) >. Log in or Register to get access to full text downloads.

  12. Diet, Genetic Factors, and the Gut Microbiome in Crohn's Disease

    OpenAIRE

    Gary D. Wu; James D. Lewis; Frederic D. Bushman

    2010-01-01

    This manuscript is part of a pilot effort on the part of NIH staff and the Nature publishing group to provide a more convenient archive for "marker papers" to be published. These "marker papers" are designed to provide the users of community resource data sets with information regarding the status and scope of individual community resource projects. For further information see editorial in September 2010 edition of Nature Genetics (Nature Genetics, 42, 729 (2010)), and t...

  13. The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease

    NARCIS (Netherlands)

    A.C.J.W. Janssens (Cécile); A.A.M. Wilde (Arthur); I.M. van Langen (Irene)

    2011-01-01

    textabstractExpectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine-to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular

  14. Elm genetic diversity and hybridization in the presence of Dutch elm disease

    Science.gov (United States)

    Johanne Brunet; Raymond P. Guries

    2017-01-01

    The impact of Dutch elm disease (DED) on the genetic diversity of slippery elm (Ulmus rubra) is summarized and its potential impact on the genetic diversity of other North American native elms, American elm (U. americana), rock elm (U. thomasii), winged elm (U. alata), cedar elm (

  15. Elm genetic diversity and hybridization in the presence of Dutch elm disease

    Science.gov (United States)

    Dutch elm disease (DED) has devastated native North American elm species for more than 75 years. The impact of DED on the genetic diversity of one native elm species, U. rubra or slippery elm, is summarized and its potential impact on the genetic diversity of the other four North American native elm...

  16. Genetic influences on incidence and case-fatality of infectious disease

    DEFF Research Database (Denmark)

    Petersen, Liselotte; Andersen, Per Kragh; Sørensen, Thorkild I A

    2010-01-01

    Family, twin and adoption studies suggest that genetic susceptibility contributes to familial aggregation of infectious diseases or to death from infections. We estimated genetic and shared environmental influences separately on the risk of acquiring an infection (incidence) and on dying from...

  17. Human genetics of infectious diseases: between proof of principle and paradigm.

    Science.gov (United States)

    Alcaïs, Alexandre; Abel, Laurent; Casanova, Jean-Laurent

    2009-09-01

    The observation that only a fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. Although many studies have provided proof of principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. However, in the future, studies in human genetics are likely to establish a new paradigm for infectious diseases.

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

    Directory of Open Access Journals (Sweden)

    Steven C Bagley

    2016-04-01

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

  19. Diagnosis of Lynch Syndrome: Genetic Testing Identifies a Potentially Deadly Hereditary Disease

    Science.gov (United States)

    ... of Lynch Syndrome Follow us A Diagnosis of Lynch Syndrome Genetic testing identifies a potentially deadly hereditary disease ... helped Jack learn what was wrong. Jack had Lynch Syndrome—an inherited disorder. Lynch Syndrome increases the risk ...

  20. The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

    DEFF Research Database (Denmark)

    Ng, Yi Shiau; Alston, Charlotte L; Diodato, Daria

    2016-01-01

    BACKGROUND: Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects. METHODS: We summarised the clinical, biochemical and molecular genetic in...

  1. A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease.

    Science.gov (United States)

    Nishioka, Kenya; Kefi, Mounir; Jasinska-Myga, Barbara; Wider, Christian; Vilariño-Güell, Carles; Ross, Owen A; Heckman, Michael G; Middleton, Lefkos T; Ishihara-Paul, Lianna; Gibson, Rachel A; Amouri, Rim; Ben Yahmed, Samia; Ben Sassi, Samia; Zouari, Mourad; El Euch, Ghada; Farrer, Matthew J; Hentati, Faycal

    2010-04-01

    Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores approximately 1.6 times higher, pundefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.

  2. Pig traders' networks on the Kenya-Uganda border highlight potential for mitigation of African swine fever virus transmission and improved ASF disease risk management.

    Science.gov (United States)

    Lichoti, Jacqueline Kasiiti; Davies, Jocelyn; Maru, Yiheyis; Kitala, Philip M; Githigia, Samuel M; Okoth, Edward; Bukachi, Salome A; Okuthe, Sam; Bishop, Richard P

    2017-05-01

    We applied social network analysis to pig trader networks on the Kenya-Uganda border. Social network analysis is a recently developed tool, which is useful for understanding value chains and improving disease control policies. We interviewed a sample of 33 traders about their experiences with trade and African swine fever (ASF), analyzed the networks they generated in purchasing pigs and selling pork and their potential contribution to modulating dissemination of the ASF virus (ASFV). The majority of the traders were aware of clinical signs of ASF and the risk of trade transmitting ASFV. Most said they avoided buying pigs from ASF outbreak villages or sick pigs but their experiences also indicated that inadvertent purchase was relatively common. Traders had early knowledge of outbreaks since they were contacted by farmers who had heard rumours and wanted to sell their pigs to avoid the risk of them dying. Individual traders bought pigs in up to nine villages, and up to six traders operated in a village. Although each trade typically spanned less than 5km, networks of the various traders, comprising movements of pigs from source villages to slaughter slabs/sites and retail outlets, and movement of pork to villages where it was consumed, linked up indirectly across the 100km×50km study area and revealed several trade pathways across the Kenya-Uganda border. ASF could potentially spread across this area and beyond through sequential pig and pork transactions. Regulation of the pig and pork trade was minimal in practice. The risk of ASFV being spread by traders was compounded by their use of poorly constructed slaughter slabs/sites with open drainage, ineffective or non-existent meat inspection services, lack of provision for biosecurity in the value chain, and sales of pork to customers who were unaware of the risks to their own pigs from contact with ASF infected pork. More effective regulation is warranted. However, limitations on government capacity, together with

  3. Chapter VIII. Contributions of propagation techniques and genetic modification to breeding - genetic engineering for disease resistance

    Science.gov (United States)

    Genetic engineering offers an opportunity to develop flower bulb crops with resistance to fungal, viral, and bacterial pathogens. Several of the flower bulb crops, Lilium spp., Gladiolus, Zantedeschia, Muscari, Hyacinthus, Narcissus, Ornithogalum, Iris, and Alstroemeria, have been transformed with t...

  4. Genetically elevated C-reactive protein and ischemic vascular disease

    DEFF Research Database (Denmark)

    Zacho, J.; Tybjaerg-Hansen, A.; Jensen, J.S.

    2008-01-01

    Background: Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association. Methods: We studied 10,276 persons from a general population cohort, including 1786 in whom...... ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. We examined another 31,992 persons from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. Finally, we compared 2238 patients...... with ischemic heart disease with 4474 control subjects and 612 patients with ischemic cerebrovascular disease with 1224 control subjects. We measured levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms. Results: The risk of ischemic heart...

  5. Genetics Home Reference: X-linked lymphoproliferative disease

    Science.gov (United States)

    ... my area? Other Names for This Condition Duncan disease Epstein-Barr virus-induced lymphoproliferative disease in males familial fatal ... the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development. ...

  6. Genetic Simulation Tools for Post-Genome Wide Association Studies of Complex Diseases

    Science.gov (United States)

    Amos, Christopher I.; Bafna, Vineet; Hauser, Elizabeth R.; Hernandez, Ryan D.; Li, Chun; Liberles, David A.; McAllister, Kimberly; Moore, Jason H.; Paltoo, Dina N.; Papanicolaou, George J.; Peng, Bo; Ritchie, Marylyn D.; Rosenfeld, Gabriel; Witte, John S.

    2014-01-01

    Genetic simulation programs are used to model data under specified assumptions to facilitate the understanding and study of complex genetic systems. Standardized data sets generated using genetic simulation are essential for the development and application of novel analytical tools in genetic epidemiology studies. With continuing advances in high-throughput genomic technologies and generation and analysis of larger, more complex data sets, there is a need for updating current approaches in genetic simulation modeling. To provide a forum to address current and emerging challenges in this area, the National Cancer Institute (NCI) sponsored a workshop, entitled “Genetic Simulation Tools for Post-Genome Wide Association Studies of Complex Diseases” at the National Institutes of Health (NIH) in Bethesda, Maryland on March 11-12, 2014. The goals of the workshop were to: (i) identify opportunities, challenges and resource needs for the development and application of genetic simulation models; (ii) improve the integration of tools for modeling and analysis of simulated data; and (iii) foster collaborations to facilitate development and applications of genetic simulation. During the course of the meeting the group identified challenges and opportunities for the science of simulation, software and methods development, and collaboration. This paper summarizes key discussions at the meeting, and highlights important challenges and opportunities to advance the field of genetic simulation. PMID:25371374

  7. Interpreting genetics in the context of eating disorders: evidence of disease, not diversity.

    Science.gov (United States)

    Easter, Michele

    2014-07-01

    How is genetic involvement interpreted for disorders whose medicalisation is contested? Framing psychiatric and behavioural disorders in terms of genetics is expected to make them seem more medical. Yet a genetic aetiology can also be used to frame behaviour as acceptable human variation, rather than a medical problem (for example, sexual orientation). I analyse responses to the idea that there is a genetic component in anorexia and bulimia nervosa (AN or BN) via semi-structured interviews with a sample of 50 women diagnosed with an eating disorder (25 had recovered). All but three volunteered that genetics would medicalise AN or BN by (i) making eating disorders seem more like 'real diseases'; implying that these disorders need (ii) professional treatment or (iii) a biologically based treatment. The results also indicate there are several counter-logics by which genetic framing could support non-medical definitions of AN or BN. I argue that genetic framing reduces perceived individual responsibility, which can support definitions of behaviour as either a reflection of disease (which entails intervention) or a reflection of normal human diversity (which does not). In the context of public scepticism as to the 'reality' of AN or BN, genetic involvement was taken as evidence of disease in ongoing negotiations about the medical and moral status of people with eating disorders. © 2013 The Author. Sociology of Health & Illness © 2013 Foundation for the Sociology of Health & Illness/John Wiley & Sons Ltd.

  8. C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Paulo Victor Sgobbi de Souza

    2015-03-01

    Full Text Available Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

  9. The molecular genetics of inflammatory, autoimmune, and infectious diseases of the sinonasal tract: a review.

    Science.gov (United States)

    Montone, Kathleen T

    2014-06-01

    The sinonasal tract is frequently affected by a variety of nonneoplastic inflammatory disease processes that are often multifactorial in their etiology but commonly have a molecular genetic component. To review the molecular genetics of a variety of nonneoplastic inflammatory diseases of the sinonasal tract. Inflammatory lesions of the sinonasal tract can be divided into 3 main categories: (1) chronic rhinosinusitis, (2) infectious diseases, and (3) autoimmune diseases/vasculitides. The molecular diagnosis and pathways of a variety of these inflammatory lesions are currently being elucidated and will shed light on disease pathogenesis and treatment. The sinonasal tract is frequently affected by inflammatory lesions that arise through complex interactions of environmental, infectious, and genetic factors. Because these lesions are all inflammatory in nature, the molecular pathology surrounding them is most commonly due to upregulation and down-regulation of genes that affect inflammatory responses and immune regulation.

  10. Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

    Science.gov (United States)

    Gomez, Felicia; Hirbo, Jibril; Tishkoff, Sarah A.

    2014-01-01

    Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent. PMID:24984772

  11. Systems genetics of complex diseases using RNA-sequencing methods

    DEFF Research Database (Denmark)

    Mazzoni, Gianluca; Kogelman, Lisette; Suravajhala, Prashanth

    2015-01-01

    Next generation sequencing technologies have enabled the generation of huge quantities of biological data, and nowadays extensive datasets at different ‘omics levels have been generated. Systems genetics is a powerful approach that allows to integrate different ‘omics level and understand the bio...

  12. Genetic epidemiology of coronary artery disease: an Asian Indian ...

    Indian Academy of Sciences (India)

    The present review aims to consolidate the available literature on the genetics of. CAD in Asian Indians ... India and the US who were participating in the Sikh Diabetes ..... to undertake systematic large-scale studies in order to under- stand the ...

  13. Chronic disease risk management: Combining genetic testing with ...

    African Journals Online (AJOL)

    Nutrigenetics has been used for decades to prevent rare monogenic disorders such as phenylketonuria. Gene-diet interaction can now also be targeted to prevent or reduce the risk of many chronic conditions long before clinical manifestation. This multidisciplinary approach unites conventional medicine with genetics and ...

  14. Triplet repeat DNA structures and human genetic disease

    Indian Academy of Sciences (India)

    Laboratory of DNA Structure and Mutagenesis, Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University System Health Sciences Center, 2121 West Holcombe Blvd., Houston, TX 77030-3303, USA; Hospital for Sick Children, Department of Genetics, 555 University Avenue, Elm Wing, ...

  15. Using CSF biomarkers to replicate genetic associations in Alzheimer's disease

    NARCIS (Netherlands)

    Schott, Jonathan M.; Abdi, Hervé; Abdul Hadi, Normi; Abdulkadir, Ahmed; Abdullah, Afnizanfaizal; Achuthan, Anusha; Adluru, Nagesh; Aggarwal, Namita; Aghajanian, Jania; Agyemang, Alex; Ahdidan, Jamila; Ahmad, Duaa; Ahmed, Fayeza; Ahmed, Shiek; Ahmed, Fareed; Akbarifar, Roshanak; Akhondi-Asl, Alireza; Aksu, Yaman; Alcauter, Sarael; Alexander, Daniel; Alin, Aylin; Alshuft, Hamza; Alvarez-Linera, Juan; Amin-Mansour, Ali; Anderson, Jeff; Anderson, Dallas; Andorn, Anne; Andrews, K. Abigail; Ang, Amma; Angersbach, Steve; Ansarian, Reza; Abhishek, Appaji M.; Appannah, Arti; Arfanakis, Konstantinos; Arif, Muhammad; Armentrout, Steven; Arrighi, Michael; Arumughababu, S. Vethanayaki; Arunagiri, Vidhya; Ashe-McNalley, Cody; Ashford, Wes; Le Page, Aurelie; Avants, Brian; Aviv, Richard; Avula, Ramesh; Ayache, Nicholas; Ayan-Oshodi, Mosun; Ayhan, Murat; Richard, Edo; Schmand, Ben

    2012-01-01

    Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to

  16. Insights into metabolic disease from studying genetics in isolated populations

    DEFF Research Database (Denmark)

    Zeggini, Eleftheria; Gloyn, Anna L; Hansen, Torben

    2016-01-01

    Over the last 10 years substantial progress has been made in our understanding of the genetic basis for type 2 diabetes and related traits. These developments have been facilitated by technological advancements that have allowed comprehensive genome-wide assessments of the impact of common geneti......, and an overview by the Session Chair, Anna Gloyn....

  17. Cytogenetic highlights and transitions.

    Science.gov (United States)

    Spinner, Nancy B

    2016-06-01

    Medical cytogenetics, genetic diagnostics, and medical genetics had their origins in the late 1950's, as evaluation of human chromosomes became possible, and it was recognized that chromosomal abnormalities could cause a variety of clinical phenotypes. Dr. Laird Jackson began his medical and scientific career just as this field was emerging and he was an early adopter and driver of several key trends in the development of these fields, notably in the area of prenatal diagnostics. Laird's greatest impact was in his work to demonstrate the clinical utility of amniocentesis, chorionic villous sampling, and chromosomal microarray analysis for prenatal diagnosis. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. [Analysis of 14 individuals who requested predictive genetic testing for hereditary neuromuscular diseases].

    Science.gov (United States)

    Yoshida, Kunihiro; Tamai, Mariko; Kubota, Takeo; Kawame, Hiroshi; Amano, Naoji; Ikeda, Shu-ichi; Fukushima, Yoshimitsu

    2002-02-01

    Predictive genetic testing for hereditary neuromuscular diseases is a delicate issue for individuals at risk and their families, as well as for medical staff because these diseases are often late-onset and intractable. Therefore careful pre- and post-test genetic counseling and psychosocial support should be provided along with such genetic testing. The Division of Clinical and Molecular Genetics was established at our hospital in May 1996 to provide skilled professional genetic counseling. Since its establishment, 14 individuals have visited our clinic to request predictive genetic testing for hereditary neuromuscular diseases (4 for myotonic dystrophy, 6 for spinocerebellar ataxia, 3 for Huntington's disease, and 1 for Alzheimer's disease). The main reasons for considering testing were to remove uncertainty about the genetic status and to plan for the future. Nine of 14 individuals requested testing for making decisions about a forthcoming marriage or pregnancy (family planning). Other reasons raised by the individuals included career or financial planning, planning for their own health care, and knowing the risk for their children. At the first genetic counseling session, all of the individuals expressed hopes of not being a gene carrier and of escaping from fear of disease, and seemed not to be mentally well prepared for an increased-risk result. To date, 7 of the 14 individuals have received genetic testing and only one, who underwent predictive genetic testing for spinocerebellar ataxia, was given an increased-risk result. The seven individuals including the one with an increased-risk result, have coped well with their new knowledge about their genetic status after the testing results were disclosed. None of them has expressed regret. In pre-test genetic counseling sessions, we consider it quite important not only to determine the psychological status of the individual, but also to make the individual try to anticipate the changes in his/her life upon

  19. Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors.

    Science.gov (United States)

    Shinohara, Mitsuru; Sato, Naoyuki; Shimamura, Munehisa; Kurinami, Hitomi; Hamasaki, Toshimitsu; Chatterjee, Amarnath; Rakugi, Hiromi; Morishita, Ryuichi

    2014-01-01

    The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.

  20. A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain.

    Science.gov (United States)

    Umoh, Mfon E; Dammer, Eric B; Dai, Jingting; Duong, Duc M; Lah, James J; Levey, Allan I; Gearing, Marla; Glass, Jonathan D; Seyfried, Nicholas T

    2018-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry-based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD Our systems-level analysis of the brain proteome integrated both differential expression and co-expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co-expression network analysis revealed 15 modules of co-expressed proteins, eight of which were significantly different across the ALS-FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell-type specificity that showed correlation with TDP-43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP-43 protein-protein interactions, revealing one module enriched with RNA-binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems-level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS-FTD disease spectrum in human brain. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  1. The challenge for genetic epidemiologists: how to analyze large numbers of SNPs in relation to complex diseases

    NARCIS (Netherlands)

    Heidema, A.G.; Boer, J.M.A.; Nagelkerke, N.; Mariman, E.C.M.; A, van der D.L.; Feskens, E.J.M.

    2006-01-01

    Genetic epidemiologists have taken the challenge to identify genetic polymorphisms involved in the development of diseases. Many have collected data on large numbers of genetic markers but are not familiar with available methods to assess their association with complex diseases. Statistical methods

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  3. Variation in phenotypic appearance of Graves' disease: effect of genetic anticipation and duration of complaints

    NARCIS (Netherlands)

    Vos, Xander; Smit, Natalie; Endert, Erik; Tijssen, Jan; Wiersinga, Wilmar

    2009-01-01

    Objective: Both genetic and environmental factors contribute to susceptibility of Graves' disease. In this study. we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of

  4. Differential diagnosis of genetic disease by DNA restriction fragment length polymorphisms

    NARCIS (Netherlands)

    Bolhuis, P. A.; Defesche, J. C.; van der Helm, H. J.

    1987-01-01

    DNA restriction fragment length polymorphisms (RFLPs) are used for diagnosis of genetic disease in families known to be affected by specific disorders, but RFLPs can be also useful for the differential diagnosis of hereditary disease. An RFLP pattern represents the inheritance of chromosomal markers

  5. International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

    Science.gov (United States)

    Boycott, Kym M; Rath, Ana; Chong, Jessica X; Hartley, Taila; Alkuraya, Fowzan S; Baynam, Gareth; Brookes, Anthony J; Brudno, Michael; Carracedo, Angel; den Dunnen, Johan T; Dyke, Stephanie O M; Estivill, Xavier; Goldblatt, Jack; Gonthier, Catherine; Groft, Stephen C; Gut, Ivo; Hamosh, Ada; Hieter, Philip; Höhn, Sophie; Hurles, Matthew E; Kaufmann, Petra; Knoppers, Bartha M; Krischer, Jeffrey P; Macek, Milan; Matthijs, Gert; Olry, Annie; Parker, Samantha; Paschall, Justin; Philippakis, Anthony A; Rehm, Heidi L; Robinson, Peter N; Sham, Pak-Chung; Stefanov, Rumen; Taruscio, Domenica; Unni, Divya; Vanstone, Megan R; Zhang, Feng; Brunner, Han; Bamshad, Michael J; Lochmüller, Hanns

    2017-05-04

    Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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

    NARCIS (Netherlands)

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

    2008-01-01

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

  7. Genetic control of disease in an experimental model for Sjögren's syndrome

    DEFF Research Database (Denmark)

    Andersson, Åsa Inga Maria

    2009-01-01

    Sjögren's syndrome is an autoimmune disease with a complex etiology depending on hereditary and environmental factors. The disease is characterized by lymphocytic infiltration and inflammation in the salivary and lacrimal glands, leading to oral and ocular dryness. To understand the genetic...

  8. Genetic determinants and stroke in children with sickle cell disease

    Directory of Open Access Journals (Sweden)

    Daniela O.W. Rodrigues

    2016-11-01

    Conclusion: There is a high incidence of stroke in male children and in children with SCA. Coexistence with α‐thal and haplotypes of the beta globin chain cluster did not show any significant association with stroke. The heterogeneity between previously evaluated populations, the non‐reproducibility between studies, and the need to identify factors associated with stroke in patients with SCA indicate the necessity of conducting further research to demonstrate the relevance of genetic factors in stroke related to SCD.

  9. Genetically elevated bilirubin and risk of ischaemic heart disease

    DEFF Research Database (Denmark)

    Stender, Stefan; Frikke-Schmidt, R; Nordestgaard, B G

    2013-01-01

    Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear.......Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear....

  10. Bodies in skin: a philosophical and theological approach to genetic skin diseases.

    Science.gov (United States)

    Walser, Angelika

    2010-03-01

    This contribution evolved from my work in a European network and is dedicated to the rare genetic skin diseases. To gain a deeper knowledge about the question, what it means to suffer from a genetic skin disease, I have discussed the concepts of skin in philosophical and theological anthropology. Presuming that ancient interpretations of skin diseases (moral and cultical impurity) are still relevant today, feminist Christian theology shows the ways of deconstructing stigmatizing paradigma by using the body as a hermeneutic category. Skin becomes the "open borderline" of the human being, pointing out both the social vulnerability and the transcendent capacity of the human person.

  11. The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility.

    Science.gov (United States)

    Charoute, Hicham; Nahili, Halima; Abidi, Omar; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Barakat, Abdelhamid

    2014-03-01

    National and ethnic mutation databases provide comprehensive information about genetic variations reported in a population or an ethnic group. In this paper, we present the Moroccan Genetic Disease Database (MGDD), a catalogue of genetic data related to diseases identified in the Moroccan population. We used the PubMed, Web of Science and Google Scholar databases to identify available articles published until April 2013. The Database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language. To date, the database contains 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases. Most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance (74.17%) and affect endocrine, nutritional and metabolic physiology. The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. Its content should be useful to improve researches in human molecular genetics, disease diagnoses and design of association studies. MGDD can be publicly accessed at http://mgdd.pasteur.ma.

  12. Genetics of Alzheimer’s Disease: Lessons Learned in Two Decades

    Directory of Open Access Journals (Sweden)

    Nilüfer Ertekin Taner

    2010-03-01

    Full Text Available Alzheimer’s disease (AD is the most common type of dementia. It is estimated that more than 35 million people worldwide will suffer from dementia in 2010. Without effective therapies, this epidemic is expected to affect more than 115 million patients worldwide by 2050. Genetic studies can help us understand the disease pathophysiology, thereby providing potential therapeutic, presymptomatic predictive and preventative avenues. Since 1990, there has been evidence for a substantial genetic component underlying the risk for AD. Three genes with autosomal dominant mutations lead to early-onset familial AD, which explains less than 1% of all AD. Apolipoprotein ε4, the only widely accepted genetic risk factor for late-onset AD, accounts for only a portion of this risk. Genetic linkage and association studies have identified multiple candidate gene regions, although many resulting candidate genes suffer from lack of replication, at least partially due to underpowered studies in the setting of genetic heterogeneity and small-tomoderate effect size. Genome-wide association studies that assess hundreds of thousands of single-nucleotide polymorphisms (SNPs in thousands of subjects have been viewed as a potentially powerful approach in uncovering common risk variations for genetically complex diseases such as AD. To date, 11 independent genome-wide association studies have been completed in late-onset AD (LOAD that led to candidate regions and genes for follow-up. These studies provide evidence for novel, plausible genetic risk factors for AD, but still fail to account for all of the estimated risk. Additional genetic risk factors of even smaller effect size, rare variants and/or structural DNA polymorphisms may exist, which may escape detection by conventional methods. Alternative approaches such as nextgeneration sequencing, use of quantitative endophenotypes, copy number variation analyses, and meta-analyses may be required. This review summarizes the

  13. Genetics of Alzheimer’s Disease: Lessons Learned in Two Decades

    Directory of Open Access Journals (Sweden)

    Nilüfer Ertekin Taner

    2010-03-01

    Full Text Available Alzheimer’s disease (AD is the most common type of dementia. It is estimated that more than 35 million people worldwide will suffer from dementia in 2010. Without effective therapies, this epidemic is expected to affect more than 115 million patients worldwide by 2050. Genetic studies can help us understand the disease pathophysiology, thereby providing potential therapeutic, presymptomatic predictive and preventative avenues. Since 1990, there has been evidence for a substantial genetic component underlying the risk for AD. Three genes with autosomal dominant mutations lead to early-onset familial AD, which explains less than 1% of all AD. Apolipoprotein ε4, the only widely accepted genetic risk factor for late-onset AD, accounts for only a portion of this risk. Genetic linkage and association studies have identified multiple candidate gene regions, although many resulting candidate genes suffer from lack of replication, at least partially due to underpowered studies in the setting of genetic heterogeneity and small-tomoderate effect size. Genome-wide association studies that assess hundreds of thousands of single-nucleotide polymorphisms (SNPs in thousands of subjects have been viewed as a potentially powerful approach in uncovering common risk variations for genetically complex diseases such as AD. To date, 11 independent genome-wide association studies have been completed in late-onset AD (LOAD that led to candidate regions and genes for follow-up. These studies provide evidence for novel, plausible genetic risk factors for AD, but still fail to account for all of the estimated risk. Additional genetic risk factors of even smaller effect size, rare variants and/or structural DNA polymorphisms may exist, which may escape detection by conventional methods. Alternative approaches such as nextgeneration sequencing, use of quantitative endophenotypes, copy number variation analyses, and meta-analyses may be required. This review summarizes the

  14. ATLAS Outreach Highlights

    CERN Document Server

    Cheatham, Susan; The ATLAS collaboration

    2016-01-01

    The ATLAS outreach team is very active, promoting particle physics to a broad range of audiences including physicists, general public, policy makers, students and teachers, and media. A selection of current outreach activities and new projects will be presented. Recent highlights include the new ATLAS public website and ATLAS Open Data, the very recent public release of 1 fb-1 of ATLAS data.

  15. Studies Highlight Biodiesel's Benefits

    Science.gov (United States)

    , Colo., July 6, 1998 — Two new studies highlight the benefits of biodiesel in reducing overall air Energy's National Renewable Energy Laboratory (NREL) conducted both studies: An Overview of Biodiesel and Petroleum Diesel Life Cycles and Biodiesel Research Progress, 1992-1997. Biodiesel is a renewable diesel

  16. Human Genome Epidemiology : A scientific foundation for using genetic information to improve health and prevent disease

    Directory of Open Access Journals (Sweden)

    Stefania Boccia

    2005-03-01

    Full Text Available

    Human health is determined by the interplay of genetic factors and the environment. In this context the recent advances in human genomics are expected to play a central role in medicine and public health by providing genetic information for disease prediction and prevention.

    After the completion of the human genome sequencing, a fundamental step will be represented by the translation of these discoveries into meaningful actions to improve health and prevent diseases, and the field of epidemiology plays a central role in this effort. These are some of the issues addressed by Human Genome Epidemiology –A scientific foundation for using genetic information to improve health and prevent disease, a volume edited by Prof. M. Khoury, Prof. J. Little, Prof.W. Burke and published by Oxford university Press 2004.

    This book describes the important role that epidemiological methods play in the continuum from gene discovery to the development and application of genetic tests. The Authors calls this continuum human genome epidemiology (HuGE to denote an evolving field of inquiry that uses systematic applications of epidemiological methods to assess the impact of human genetic variation on health and disease.

    The book is divided into four sections and it is structured to allow readers to proceed systematically from the fundamentals of genome technology and discovery, to the epidemiological approaches, to gene characterisation, to the evaluation of genetic tests and their use in health services and public health.

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

    Science.gov (United States)

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

    2015-02-14

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

  18. McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient.

    Science.gov (United States)

    Vasilev, Vladimir; Daly, Adrian F; Thiry, Albert; Petrossians, Patrick; Fina, Frederic; Rostomyan, Liliya; Silvy, Monique; Enjalbert, Alain; Barlier, Anne; Beckers, Albert

    2014-10-01

    McCune Albright syndrome (MAS) is a clinical association of endocrine and nonendocrine anomalies caused by postzygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α-subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular, and adrenal disease. Other rarer disease related features are emerging. The objective of the investigation was to study the pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and nonclassically affected tissues. This was a comprehensive autopsy and genetic analysis. The study was conducted at a tertiary referral university hospital. An adult male patient with MAS and severe disease burden including gigantism was the subject of the study. Interventions included clinical, hormonal, and radiographic studies and gross and microscopic pathology analyses, conventional PCR, and droplet digital PCR analyses of affected and nonaffected tissues. Pathological findings and the presence of GNAS1 mutations were measured. The patient was diagnosed with MAS syndrome at 6 years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism, and hyperparathyroidism were diagnosed throughout the adult period. The patient died at the age of 39 years from a pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS1 mutation distributed across many endocrine and nonendocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism and hyperplasia of the thymus and endocrine pancreas. This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the

  19. Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Juul, Klaus; Tybjærg-Hansen, Anne; Marklund, Stefan

    2006-01-01

    RATIONALE: Increased oxidative stress is involved in chronic obstructive pulmonary disease (COPD); however, plasma and bronchial lining fluid contains the antioxidant extracellular superoxide dismutase. Approximately 2% of white individuals carry the R213G polymorphism in the gene encoding extrac...

  20. Genetics Home Reference: Charcot-Marie-Tooth disease

    Science.gov (United States)

    ... CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome. Some researchers believe that this condition ... Dejerine Sottas Disease National Organization for Rare Disorders: Rosenberg-Chutorian Syndrome National Organization for Rare Disorders: Roussy- ...

  1. Increased genetic risk for obesity in premature coronary artery disease.

    Science.gov (United States)

    Cole, Christopher B; Nikpay, Majid; Stewart, Alexandre F R; McPherson, Ruth

    2016-04-01

    There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this question in a population of 5831 early onset CAD cases without diabetes mellitus and 3832 elderly healthy control subjects, all of strictly European ancestry, with adjustment for traditional risk factors (TRFs). We then estimated the genetic correlation between these BMI and CAD (rg) by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between these two traits. GRSBMI significantly (P=2.12 × 10(-12)) associated with CAD status in a multivariate model adjusted for TRFs, with a per allele odds ratio (OR) of 1.06 (95% CI 1.042-1.076). The addition of GRSBMI to TRFs explained 0.75% of CAD variance and yielded a continuous net recombination index of 16.54% (95% CI=11.82-21.26%, P<0.0001). To test whether GRSBMI explained CAD status when adjusted for measured BMI, separate models were constructed in which the score and BMI were either included as covariates or not. The addition of BMI explained ~1.9% of CAD variance and GRSBMI plus BMI explained 2.65% of CAD variance. Finally, using bivariate restricted maximum likelihood analysis, we provide strong evidence of genome-wide pleiotropy between obesity and CAD. This analysis supports the hypothesis that obesity is a causal risk factor for CAD.

  2. Genetic evaluation of Addison's disease in the Portuguese Water Dog

    Directory of Open Access Journals (Sweden)

    Belanger JM

    2006-05-01

    Full Text Available Abstract Background Addison's disease, also known as hypoadrenocorticism, has been reported in many individual dogs, although some breeds exhibit a greater incidence than the population as a whole. Addison's is presumed to be an autoimmune mediated hereditary defect but the mode of inheritance remains unclear. In particular, the heritability and mode of inheritance have not been defined for the Portuguese Water Dog although Addison's is known to be prevalent in the breed. Results The analyses present clear evidence that establishes Addison's disease as an inherited disorder in the Portuguese Water Dog with an estimate of heritability of 0.49 (± 0.16; there were no differences in risk for disease across sexes (p > 0.49. Further, the complex segregation analysis provides suggestive evidence that Addison's disease in the Portuguese Water Dog is inherited under the control of a single, autosomal recessive locus. Conclusion The high heritability and mode of inheritance of Addison's disease in the Portuguese Water Dog should enable the detection of segregating markers in a genome-wide scan and the identification of a locus linked to Addison's. Though the confirmation of Addison's disease as an autosomal recessive disorder must wait until the gene is identified, breeders of these dogs may wish to keep the present findings in mind as they plan their breeding programs to select against producing affected dogs.

  3. Genetic evaluation of Addison's disease in the Portuguese Water Dog.

    Science.gov (United States)

    Oberbauer, A M; Bell, J S; Belanger, J M; Famula, T R

    2006-05-02

    Addison's disease, also known as hypoadrenocorticism, has been reported in many individual dogs, although some breeds exhibit a greater incidence than the population as a whole. Addison's is presumed to be an autoimmune mediated hereditary defect but the mode of inheritance remains unclear. In particular, the heritability and mode of inheritance have not been defined for the Portuguese Water Dog although Addison's is known to be prevalent in the breed. The analyses present clear evidence that establishes Addison's disease as an inherited disorder in the Portuguese Water Dog with an estimate of heritability of 0.49 (+/- 0.16); there were no differences in risk for disease across sexes (p > 0.49). Further, the complex segregation analysis provides suggestive evidence that Addison's disease in the Portuguese Water Dog is inherited under the control of a single, autosomal recessive locus. The high heritability and mode of inheritance of Addison's disease in the Portuguese Water Dog should enable the detection of segregating markers in a genome-wide scan and the identification of a locus linked to Addison's. Though the confirmation of Addison's disease as an autosomal recessive disorder must wait until the gene is identified, breeders of these dogs may wish to keep the present findings in mind as they plan their breeding programs to select against producing affected dogs.

  4. Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women

    DEFF Research Database (Denmark)

    Havndrup, Ole; Christiansen, Michael; Stoevring, Birgitte

    2010-01-01

    AIMS: Fabry disease, an X-linked storage disorder caused by defective lysosomal enzyme alpha-galactosidase A activity, may resemble sarcomere-gene-associated hypertrophic cardiomyopathy (HCM). The 'cardiac variant' of Fabry disease which only affects the heart may be missed unless specifically te...... therapy, supports systematic testing for Fabry disease. Enzyme measurements are sufficient in men, but genetic testing is needed in women....

  5. Human genetics of infectious diseases: between proof of principle and paradigm

    OpenAIRE

    Alcaïs, Alexandre; Abel, Laurent; Casanova, Jean-Laurent

    2009-01-01

    The observation that only a fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. Although many studies have provided proo...

  6. Breeding, genetic and genomic of citrus for disease resistance

    Directory of Open Access Journals (Sweden)

    Marcos A. Machado

    2011-10-01

    Full Text Available Although the citriculture is one of the most important economic activities in Brazil, it is based on a small number of varieties. This fact has contributed for the vulnerability of the culture regarding the phytosanitary problems. A higher number of varieties/genotypes with potential for commercial growing, either for the industry or fresh market, has been one of the main objectives of citrus breeding programs. The genetic breeding of citrus has improved, in the last decades, due to the possibility of an association between biotechnological tools and classical methods of breeding. The use of molecular markers for early selection of zygotic seedlings from controlled crosses resulted in the possibility of selection of a high number of new combination and, as a consequence, the establishment of a great number of hybrids in field experiments. The faster new tools are incorporated in the program, the faster is possibility to reach new genotypes that can be tested as a new variety. Good traits should be kept or incorporate, whereas bad traits have to be excluded or minimized in the new genotype. Scion and rootstock can not be considered separately, and graft compatibility, fruit quality and productivity are essential traits to be evaluated in the last stages of the program. The mapping of QTLs has favored breeding programs of several perennial species and in citrus it was possible to map several characteristics with qualitative and quantitative inheritance. The existence of linkage maps and QTLs already mapped, the development of EST and BAC library and the sequencing of the Citrus complete genome altogether make very demanding and urgent the exploration of such data to launch a wider genetic study of citrus. The rising of information on genome of several organisms has opened new approaches looking for integration between breeding, genetic and genome. Genome assisted selection (GAS involves more than gene or complete genome sequencing and is becoming

  7. Understanding of and attitudes to genetic testing for inherited retinal disease: a patient perspective.

    Science.gov (United States)

    Willis, T A; Potrata, B; Ahmed, M; Hewison, J; Gale, R; Downey, L; McKibbin, M

    2013-09-01

    The views of people with inherited retinal disease are important to help develop health policy and plan services. This study aimed to record levels of understanding of and attitudes to genetic testing for inherited retinal disease, and views on the availability of testing. Telephone questionnaires comprising quantitative and qualitative items were completed with adults with inherited retinal disease. Participants were recruited via postal invitation (response rate 48%), approach at clinic or newsletters of relevant charitable organisations. Questionnaires were completed with 200 participants. Responses indicated that participants' perceived understanding of genetic testing for inherited retinal disease was variable. The majority (90%) considered testing to be good/very good and would be likely to undergo genetic testing (90%) if offered. Most supported the provision of diagnostic (97%) and predictive (92%) testing, but support was less strong for testing as part of reproductive planning. Most (87%) agreed with the statement that testing should be offered only after the individual has received genetic counselling from a professional. Subgroup analyses revealed differences associated with participant age, gender, education level and ethnicity (p<0.02). Participants reported a range of perceived benefits (eg, family planning, access to treatment) and risks (eg, impact upon family relationships, emotional consequences). Adults with inherited retinal disease strongly support the provision of publicly funded genetic testing. Support was stronger for diagnostic and predictive testing than for testing as part of reproductive planning.

  8. Perceptions of genetic discrimination among people at risk for Huntington?s disease: a cross sectional survey

    OpenAIRE

    Bombard, Yvonne; Veenstra, Gerry; Friedman, Jan M; Creighton, Susan; Currie, Lauren; Paulsen, Jane S; Bottorff, Joan L; Hayden, Michael R

    2009-01-01

    Objective To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington?s disease who had undergone genetic testing or remained untested. Design Cross sectional, self reported survey. Setting Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. Participants 233 genetically tested and untested asymptomatic people at risk for Huntington?s disease (response rate 80%): 167 underwent testing (83 had the Huntingt...

  9. Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease.

    Science.gov (United States)

    Kanatsu, Kunihiko; Tomita, Taisuke

    2017-01-01

    Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1 . In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2 . We review the recent findings related to the molecular mechanisms by which these genetic risk factors contribute to AD, and our perspectives regarding the etiology of AD for the development of therapeutic agents.

  10. Insights into the genetics of gastroesophageal reflux disease (GERD) and GERD-related disorders.

    Science.gov (United States)

    Böhmer, A C; Schumacher, J

    2017-02-01

    Gastroesophageal reflux disease (GERD) is associated with obesity and hiatal hernia, and often precedes the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). Epidemiological studies show that the global prevalence of GERD is increasing. GERD is a multifactorial disease with a complex genetic architecture. Genome-wide association studies (GWAS) have provided initial insights into the genetic background of GERD. The present review summarizes current knowledge of the genetics of GERD and a possible genetic overlap between GERD and BE and EA. The review discusses genes and cellular pathways that have been implicated through GWAS, and provides an outlook on how future molecular research will enhance understanding of GERD pathophysiology. © 2017 John Wiley & Sons Ltd.

  11. The interaction of host genetics and disease processes in chronic livestock disease: a simulation model of ovine footrot.

    Science.gov (United States)

    Russell, V N L; Green, L E; Bishop, S C; Medley, G F

    2013-03-01

    A stochastic, individual-based, simulation model of footrot in a flock of 200 ewes was developed that included flock demography, disease processes, host genetic variation for traits influencing infection and disease processes, and bacterial contamination of the environment. Sensitivity analyses were performed using ANOVA to examine the contribution of unknown parameters to outcome variation. The infection rate and bacterial death rate were the most significant factors determining the observed prevalence of footrot, as well as the heritability of resistance. The dominance of infection parameters in determining outcomes implies that observational data cannot be used to accurately estimate the strength of genetic control of underlying traits describing the infection process, i.e. resistance. Further work will allow us to address the potential for genetic selection to control ovine footrot. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Global transcriptional analysis of psoriatic skin and blood confirms known disease-associated pathways and highlights novel genomic "hot spots" for differentially expressed genes.

    Science.gov (United States)

    Coda, Alvin B; Icen, Murat; Smith, Jason R; Sinha, Animesh A

    2012-07-01

    There are major gaps in our knowledge regarding the exact mechanisms and genetic basis of psoriasis. To investigate the pathogenesis of psoriasis, gene expression in 10 skin (5 lesional, 5 nonlesional) and 11 blood (6 psoriatic, 5 nonpsoriatic) samples were examined using Affymetrix HG-U95A microarrays. We detected 535 (425 upregulated, 110 downregulated) DEGs in lesional skin at 1% false discovery rate (FDR). Combining nine microarray studies comparing lesional and nonlesional psoriatic skin, 34.5% of dysregulated genes were overlapped in multiple studies. We further identified 20 skin and 2 blood associated transcriptional "hot spots" at specified genomic locations. At 5% FDR, 11.8% skin and 10.4% blood DEGs in our study mapped to one of the 12 PSORS loci. DEGs that overlap with PSORS loci may offer prioritized targets for downstream genetic fine mapping studies. Novel DEG "hot spots" may provide new targets for defining susceptibility loci in future studies. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. FY 2016 Research Highlights

    Energy Technology Data Exchange (ETDEWEB)

    2017-03-23

    This fact sheet summarizes the research highlights for the Clean Energy Manufacturing Analysis Center (CEMAC) for Fiscal Year 2106. Topics covered include additive manufacturing for the wind industry, biomass-based chemicals substitutions, carbon fiber manufacturing facility siting, geothermal power plant turbines, hydrogen refueling stations, hydropower turbines, LEDs and lighting, light-duty automotive lithium-ion cells, magnetocaloric refrigeration, silicon carbide power electronics for variable frequency motor drives, solar photovoltaics, and wide bandgap semiconductor opportunities in power electronics.

  14. Indirect Genetic Effects and the Spread of Infectious Disease: Are We Capturing the Full Heritable Variation Underlying Disease Prevalence?

    NARCIS (Netherlands)

    Lipschutz-Powell, D.; Woolliams, J.A.; Bijma, P.; Doeschl-Wilson, A.B.

    2012-01-01

    Reducing disease prevalence through selection for host resistance offers a desirable alternative to chemical treatment. Selection for host resistance has proven difficult, however, due to low heritability estimates. These low estimates may be caused by a failure to capture all the relevant genetic

  15. Evaluation of a genetically modified foot-and-mouth disease virus vaccine candidate generated by reverse genetics

    Science.gov (United States)

    2012-01-01

    Background Foot-and-mouth disease (FMD) is the most economically important and highly contagious disease of cloven-hoofed animals worldwide. Control of the disease has been mainly based on large-scale vaccinations with whole-virus inactivated vaccines. In recent years, a series of outbreaks of type O FMD occurred in China (including Chinese Taipei, Chinese Hong Kong) posed a tremendous threat to Chinese animal husbandry. Its causative agent, type O FMDV, has evolved into three topotypes (East–South Asia (ME-SA), Southeast Asia (SEA), Cathay (CHY)) in these regions, which represents an important obstacle to disease control. The available FMD vaccine in China shows generally good protection against ME-SA and SEA topotype viruses infection, but affords insufficient protection against some variants of the CHY topotype. Therefore, the choice of a new vaccine strain is of fundamental importance. Results The present study describes the generation of a full-length infectious cDNA clone of FMDV vaccine strain and a genetically modified virus with some amino acid substitutions in antigenic sites 1, 3, and 4, based on the established infectious clone. The recombinant viruses had similar growth properties to the wild O/HN/CHA/93 virus. All swine immunized with inactivated vaccine prepared from the O/HN/CHA/93 were fully protected from challenge with the viruses of ME-SA and SEA topotypes and partially protected against challenge with the virus of CHY topotype at 28 days post-immunization. In contrast, the swine inoculated with the genetically modified vaccine were completely protected from the infection of viruses of the three topotypes. Conclusions Some amino acid substitutions in the FMDV vaccine strain genome did not have an effect on the ability of viral replication in vitro. The vaccine prepared from genetically modified FMDV by reverse genetics significantly improved the protective efficacy to the variant of the CHY topotype, compared with the wild O/HN/CHA/93 virus

  16. Evaluation of a genetically modified foot-and-mouth disease virus vaccine candidate generated by reverse genetics

    Directory of Open Access Journals (Sweden)

    Li Pinghua

    2012-05-01

    Full Text Available Abstract Background Foot-and-mouth disease (FMD is the most economically important and highly contagious disease of cloven-hoofed animals worldwide. Control of the disease has been mainly based on large-scale vaccinations with whole-virus inactivated vaccines. In recent years, a series of outbreaks of type O FMD occurred in China (including Chinese Taipei, Chinese Hong Kong posed a tremendous threat to Chinese animal husbandry. Its causative agent, type O FMDV, has evolved into three topotypes (East–South Asia (ME-SA, Southeast Asia (SEA, Cathay (CHY in these regions, which represents an important obstacle to disease control. The available FMD vaccine in China shows generally good protection against ME-SA and SEA topotype viruses infection, but affords insufficient protection against some variants of the CHY topotype. Therefore, the choice of a new vaccine strain is of fundamental importance. Results The present study describes the generation of a full-length infectious cDNA clone of FMDV vaccine strain and a genetically modified virus with some amino acid substitutions in antigenic sites 1, 3, and 4, based on the established infectious clone. The recombinant viruses had similar growth properties to the wild O/HN/CHA/93 virus. All swine immunized with inactivated vaccine prepared from the O/HN/CHA/93 were fully protected from challenge with the viruses of ME-SA and SEA topotypes and partially protected against challenge with the virus of CHY topotype at 28 days post-immunization. In contrast, the swine inoculated with the genetically modified vaccine were completely protected from the infection of viruses of the three topotypes. Conclusions Some amino acid substitutions in the FMDV vaccine strain genome did not have an effect on the ability of viral replication in vitro. The vaccine prepared from genetically modified FMDV by reverse genetics significantly improved the protective efficacy to the variant of the CHY topotype, compared with the

  17. Disclosing Genetic Risk for Coronary Heart Disease: Attitudes Toward Personal Information in Health Records.

    Science.gov (United States)

    Brown, Sherry-Ann; Jouni, Hayan; Marroush, Tariq S; Kullo, Iftikhar J

    2017-04-01

    Incorporating genetic risk information in electronic health records (EHRs) will facilitate implementation of genomic medicine in clinical practice. However, little is known about patients' attitudes toward incorporation of genetic risk information as a component of personal health information in EHRs. This study investigated whether disclosure of a genetic risk score (GRS) for coronary heart disease influences attitudes toward incorporation of personal health information including genetic risk in EHRs. Participants aged 45-65 years with intermediate 10-year coronary heart disease risk were randomized to receive a conventional risk score (CRS) alone or with a GRS from a genetic counselor, followed by shared decision making with a physician using the same standard presentation and information templates for all study participants. The CRS and GRS were then incorporated into the EHR and made accessible to both patients and physicians. Baseline and post-disclosure surveys were completed to assess whether attitudes differed by GRS disclosure. Data were collected from 2013 to 2015 and analyzed in 2015-2016. GRS and CRS participants reported similar positive attitudes toward incorporation of genetic risk information in the EHR. Compared with CRS participants, participants with high GRS were more concerned about the confidentiality of genetic risk information (OR=3.67, 95% CI=1.29, 12.32, p=0.01). Post-disclosure, frequency of patient portal access was associated with positive attitudes. Participants in this study of coronary heart disease risk disclosure overall had positive attitudes toward incorporation of genetic risk information in EHRs, although those who received genetic risk information had concerns about confidentiality. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Genetic analysis of disease susceptibility in the Arabidopsis-Hyaloperonospora parasitica interaction

    NARCIS (Netherlands)

    Damme, M.M.A. van

    2007-01-01

    On a global scale the impact and costs of plant diseases on agriculture is enormous, highlighting the importance of the research on this topic. Plant disease is the result of a compatible interaction between plants and adapted pathogens. The knowledge on the molecular mechanisms underlying

  19. Genetic shifting: a novel approach for controlling vector-borne diseases

    OpenAIRE

    Powell, Jeffrey R.; Tabachnick, Walter J.

    2014-01-01

    Rendering populations of vectors of diseases incapable of transmitting pathogens through genetic methods has long been a goal of vector geneticists. We outline a method to achieve this goal that does not involve introduction of any new genetic variants to the target population. Rather we propose that shifting the frequencies of naturally occurring alleles that confer refractoriness to transmission can reduce transmission below a sustainable level. The program employs methods successfully used...

  20. EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease

    OpenAIRE

    Losekoot, Monique; van Belzen, Martine J; Seneca, Sara; Bauer, Peter; Stenhouse, Susan A R; Barton, David E

    2012-01-01

    Huntington disease (HD) is caused by the expansion of an unstable polymorphic trinucleotide (CAG)n repeat in exon 1 of the HTT gene, which translates into an extended polyglutamine tract in the protein. Laboratory diagnosis of HD involves estimation of the number of CAG repeats. Molecular genetic testing for HD is offered in a wide range of laboratories both within and outside the European community. In order to measure the quality and raise the standard of molecular genetic testing in these ...

  1. THE MITOCHONDRIAL PARADIGM FOR CARDIOVASCULAR DISEASE SUSCEPTIBILITY AND CELLULAR FUNCTION: A COMPLEMENTARY CONCEPT TO MENDELIAN GENETICS

    OpenAIRE

    Kryzwanski, David M.; Moellering, Douglas; Fetterman, Jessica L.; Dunham-Snary, Kimberly J.; Sammy, Melissa J.; Ballinger, Scott W.

    2011-01-01

    While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function in determining CVD susceptibility from the standpoint that the orig...

  2. Parkinson's disease and pesticides: A meta-analysis of disease connection and genetic alterations.

    Science.gov (United States)

    Ahmed, Hussien; Abushouk, Abdelrahman Ibrahim; Gabr, Mohamed; Negida, Ahmed; Abdel-Daim, Mohamed M

    2017-06-01

    Parkinson's disease (PD) is a globally prevalent, multifactorial disorder that occurs due to interactions between genetic and environmental factors. Observational studies have shown a link between exposure to pesticides and the risk of PD. We performed this study to systemically review published case-control studies and estimate quantitatively the association between pesticide exposure and PD. We searched Medline (through PubMed) for eligible case-control studies. The association between pesticide exposure and PD risk or occurrence of certain genetic alterations, related to the pathogenesis of PD was presented as odds ratios (OR) and pooled under the random effects model, using the statistical add-in (MetaXL, version 5.0). The pooled result showed that exposure to pesticides is linked to PD (OR 1.46, 95% CI [1.21, 1.77]), but there was a significant heterogeneity among included studies. Exposure to pesticides increased the risk of alterations in different PD pathogenesis-related genes, such as GST (OR 1.97, 95% CI [1.41, 2.76]), PON-1 (OR 1.32, 95% CI [1.09, 1.6]), MDR1 (OR 2.06, 95% CI [1.58, 2.68]), and SNCA genes (OR 1.28, 95% CI [1.02, 1.37]). There was no statistically significant association between exposure to pesticides and alteration of CYP2D6 (OR 1.19, 95% CI [0.91, 1.54]), SLC6A3 (OR 0.74, 95% CI [0.55, 1]), MnSOD (OR 1.45, 95% CI [0.97, 2.16]), NQO1 (OR 1.35, 95% CI [0.91, 2.01]), and PON-2 genes (OR 0.88, 95% CI [0.53, 1.45]). In conclusion, this meta-analysis provides evidence that pesticide exposure is significantly associated with the risk of PD and alterations in genes involved in PD pathogenesis. However, the underlying mechanism of this association and the effect of the duration of exposure or the type of pesticides should be addressed by future research. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2011-01-01

    To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...... of such genetic determinants with cardiovascular disease risk will either favor or disfavor that these lipoproteins are causally related to cardiovascular disease....

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  5. Amniotic Fluid Stem Cells: A Novel Source for Modeling of Human Genetic Diseases

    Directory of Open Access Journals (Sweden)

    Ivana Antonucci

    2016-04-01

    Full Text Available In recent years, great interest has been devoted to the use of Induced Pluripotent Stem cells (iPS for modeling of human genetic diseases, due to the possibility of reprogramming somatic cells of affected patients into pluripotent cells, enabling differentiation into several cell types, and allowing investigations into the molecular mechanisms of the disease. However, the protocol of iPS generation still suffers from technical limitations, showing low efficiency, being expensive and time consuming. Amniotic Fluid Stem cells (AFS represent a potential alternative novel source of stem cells for modeling of human genetic diseases. In fact, by means of prenatal diagnosis, a number of fetuses affected by chromosomal or Mendelian diseases can be identified, and the amniotic fluid collected for genetic testing can be used, after diagnosis, for the isolation, culture and differentiation of AFS cells. This can provide a useful stem cell model for the investigation of the molecular basis of the diagnosed disease without the necessity of producing iPS, since AFS cells show some features of pluripotency and are able to differentiate in cells derived from all three germ layers “in vitro”. In this article, we describe the potential benefits provided by using AFS cells in the modeling of human genetic diseases.

  6. Using induced pluripotent stem cells to explore genetic and epigenetic variation associated with Alzheimer's disease.

    Science.gov (United States)

    Imm, Jennifer; Kerrigan, Talitha L; Jeffries, Aaron; Lunnon, Katie

    2017-11-01

    It is thought that both genetic and epigenetic variation play a role in Alzheimer's disease initiation and progression. With the advent of somatic cell reprogramming into induced pluripotent stem cells it is now possible to generate patient-derived cells that are able to more accurately model and recapitulate disease. Furthermore, by combining this with recent advances in (epi)genome editing technologies, it is possible to begin to examine the functional consequence of previously nominated genetic variants and infer epigenetic causality from recently identified epigenetic variants. In this review, we explore the role of genetic and epigenetic variation in Alzheimer's disease and how the functional relevance of nominated loci can be investigated using induced pluripotent stem cells and (epi)genome editing techniques.

  7. Genetic influences on the development of fibrosis in Crohn’s Disease

    Directory of Open Access Journals (Sweden)

    Bram eVerstockt

    2016-05-01

    Full Text Available Fibrostenotic strictures are an important complication in patients with Crohn’s Disease, very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual, and is influenced by an interplay with environmental, immunological and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here we review the genetic factors that have been associated with the development of fibrosis in patients with Crohn’s disease, as well as their potential pathophysiological mechanism(s. We also hypothesize on clinical implications if any, and future research directions.

  8. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients

    DEFF Research Database (Denmark)

    Brorsson, Caroline A; Nielsen, Lotte B; Andersen, Marie-Louise

    2016-01-01

    Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type...... 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease...... constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several...

  9. From mother to daughter. Psychic disease: genetic or environmental influence?

    Directory of Open Access Journals (Sweden)

    Roberto Infrasca

    2011-09-01

    Full Text Available The problem of genetic versus environmental influences in psychiatric disorders is widely discussed in biomedical literature, but remains still controversial. Familiarity has been observed in some disesase, such as obsessive-compulsive disorder and panic attack disorder. In this study we analyse three generations of women, for a total of 4 women (a mother, her two daughters, and a granddaughter followed by our Psychiatric Department for depressive and anxiety disorders. The aim of the study was to assess wheather there are similarities among the clinical status of the four women, and verify the relationship among those disorders. The Minnesota Multiphasic Personality Inventory (MMPI was administered to all the patients and the scores obtained were compared. We found out that the many aspects and psychological traits were present in all the four women. These similarities suggest the presence of a dynamic trans-generational transmission.

  10. Invasive Group A Streptococcal Disease. National Epidemiology and Genetic Analysis

    NARCIS (Netherlands)

    Vlaminckx, B.J.M.

    2006-01-01

    Infections with group A streptococci (GAS), or S. pyogenes, range from mild and superficial to very severe and lethal invasive disease. In severe invasive GAS infections, hypotension and multiorgan failure may develop rapidly resulting in the development of toxic shock-like syndrome (TSS). In the

  11. Genetic overlap between apparently sporadic motor neuron diseases

    NARCIS (Netherlands)

    van Blitterswijk, Marka; Vlam, Lotte; van Es, Michael A.; van der Pol, W.-Ludo; Hennekam, Eric A. M.; Dooijes, Dennis; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne; Veldink, Jan H.; van den Berg, Leonard H.

    2012-01-01

    Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and

  12. Genetic variation of Border disease virus species strains

    Directory of Open Access Journals (Sweden)

    Massimo Giangaspero

    2011-12-01

    Full Text Available The 5´-untranslated region of Pestivirus strains isolated from domestic and wild animals were analysed to determine their taxonomic status according to nucleotide changes in the secondary genomic structure using the palindromic nucleotide substitutions (PNS method. A total of 131 isolates out of 536 Pestivirus strains evaluated, were clustered as Border disease virus (BDV species. The BDV strains were further divided into at least 8 genotypes or subspecies. Thirty-two isolates from small ruminants suffering from clinical symptoms of Border disease were clustered into bovine viral diarrhoea virus 1 (BVDV-1, BVDV-2 and classical swine fever (hog cholera virus species and also into the tentative BDV-2 species. Since the definition of an infectious disease is based primarily on a specific causative pathogen and taking into account the heterogeneity of the genus Pestivirus, clinical cases should be named according to the laboratory results. The PNS procedure could be useful for laboratory diagnosis of Border disease in domestic and wild ruminants.

  13. Fibroblasts of skin fragments as a tool for the investigation of genetic diseases: technical recommendations

    Directory of Open Access Journals (Sweden)

    Coelho Janice Carneiro

    2000-01-01

    Full Text Available Skin biopsies are frequently indicated for investigation and/or confirmation of genetic disorders. Although relatively simple and noninvasive, these procedures require care in order to increase probability of success and to avoid patient discomfort and unnecessary repeated analyses and associated laboratory fees. The present report highlights the importance of skin biopsies in genetic disorder diagnosis and presents general rules for collecting, storing, transporting and processing samples. We recommend its reading to professionals intending to use this important and sometimes fundamental diagnostic tool.

  14. Management of colonic diverticular disease in the third millennium: Highlights from a symposium held during the United European Gastroenterology Week 2017

    Science.gov (United States)

    Barbara, Giovanni; Lanas, Angel; Strate, Lisa L.

    2018-01-01

    Diverticulosis is a common anatomical condition, which appears to be age-dependent. Individuals who develop chronic gastrointestinal symptoms or complications are referred to as having diverticular disease. Although the diagnosis of this condition can be relatively straightforward, randomized controlled trials are scarce and management often follows tradition rather than principles of evidence-based medicine. This report deals with the topics discussed during a symposium held during the United European Gastroenterology Week (Barcelona, October 2017). During the meeting, the role of dysbiosis in the pathogenesis of diverticular disease and its treatment were thoroughly discussed, by examining the efficacy and mechanisms of action of the currently used drugs. Recent studies have shown the presence of dysbiosis in patients with diverticular disease and suggest an imbalance in favor of bacteria with pro-inflammatory and pathogenetic potential. These microbiota changes correlate with mucosal immune activation, mirrored by a marked increase of macrophages in colonic mucosa, both in the diverticular region and at distant sites. The low-grade inflammation, driven by bacteria-induced immune activation, could be involved in the pathophysiology of symptoms. As a consequence, pharmacological approaches targeting enteric bacteria (with poorly absorbed antibiotics, like rifaximin, or probiotics) or intestinal inflammation (with 5-ASA derivatives or rifaximin) have shown capability of controlling symptoms and also preventing complications, albeit more research is needed to establish the optimal regimen (daily dose and duration) of therapy. Well-designed randomized-controlled trials (RCTs), including homogeneous populations of patients, are therefore needed. The future of management of many GI diseases, including symptomatic uncomplicated diverticular disease, will rely on the so-called ‘microbiota-directed therapies’. PMID:29844795

  15. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease

    DEFF Research Database (Denmark)

    Benn, Marianne; Nordestgaard, Børge G.; Frikke-Schmidt, Ruth

    2017-01-01

     Risk of Alzheimer's disease, vascular dementia, all dementia, and Parkinson's disease.Results In observational analyses, the multifactorially adjusted hazard ratio for Parkinson's disease in participants with an LDL cholesterol level ....79), whereas the corresponding hazard ratios for Alzheimer's disease, vascular dementia, or any dementia did not differ from 1.0. PCSK9 and HMGCR variants combined were associated with a 9.3% lower LDL cholesterol level. In genetic, causal analyses adjusted for age, sex, and year of birth, the risk ratios...... for a lifelong 1 mmol/L lower LDL cholesterol level were 0.57 (0.27 to 1.17) for Alzheimer's disease, 0.81 (0.34 to 1.89) for vascular dementia, 0.66 (0.34 to 1.26) for any dementia, and 1.02 (0.26 to 4.00) for Parkinson's disease. Summary level data from the International Genomics of Alzheimer's Project using...

  16. A comparative analysis of molecular genetic and conventional cytogenetic detection of diagnostically important translocations in more than 400 cases of acute leukemia, highlighting the frequency of false-negative conventional cytogenetics.

    Science.gov (United States)

    King, Rebecca L; Naghashpour, Mojdeh; Watt, Christopher D; Morrissette, Jennifer J D; Bagg, Adam

    2011-06-01

    In this study, we correlated the results of concurrent molecular and cytogenetic detection of entity-defining translocations in adults with acute leukemia to determine the frequency of cryptic translocations missed by conventional cytogenetics (CC) and of recurrent, prognostically relevant translocations not detectable by multiplex reverse transcriptase-polymerase chain reaction (MRP). During a 5.5-year period, 442 diagnostic acute leukemia specimens were submitted for MRP-based detection of 7 common recurrent translocations: t(8;21), t(15;17), inv(16), t(9;22), t(12;21), t(4;11), and t(1;19), with a detection rate of 15.2% (67/442). CC was performed in 330 (74.7%) of 442 cases. In 7 of these 330 cases, CC missed the translocation detected by MRP. In 50 additional cases, CC revealed 1 of the MRP-detectable translocations (all were also MRP positive), yielding a false-negative rate of 12% (7/57) for the CC assay. The remaining 140 of 190 cases with clonal cytogenetic changes harbored abnormalities that were not targeted by the MRP assay, including 8 that define specific acute myeloid leukemia entities. This study revealed the frequent occurrence of false-negative, entity-defining CC analysis and highlighted the complementary nature of MRP and CC approaches in detecting genetic abnormalities in acute leukemia.

  17. IGC highlights 1988

    International Nuclear Information System (INIS)

    1989-01-01

    The major thrust of the research and development (R and D) activities of the Indira Gandhi Centre for Atomic Research (IGCAR), Kalpakkam is oriented towards mastering fast breeder reactor (FBR) technology. Towards this end, its current R and D activities are carried out in a wide variety of disciplines. Highlights of its R and D activities during 1988 are summarised under the headings: Reactor Engineering and Design, Reactor Physics and Safety, Materials Science and Technology, Sodium Chemistry and Technology, Fuel Reprocessing and Electronics and Instrumentation. The text is illustrated with a number of figures, graphs and coloured pictures. (M.G.B.). figs., tabs

  18. BARC highlights '88

    International Nuclear Information System (INIS)

    1989-01-01

    Highlights of research and development activities of the Bhabha Atomic Research Centre (BARC), Bombay during 1988 are presented in chapters entitled: Physical Sciences, Chemical Sciences, Materials and Materials Sciences, Radioisotopes, Reactors, Fuel Cycle, Radiological Safety and Protection, Electronics and Instrumentation, Engineering Services, and Life Sciences. Main thrust of the R and D activities of BARC is on nuclear power reactor technology and all stages of nuclear fuel cycle. Some activities are also in the frontier areas such as high temperature superconductivity and inertial confinement fusion. (M.G.B.). figs., tabs., coloured ills

  19. Genetic aspects of hypertension and metabolic disease in the obstructive sleep apnoea-hypopnoea syndrome

    DEFF Research Database (Denmark)

    Riha, R.L.; Diefenbach, K.; Jennum, P.

    2008-01-01

    Though it has long been recognised that there is a hereditary component to the obstructive steep apnoea/hypopnoea syndrome (OSAHS), identifying its genetic basis remains elusive. Hypertension and metabolic syndrome, Like OSAHS, are polygenic disorders, physiologically complex and the product...... phenotyping, which has hampered genetic dissection of these diseases; in addition, sleep-disordered breathing has not been factored into most studies dealing with essential hypertension or metabolic syndrome. Genome-wide scans have yielded inconsistent results in all three disorders under discussion...... for the expression of cardiovascular disease and metabolic syndrome in the context of OSAHS. (C) 2007 Elsevier Ltd. All rights reserved Udgivelsesdato: 2008/2...

  20. Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses

    Directory of Open Access Journals (Sweden)

    Carsten Bergmann

    2018-02-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD. A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD. For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic

  1. Genetic design of pigs as experimental models in the combat between chronic diseases and healthy aging

    DEFF Research Database (Denmark)

    Bolund, Lars

    2012-01-01

    with and without intervention. The genome of different pig breeds have been sequenced, revealing that the pig is genetically more similar to man than conventional laboratory animals - in agreement with the similarities in organ development, physiology and metabolism. Genetically designed minipigs (Göttingen...... pigs. We can also produce clones of pigs, some disease prone and some fluorescing, to perform experiments in regenerative medicine where the fate of healthy fluorescent cells can be followed in the, basically identical, disease prone animals. It is also our hope that our pig models can contribute...

  2. The genetic variance of resistance in M3 lines of rice against leaf blight disease

    International Nuclear Information System (INIS)

    Mugiono

    1979-01-01

    Seeds of Pelita I/1 rice variety were irradiated with 20, 30, 40 and 50 krad of gamma rays from a 60 Co source. Plants of M 3 lines were inoculated with bacterial leaf blight, Xanthomonas oryzae (Uzeda and Ishiyama) Downson, using clipping method. The coefficient of genetic variability of resistance against leaf blight disease increased with increasing dose. Highly significant difference in the genetic variance of resistance were found between the treated samples and the control. Dose of 20 krad gave good probability for selection of plants resistant against leaf blight disease. (author)

  3. A Baseline Algorithm for Molecular Diagnosis of Genetic Eye Diseases: Ophthalmologist’s Perspective

    Directory of Open Access Journals (Sweden)

    Hande Taylan Şekeroğlu

    2016-12-01

    Full Text Available To the Editor: Genetic eye diseases constitute a large and heterogeneous group. Individual diseases may cause multiple structural/functional anomalies and developmental features. Family history may be suggestive; however, it may also be challenging, particularly in late-onset conditions or in cases of variable expression. In the current era of genetic advances, diagnosis of a genetic eye disease is facilitated by well-established collaboration between ophthalmologists and geneticists, as increasingly more patients will be asking for genetic counseling and prenatal diagnosis in addition to ophthalmologic management. Molecular investigation of a genetic eye disease requires customized analysis and advanced technology in addition to the requisite detailed family history and accurate ophthalmological diagnosis. A common indication for genetic testing is the validation of a preliminary diagnosis made in clinical practice. The need to determine the prognostic implications of the genotype, assessment of the recurrence risk and in particular, the possibility of specific gene therapy in the near future encourages clinicians to pursue genetic research. We present here a baseline algorithm covering common genetic mechanisms in order to outline a basic molecular approach for ophthalmologists. The first step of the flow chart, a prudent clinical examination with complete description of the phenotype, is indispensible for making a precise and accurate preliminary diagnosis (Figure 1. If the phenotype is pathognomonic, Sanger sequencing is preferred for confirmation.1 A previously established genotype-phenotype correlation may add to the value, either by providing accurate prognostic information or by indicating which particular mutation to look for. One such example may be electroretinographic supranormal rod response, indicating KCNV2 mutation type cone dystrophy, which can be precisely detected by Sanger sequencing or qPCR.2 Conventional karyotyping reveals

  4. Clinical and genetic data of Huntington disease in Moroccan patients

    African Journals Online (AJOL)

    1. Equipe de Recherche sur les Maladies Neurodégénératives, Faculté de Médecine et de Pharmacie, Université ... Service de Neurologie et de Neurogénétique, Hôpital des Spécialités de Rabat, Morocco. 3. ... ed person have a 50% risk of inheriting the disease. It ... deficit, loss of motivation, concentration problems, dif-.

  5. Genetic homogeneity of autoimmune polyglandular disease type I

    Energy Technology Data Exchange (ETDEWEB)

    Bjoerses, P.; Aaltonen, J.; Vikman, A. [Univ. of Helsinki (Finland)] [and others

    1996-10-01

    Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pair-wise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for {approximately}90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21. 21 refs., 3 figs., 3 tabs.

  6. Risk factors for type 2 diabetes and cardiovascular disease in Mexican adult from different socio-economic levels. Highlights and achievements

    Energy Technology Data Exchange (ETDEWEB)

    Valencia Juillerat, M E [Centro de Investigacion en Alimentacion y Desarrollo (CIAD), Sonara (Mexico)

    2002-07-01

    Obesity, type 2 diabetes and cardiovascular disease (CVD) are a major concern in many parts of the world. In northern Mexico, these problems have been reported to be higher than in the rest of the country. To assess the different risk factors based on body status (body composition, body size, fat distribution) and lifestyle factors (diet and physical activity) for the development of type 2 diabetes and CVD in men and women from different socioeconomic levels in north-west Mexico.

  7. Risk factors for type 2 diabetes and cardiovascular disease in Mexican adult from different socio-economic levels. Highlights and achievements

    International Nuclear Information System (INIS)

    Valencia Juillerat, M.E.

    2002-01-01

    Obesity, type 2 diabetes and cardiovascular disease (CVD) are a major concern in many parts of the world. In northern Mexico, these problems have been reported to be higher than in the rest of the country. To assess the different risk factors based on body status (body composition, body size, fat distribution) and lifestyle factors (diet and physical activity) for the development of type 2 diabetes and CVD in men and women from different socioeconomic levels in north-west Mexico

  8. Nanomedicine highlights in atherosclerosis

    International Nuclear Information System (INIS)

    Karagkiozaki, Varvara

    2013-01-01

    Atherosclerosis is a multifactorial disease and many different approaches have been attempted for its accurate diagnosis and treatment. The disease is induced by a low-grade inflammatory process in the vascular wall, leading through a cascade of events to the eventual formation of atheromatous plaque and arterial stenosis. Different types of cells participate in the process making more difficult to recognize the potential cellular targets within the plaques for their effective treatment. The rise of nanomedicine over the last decade has provided new types of drug delivery nanosystems that are able to be delivered to a specific diseased site of the vessel for imaging while simultaneously act as therapeutic agents. In this paper, a review of the recent advances in nanomedicine that has provided novel insights to the disease diagnosis and treatment will be given in line with different nanotechnology-based approaches to advance the cardiovascular stents. The main complications of bare metal stents such as restenosis and of drug-eluting stents which is the late stent thrombosis are analyzed to comprehend the demand for emerging therapeutic strategies based on nanotechnology.

  9. Nanomedicine highlights in atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Karagkiozaki, Varvara, E-mail: vakaragk@physics.auth.gr [Aristotle University of Thessaloniki, Nanomedicine Group, Laboratory for Thin Films-Nanosystems and Nanometrology (LTFN), Physics Department (Greece)

    2013-04-15

    Atherosclerosis is a multifactorial disease and many different approaches have been attempted for its accurate diagnosis and treatment. The disease is induced by a low-grade inflammatory process in the vascular wall, leading through a cascade of events to the eventual formation of atheromatous plaque and arterial stenosis. Different types of cells participate in the process making more difficult to recognize the potential cellular targets within the plaques for their effective treatment. The rise of nanomedicine over the last decade has provided new types of drug delivery nanosystems that are able to be delivered to a specific diseased site of the vessel for imaging while simultaneously act as therapeutic agents. In this paper, a review of the recent advances in nanomedicine that has provided novel insights to the disease diagnosis and treatment will be given in line with different nanotechnology-based approaches to advance the cardiovascular stents. The main complications of bare metal stents such as restenosis and of drug-eluting stents which is the late stent thrombosis are analyzed to comprehend the demand for emerging therapeutic strategies based on nanotechnology.

  10. Evolution, revolution and heresy in the genetics of infectious disease susceptibility

    Science.gov (United States)

    Hill, Adrian V. S.

    2012-01-01

    Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference. PMID:22312051

  11. Evolution, revolution and heresy in the genetics of infectious disease susceptibility.

    Science.gov (United States)

    Hill, Adrian V S

    2012-03-19

    Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case-control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.

  12. A unified pathogenesis for kidney diseases, including genetic diseases and cancers, by the protein-homeostasis-system hypothesis.

    Science.gov (United States)

    Lee, Kyung-Yil

    2017-06-01

    Every cell of an organism is separated and protected by a cell membrane. It is proposed that harmony between intercellular communication and the health of an organism is controlled by a system, designated the protein-homeostasis-system (PHS). Kidneys consist of a variety of types of renal cells, each with its own characteristic cell-receptor interactions and producing characteristic proteins. A functional union of these renal cells can be determined by various renal function tests, and harmonious intercellular communication is essential for the healthy state of the host. Injury to a kind of renal cells can impair renal function and induce an imbalance in total body health. Every acute or chronic renal disease has unknown etiologic substances that are responsible for renal cell injury at the molecular level. The immune/repair system of the host should control the etiologic substances acting against renal cells; if this system fails, the disease progresses to end stage renal disease. Each renal disease has its characteristic pathologic lesions where immune cells and immune proteins, such as immunoglobulins and complements, are infiltrated. These immune cells and immune proteins may control the etiologic substances involved in renal pathologic lesions. Also, genetic renal diseases and cancers may originate from a protein deficiency or malfunctioning protein under the PHS. A unified pathogenesis for renal diseases, including acute glomerulonephritis, idiopathic nephrotic syndrome, immunoglobulin A nephropathy, genetic renal diseases such as Alport syndrome, and malignancies such as Wilms tumor and renal cell carcinoma, is proposed using the PHS hypothesis.

  13. Genetic transformation of deciduous fruit trees conferring resistance against diseases

    International Nuclear Information System (INIS)

    Mansvelt, E.L.; Glyn-Woods, T.; Watts, L.; Rabie, A.; Appel, M.; Bellstedt, D.U.

    1998-01-01

    Long breeding cycles make cultivar development a lengthy process in deciduous fruit species. Gene transfer is, accordingly, a goal with significant commercial value. In many plant species, especially in woody plants, a prerequisite for genetic engineering is the ability to regenerate plants from transformed cells. Development of single cell regeneration is the first step towards exploration of gene transfer techniques. In this investigation media for plum and apple leaf disk regeneration were developed. Transformation experiments were performed. The vector EHA105 containing the gus-intron gene was found to be effective for gene transfer. Induction of the virG genes with aceto-syringone did not enhance transformation. Cefotaxime that was supplemented in the plum selection medium to suppress the Agrobacterium vector seriously inhibited leaf disk regeneration. However, in applies it was not detrimental. With further apple transformation experiments, factors such as preculturing, age of leaves, sucrose and cefotaxime concentrations did not increase the transformation efficiency of the marker gene. The harpin protein, essential for the pathogenicity of Pseudomonas syringae pv. syringae which incites bacterial canker of stone fruit, ws amplified and cloned into an expression vector. The fusion protein was purified. This will be used in future studies to elucidate the host-pathogen interaction, and to identify antibacterial genes. (author)

  14. The genetics of tolerance to tristeza disease in citrus rootstocks

    Directory of Open Access Journals (Sweden)

    Rita Bordignon

    2004-01-01

    Full Text Available Controlled pollinations between four elite citrus rootstocks, Citrus limonia - 'Limeira' rangpur lime (Cravo, C. sunki - 'Sunki' mandarin (Sunki, C. aurantium - 'São Paulo' sour orange (Azeda and Poncirus trifoliata - 'Davis A' trifoliate orange (Trifoliata, resulted in 1614 nucelar and 1938 hybrid plants identified by the isozyme loci Pgi-1, Pgm-1, Got-1, Got-2, Aps-1, Me-1, Prxa-1 and or by the morphological markers broadness of leaf petiole wing or trifoliolate leaves. Tolerance to the citrus tristeza virus (CTV was evaluated under nursery and field conditions for several years by the reaction of Valencia orange infected with a severe strain of CTV and grafted onto the hybrids and nucellar clones. Genetic analyses indicated that tolerance was controlled by at least two loci designated here as Az and t interacting in dominant-recessive epistasis. Genotypes Az__ __ __ and __ __ tt were tolerant while azaz T__ was intolerant. The intolerant Azeda was azaz TT, the tolerant rootstocks Sunki and Cravo were Azaz tt and the Trifoliata was Azaz TT. The different degrees of intolerance seen in some hybrids may reflect the inability of segregating modifiers from parental clones to overcome the epistatic interaction that controls the major tolerance reaction.

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

    Directory of Open Access Journals (Sweden)

    Simone Cristina Pinto Matheus Fischer

    2018-02-01

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

  16. Highlights from CMS

    CERN Document Server

    Autermann, Christian

    2018-01-01

    This article summarizes the latest highlights from the CMS experiment as presented at the Lepton Photon conference 2017 in Guangzhou, China. A selection of the latest physics results, the latest detector upgrades, and the current detector status are discussed. CMS has analyzed the full dataset of proton-proton collision data delivered by the LHC in 2016 at a center-of-mass energy of $13$\\,TeV corresponding to an integrated luminosity of $40$\\,fb$^{-1}$. The leap in center-of-mass energy and in luminosity with respect to the $7$ and $8$\\,TeV runs enabled interesting and relevant new physics results. A new silicon pixel tracking detector was installed during the LHC shutdown 2016/17 and has successfully started operation.

  17. PSI scientific highlights 2012

    International Nuclear Information System (INIS)

    Piwnicki, P.; Dury, T.

    2013-05-01

    This comprehensive report issued by the Paul Scherrer Institute (PSI) reviews research in various areas carried out by the institute in 2012. Also, the various facilities to be found at the institute are described. Research focus and highlights are discussed. These include work done using synchrotron light, neutrons and muons as well as work done in the particle physics, microtechnology and nanotechnology areas. Further areas of research include biomolecular research, radiopharmacy, radiochemistry and environmental chemistry. Other areas covered include general energy research and work done at the Competence Center for Energy and Mobility CCEM, work done on nuclear energy safety as well as systems analysis in the environmental and energy areas. The report is concluded with facts and figures on the PSI, its Advisory Board and its organisational structures

  18. PSI scientific highlights 2011

    International Nuclear Information System (INIS)

    Piwnicki, P.

    2012-04-01

    This comprehensive report for the Swiss Federal Office of Energy (SFOE) presents the major highlights of the work done at the Paul Scherrer Institute, Switzerland, in 2011. According to the institute's director, work was concerned with the design and analysis of advanced materials with new functionalities, for application in fields as diverse as communications and energy technology, transportation, construction and medicine. Of particular topical interest are research projects on materials for application in the field of energy, for example for improving batteries for future electrically powered vehicles. Another example is in the field of catalysts. Environmentally harmful compounds, such as nitrogen oxide and sulphur dioxide produced in an engine, are transformed into nontoxic gases through catalytic conversion. Work progress on the SwissFEL installation is noted, including a breakthrough for SwissFEL main Linac C-band accelerating systems. Further topics in relation to the SwissFEL system are noted. Planning of the initial set of experimental stations at the SwissFEL is discussed and close collaboration with growing number of user communities is noted. Cross-Correlation Scattering, and a theoretical framework for this method is being developed and experimentally verified, using artificial nanostructures and synchrotron radiation. Highlights of further research work are discussed, including topics such as Synchrotron light, work done on neutrons and muons, particle physics, micro and nanotechnology as well as on biomolecular research and radiopharmacy. Large research facilities are discussed as is the PSI proton therapy installation. General energy topics are looked at, as are nuclear energy and safety aspects and environmental and energy systems analysis. Various further work includes factors causing glacier retreat and aerosols. User facilities are listed, including accelerators, the SLS light source, the SINQ neutron source, the UCN ultra-cold neutron source

  19. Probability Model of Allele Frequency of Alzheimer’s Disease Genetic Risk Factor

    Directory of Open Access Journals (Sweden)

    Afshin Fayyaz-Movaghar

    2016-06-01

    Full Text Available Background and Purpose: The identification of genetics risk factors of human diseases is very important. This study is conducted to model the allele frequencies (AFs of Alzheimer’s disease. Materials and Methods: In this study, several candidate probability distributions are fitted on a data set of Alzheimer’s disease genetic risk factor. Unknown parameters of the considered distributions are estimated, and some criterions of goodness-of-fit are calculated for the sake of comparison. Results: Based on some statistical criterions, the beta distribution gives the best fit on AFs. However, the estimate values of the parameters of beta distribution lead us to the standard uniform distribution. Conclusion: The AFs of Alzheimer’s disease follow the standard uniform distribution.

  20. Many Genes—One Disease? Genetics of Nephronophthisis (NPHP and NPHP-Associated Disorders

    Directory of Open Access Journals (Sweden)

    Shalabh Srivastava

    2018-01-01

    Full Text Available Nephronophthisis (NPHP is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required.

  1. Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies.

    Science.gov (United States)

    Langlais, David; Fodil, Nassima; Gros, Philippe

    2017-04-26

    Genome technologies have defined a complex genetic architecture in major infectious, inflammatory, and autoimmune disorders. High density marker arrays and Immunochips have powered genome-wide association studies (GWAS) that have mapped nearly 450 genetic risk loci in 22 major inflammatory diseases, including a core of common genes that play a central role in pathological inflammation. Whole-exome and whole-genome sequencing have identified more than 265 genes in which mutations cause primary immunodeficiencies and rare forms of severe inflammatory bowel disease. Combined analysis of inflammatory disease GWAS and primary immunodeficiencies point to shared proteins and pathways that are required for immune cell development and protection against infections and are also associated with pathological inflammation. Finally, sequencing of chromatin immunoprecipitates containing specific transcription factors, with parallel RNA sequencing, has charted epigenetic regulation of gene expression by proinflammatory transcription factors in immune cells, providing complementary information to characterize morbid genes at infectious and inflammatory disease loci.

  2. Human genetics of infectious diseases: Unique insights into immunological redundancy.

    Science.gov (United States)

    Casanova, Jean-Laurent; Abel, Laurent

    2018-04-01

    For almost any given human-tropic virus, bacterium, fungus, or parasite, the clinical outcome of primary infection is enormously variable, ranging from asymptomatic to lethal infection. This variability has long been thought to be largely determined by the germline genetics of the human host, and this is increasingly being demonstrated to be the case. The number and diversity of known inborn errors of immunity is continually increasing, and we focus here on autosomal and X-linked recessive traits underlying complete deficiencies of the encoded protein. Schematically, four types of infectious phenotype have been observed in individuals with such deficiencies, each providing information about the redundancy of the corresponding human gene, in terms of host defense in natural conditions. The lack of a protein can confer vulnerability to a broad range of microbes in most, if not all patients, through the disruption of a key immunological component. In such cases, the gene concerned is of low redundancy. However, the lack of a protein may also confer vulnerability to a narrow range of microbes, sometimes a single pathogen, and not necessarily in all patients. In such cases, the gene concerned is highly redundant. Conversely, the deficiency may be apparently neutral, conferring no detectable predisposition to infection in any individual. In such cases, the gene concerned is completely redundant. Finally, the lack of a protein may, paradoxically, be advantageous to the host, conferring resistance to one or more infections. In such cases, the gene is considered to display beneficial redundancy. These findings reflect the current state of evolution of humans and microbes, and should not be considered predictive of redundancy, or of a lack of redundancy, in the distant future. Nevertheless, these observations are of potential interest to present-day biologists testing immunological hypotheses experimentally and physicians managing patients with immunological or infectious

  3. Application of computational methods in genetic study of inflammatory bowel disease.

    Science.gov (United States)

    Li, Jin; Wei, Zhi; Hakonarson, Hakon

    2016-01-21

    Genetic factors play an important role in the etiology of inflammatory bowel disease (IBD). The launch of genome-wide association study (GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.

  4. Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

    Directory of Open Access Journals (Sweden)

    Paola Dongiovanni

    2013-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH, a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs, represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.

  5. Genetic Similarity between Cotton Leafroll Dwarf Virus and Chickpea Stunt Disease Associated Virus in India

    Directory of Open Access Journals (Sweden)

    Arup Kumar Mukherjee

    2016-12-01

    Full Text Available The cotton leafroll dwarf virus (CLRDV is one of the most devastating pathogens of cotton. This malady, known as cotton blue disease, is widespread in South America where it causes huge crop losses. Recently the disease has been reported from India. We noticed occurrence of cotton blue disease and chickpea stunt disease in adjoining cotton and chickpea fields and got interested in knowing if these two viral diseases have some association. By genetic studies, we have shown here that CLRDV is very close to chickpea stunt disease associated virus (CpSDaV. We were successful in transmitting the CLRDV from cotton to chickpea. Our studies indicate that CpSDaV and CLRDV in India are possibly two different strains of the same virus. These findings would be helpful in managing these serious diseases by altering the cropping patterns.

  6. Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension.

    OpenAIRE

    Smithies, O; Maeda, N

    1995-01-01

    Gene targeting allows precise, predetermined changes to be made in a chosen gene in the mouse genome. To date, targeting has been used most often for generation of animals completely lacking the product of a gene of interest. The resulting "knockout" mice have confirmed some hypotheses, have upset others, but have rarely been uninformative. Models of several human genetic diseases have been produced by targeting--including Gaucher disease, cystic fibrosis, and the fragile X syndrome. These di...

  7. Global and disease-associated genetic variation in the human Fanconi anemia gene family

    OpenAIRE

    Rogers, Kai J.; Fu, Wenqing; Akey, Joshua M.; Monnat, Raymond J.

    2014-01-01

    Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population gen...

  8. Bias, accuracy and impact of indirect genetic effects in infectious diseases

    Directory of Open Access Journals (Sweden)

    Debby eLipschutz-Powell

    2012-10-01

    Full Text Available Selection for improved host response to infectious disease offers a desirable alternative to chemical treatment but has proven difficult in practice, due to low heritability estimates of disease traits. Disease data from field studies is often binary, indicating whether an individual has become infected or not following exposure to an infectious disease. Numerous studies have shown that from this data one can infer genetic variation in individuals’ underlying susceptibility. In a previous study, we showed that with an Indirect Genetic Effect (IGE model it is possible to capture some genetic variation in infectivity, if present, as well as in susceptibility. Infectivity is the propensity of transmitting infection upon contact with a susceptible individual. It is an important factor determining the severity of an epidemic. However, there are severe shortcomings with the Standard IGE models as they do not accommodate the dynamic nature of disease data. Here we adjust the Standard IGE model to (1 make expression of infectivity dependent on the individuals’ disease status (Case Model and (2 to include timing of infection (Case-ordered Model. The models are evaluated by comparing impact of selection, bias and accuracy of each model using simulated binary disease data. These were generated for populations with known variation in susceptibility and infectivity thus allowing comparisons between estimated and true breeding values. Overall the Case Model provided better estimates for host genetic susceptibility and infectivity compared to the Standard Model in terms of bias, impact and accuracy. Furthermore, these estimates were strongly influenced by epidemiological characteristics. However, surprisingly, the Case Ordered model performed considerably worse than the Standard and the Case Models, pointing towards limitations in incorporating disease dynamics into conventional variance component estimation methodology and software used in animal breeding.

  9. Connecting Gaucher and Parkinson Disease: Considerations for Clinical and Research Genetic Counseling Settings.

    Science.gov (United States)

    Cook, Lola; Schulze, Jeanine

    2017-12-01

    There are multiple autosomal recessive disorders in which carriers may be at risk for other diseases. This observation calls into question the previous understanding that carriers of autosomal recessive disorders escape clinical consequences. We also know that childhood genetic conditions may have adult disease counterparts (Zimran et al., The Israel Medical Association Journal: IMAJ, 16(11), 723-724, 2014). Individuals who have Gaucher disease and carriers of the disorder are at increased risk for a seemingly unrelated and complex neurological condition, Parkinson disease. Parkinson disease is, in part, caused by the same mutations in the GBA gene that lead to Gaucher disease, and the two conditions are thought to have shared pathophysiology. Briefly reviewed are how these two diseases historically became linked, where their paths cross, potential problems and considerations in disclosure of the link, and current guidelines and research in this area. Genetic counseling experience with a large Parkinson disease cohort is used as a starting point to question the state of clinical and nonclinical practice in disclosing this unusual connection We conclude that more research and discussion are needed to inform practice regarding the crossroads of Gaucher and Parkinson disease.

  10. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    KAUST Repository

    Hoehndorf, Robert

    2015-06-08

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  11. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    Science.gov (United States)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  12. Genetic shifting: a novel approach for controlling vector-borne diseases.

    Science.gov (United States)

    Powell, Jeffrey R; Tabachnick, Walter J

    2014-06-01

    Rendering populations of vectors of diseases incapable of transmitting pathogens through genetic methods has long been a goal of vector geneticists. We outline a method to achieve this goal that does not involve the introduction of any new genetic variants to the target population. Rather we propose that shifting the frequencies of naturally occurring alleles that confer refractoriness to transmission can reduce transmission below a sustainable level. The program employs methods successfully used in plant and animal breeding. Because no artificially constructed genetically modified organisms (GMOs) are introduced into the environment, the method is minimally controversial. We use Aedes aegypti and dengue virus (DENV) for illustrative purposes but point out that the proposed program is generally applicable to vector-borne disease control. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Toward molecular pathogenesis of an autoimmune disease: Refined genetic mapping of autoimmune polyglandular disease type I (APECED)

    Energy Technology Data Exchange (ETDEWEB)

    Aaltonen, J.; Bjoerses, P.; Peltonen, L. [National Public Health Institute, Helsinki (Finland)] [and others

    1994-09-01

    Autoimmune reactions encoupled to many human diseases are still only partially understood. Unravelling the molecular pathogenesis of inherited diseases with a strong autoimmune component in their clinical expression could help to dissect individual components in the molecular background of abnormal immune response. One such genetic disorder is autosomal recessive autoimmune polyglandular disease type I (PGD I), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, MIM 240300). The disease is especially enriched in the genetically isolated population of Finland and we have assigned the APECED locus to human chromosome 21q22.3 in 14 Finnish families by linkage analyses. The best positional lod score of 6.49 was observed with marker D21S49. Based on the history of the Finns, the gene pool of this population clearly demonstrates the consequences of a founder effect and consequent isolation. In the Finnish population, we can take advantage of linkage disequilibrium and allelic association studies to more precisely define the critical DNA region for our disease gene of interest than would be possible by linkage analyses alone. We are now able to define the chromosomal region of interest between two flanking markers locating 1 cM apart. Linkage disequilibrium is observed with three of the markers used in the analyses and this suggests a distance of less than 500 kb to the disease locus, well approachable with molecular cloning techniques. Overlapping YAC and cosmid clones spanning our region of interest will facilitate the cloning of APECED gene in the near future.

  14. Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Juul, Klaus; Tybjærg-Hansen, Anne; Marklund, Stefan

    2006-01-01

    RATIONALE: Increased oxidative stress is involved in chronic obstructive pulmonary disease (COPD); however, plasma and bronchial lining fluid contains the antioxidant extracellular superoxide dismutase. Approximately 2% of white individuals carry the R213G polymorphism in the gene encoding......-sectionally and prospectively (during 24 yr) 9,258 individuals from the Danish general population genotyped for R213G. MEASUREMENTS: We determined plasma extracellular superoxide dismutase concentration, pulmonary function and COPD diagnosed by means of spirometry or through national hospitalization and death registers. MAIN...... extracellular superoxide dismutase, which increases plasma extracellular superoxide dismutase 10-fold and presumably also renders bronchial lining fluid high in extracellular superoxide dismutase. OBJECTIVE: We tested the hypothesis that R213G reduces the risk of COPD. METHODS: We studied cross...

  15. Impact of gender and genetics on emotion processing in Parkinson's disease - A multimodal study

    Directory of Open Access Journals (Sweden)

    Julia Heller

    Full Text Available Background: Parkinson's disease (PD has been suggested to affect males and females differently. Neuropsychiatric symptoms are common and disabling in PD. However, previous studies focusing on emotion recognition in PD have neglected the confounder of gender and lack evidence on the underlying endocrinal and genetic mechanisms. Moreover, while there are many imaging studies on emotion processing in PD, gender-related analyses of neural data are scarce. We therefore aimed at exploring the interplay of the named factors on emotion recognition and processing in PD. Methods: 51 non-demented PD patients (26 male and 44 age- and gender-matched healthy controls (HC; 25 male were examined clinically and neuropsychologically including an emotion recognition task (Ekman 60faces test. A subsample of 25 patients and 31 HC underwent task-based functional magnetic resonance imaging (fMRI comprised of videos of emotional facial expressions. To examine the impact of hormones and genetics on emotion processing, blood samples were taken for endocrinal (testosterone, estradiol, progesterone and genetic testing (5-HTTLPR, Val158Met COMT polymorphisms. Results: No group or gender differences emerged regarding cognitive abilities. Male but not female PD patients exhibited confined impairments in recognizing the emotion anger accompanied by diminished neural response to facial expressions (e.g. in the putamen and insula. Endocrinologically, fear recognition was positively correlated with estrogen levels in female patients, while on the genetic level we found an effect of Val158Met COMT genotype on the recognition of fear in PD patients. Conclusions: Our study provides evidence that impaired emotion processing in PD specifically affects male patients, and that hormones and genetics contribute to emotion recognition performance. Further research on the underlying neural, endocrinological and genetic mechanisms of specific symptoms in PD is of clinical relevance, as it

  16. Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

    DEFF Research Database (Denmark)

    Baillie, J. Kenneth; Bretherick, Andrew; Haley, Christopher S.

    2018-01-01

    Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcrip...

  17. The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

    Czech Academy of Sciences Publication Activity Database

    Ng, Y. S.; Alston, Ch. L.; Diodato, D.; Morris, A. A.; Ulrick, N.; Kmoch, S.; Houštěk, Josef; Martinelli, D.; Haghighi, A.; Atiq, M.; Gamero, M. A.; Garcia-Martinez, E.; Kratochvílová, H.; Santra, S.; Brown, R. M.; Brown, G. K.; Ragge, N.; Monavari, A.; Pysden, K.; Ravn, K.; Casey, J. P.; Khan, A.; Chakrapani, A.; Vassallo, G.; Simons, C.; McKeever, K.; O´Sullivan, S.; Childs, A.-M.; Ostergaard, E.; Vanderver, A.; Goldstein, A.; Vogt, J.; Taylor, R. W.; McFarland, R.

    2016-01-01

    Roč. 53, č. 11 (2016), s. 768-775 ISSN 0022-2593 R&D Projects: GA ČR(CZ) GB14-36804G Institutional support: RVO:67985823 Keywords : congenital sensorineural deafness * lactic acidosis * mitochondrial respiratory chain deficiencies * prognosis * renal disease Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.451, year: 2016

  18. Dancing in the dark? The status of late-onset Alzheimer's disease genetics.

    Science.gov (United States)

    Bertram, L; Tanzi, R E

    2001-10-01

    Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. Recent estimates suggest that possibly over 70% of the genetic variance for the disease remains unaccounted for by apolipoprotein E (APOE) and the three known early-onset AD genes (APP, PSEN1, PSEN2). Specifically, one recent segregation analysis predicted the existence of up to four additional susceptibility genes having a similar or greater effect than APOE. However, most of the nearly three dozen putative AD loci proposed to date have only been inconsistently replicated in follow up analyses and more studies are necessary to distinguish false-positive findings from genuine signals. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk-profiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. In this review, we will present a brief overview of analytic tools in complex disease genetics, as well as a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on chromosomes 12, 10, and 9.

  19. Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

    NARCIS (Netherlands)

    Feng, Yen Chen Anne; Cho, Kelly; Lindstrom, Sara; Kraft, Peter; Cormack, Jean; Blalock, Kendra; Campbell, Peter T.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Figueiredo, Jane; James Gauderman, W.; Gong, Jian; Green, Roger C.; Gruber, Stephen B.; Harju, John F.; Harrison, Tabitha A.; Jacobs, Eric J; Jenkins, Mark A.; Jiao, Shuo; Li, Li; Lin, Yi; Manion, Frank J.; Moreno, Victor; Mukherjee, Bhramar; Peters, Ulrike; Raskin, Leon; Schumacher, Fredrick R.; Seminara, Daniela; Severi, Gianluca; Stenzel, Stephanie L.; Thomas, Duncan C.; Hopper, John L.; Southey, Melissa C.; Makalic, Enes; Schmidt, Daniel F.; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; Dos-Santos-Silva, Isabel; Hunter, David J.; Lindström, Sara; Kraft, Peter; Ahsan, Habib; Whittemore, Alice S.; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A.; van der Luijt, Rob B.; Uitterlinden, Andre G; Hofman, Albert; Meindl, Alfons; Schmutzler, Rita K.; Müller-Myhsok, Bertram; Lichtner, Peter; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Crisponi, Laura; Hall, Per; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Easton, Douglas F.; Turnbull, Clare A.; Rahman, Nazneen; Kote-Jarai, Zsofia; Muir, Kenneth; Giles, Graham G.; Severi, Gianluca; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher; Schumacher, Fred; Travis, Ruth C.; Riboli, Elio; Kraft, Peter; Hunter, David J.; Gapstur, Susan M.; Berndt, Sonja I.; Chanock, Stephen J.; Han, Younghun; Su, Li; Wei, Yongyue; Hung, Rayjean J.; Brhane, Yonathan; McLaughlin, John; Brennan, Paul; McKay, James D.; Bickeböller, Heike; Rosenberger, Albert; Houlston, Richard S.; Caporaso, Neil E; Landi, Maria Teresa; Heinrich, Joachim; Risch, Angela; Wu, Xifeng; Ye, Yuanqing; Christiani, David C.; Amos, Christopher I; Liang, Liming; Driver, Jane A.; IGAP Consortium, Colorectal Transdisciplinary Study (CORECT); Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)

    2017-01-01

    Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from

  20. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    Science.gov (United States)

    The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CA...

  1. Host genetics of Epstein-Barr virus infection, latency and disease.

    Science.gov (United States)

    Houldcroft, Charlotte J; Kellam, Paul

    2015-03-01

    Epstein-Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host-EBV interaction. © 2014 The Authors Reviews in Medical Virology published by John Wiley & Sons Ltd.

  2. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    NARCIS (Netherlands)

    Meurs, J.B.J. van; Pare, G.; Schwartz, S.M.; Hazra, A.; Tanaka, T.; Vermeulen, S.; Cotlarciuc, I.; Yuan, X.; Malarstig, A.; Bandinelli, S.; Bis, J.C.; Blom, H.; Brown, M.J.; Chen, C.; Chen, Y.D.; Clarke, R.J.; Dehghan, A.; Erdmann, J.; Ferrucci, L.; Hamsten, A.; Hofman, A.; Hunter, D.J.; Goel, A.; Johnson, A.D.; Kathiresan, S.; Kampman, E.; Kiel, D.P.; Kiemeney, L.A.L.M.; Chambers, J.C.; Kraft, P.; Lindemans, J.; McKnight, B.; Nelson, C.P.; O'Donnell, C.J.; Psaty, B.M.; Ridker, P.M.; Rivadeneira, F.; Rose, L.M.; Seedorf, U.; Siscovick, D.S.; Schunkert, H.; Selhub, J.; Ueland, P.M.; Vollenweider, P.; Waeber, G.; Waterworth, D.M.; Watkins, H.; Witteman, J.C.; Heijer, M. den; Jacques, P.; Uitterlinden, A.G.; Kooner, J.S.; Rader, D.J.; Reilly, M.P.; Mooser, V.; Chasman, D.I.; Samani, N.J.; Ahmadi, K.R.

    2013-01-01

    BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations

  3. A patient centred approach to care planning for patients with chronic genetic diseases

    Directory of Open Access Journals (Sweden)

    Alastair Kent

    2013-03-01

    Full Text Available This essay proposes seven pre-requisites for the creation of effective programmes of care and support for patients living with the consequences of chronic genetic diseases. It then goes on to discuss the role of patient organisations and other stakeholders in bringing about the development and implementation of these.

  4. Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease.

    Science.gov (United States)

    Dilliott, Allison A; Farhan, Sali M K; Ghani, Mahdi; Sato, Christine; Liang, Eric; Zhang, Ming; McIntyre, Adam D; Cao, Henian; Racacho, Lemuel; Robinson, John F; Strong, Michael J; Masellis, Mario; Bulman, Dennis E; Rogaeva, Ekaterina; Lang, Anthony; Tartaglia, Carmela; Finger, Elizabeth; Zinman, Lorne; Turnbull, John; Freedman, Morris; Swartz, Rick; Black, Sandra E; Hegele, Robert A

    2018-04-04

    Next-generation sequencing (NGS) is quickly revolutionizing how research into the genetic determinants of constitutional disease is performed. The technique is highly efficient with millions of sequencing reads being produced in a short time span and at relatively low cost. Specifically, targeted NGS is able to focus investigations to genomic regions of particular interest based on the disease of study. Not only does this further reduce costs and increase the speed of the process, but it lessens the computational burden that often accompanies NGS. Although targeted NGS is restricted to certain regions of the genome, preventing identification of potential novel loci of interest, it can be an excellent technique when faced with a phenotypically and genetically heterogeneous disease, for which there are previously known genetic associations. Because of the complex nature of the sequencing technique, it is important to closely adhere to protocols and methodologies in order to achieve sequencing reads of high coverage and quality. Further, once sequencing reads are obtained, a sophisticated bioinformatics workflow is utilized to accurately map reads to a reference genome, to call variants, and to ensure the variants pass quality metrics. Variants must also be annotated and curated based on their clinical significance, which can be standardized by applying the American College of Medical Genetics and Genomics Pathogenicity Guidelines. The methods presented herein will display the steps involved in generating and analyzing NGS data from a targeted sequencing panel, using the ONDRISeq neurodegenerative disease panel as a model, to identify variants that may be of clinical significance.

  5. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease

    NARCIS (Netherlands)

    Gutierrez-Achury, Javier; Zhernakova, Alexandra; Pulit, Sara L.; Trynka, Gosia; Hunt, Karen A.; Romanos, Jihane; Raychaudhuri, Soumya; van Heel, David A.; Wijmenga, Cisca; de Balcker, Paul I. W.

    Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and

  6. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

    NARCIS (Netherlands)

    S. Reppe (Sjur); Y. Wang (Yunpeng); W.K. Thompson (Wesley K.); L.K. McEvoy (Linda K.); N.J. Schork (Nicholas); V. Zuber (Verena); M. Leblanc (Marissa); F. Bettella (Francesco); I.G. Mills (Ian G.); R.S. Desikan (Rahul S.); S. Djurovic (Srdjan); K.M. Gautvik (Kaare); A.M. Dale (Anders); O.A. Andreassen (Ole); K. Estrada Gil (Karol); U. Styrkarsdottir (Unnur); E. Evangelou (Evangelos); Y.-H. Hsu (Yi-Hsiang); E.L. Duncan (Emma); E.E. Ntzani (Evangelia); L. Oei (Ling); O.M.E. Albagha (Omar M.); N. Amin (Najaf); J.P. Kemp (John); D.L. Koller (Daniel); G. Li (Guo); C.-T. Liu (Ching-Ti); R.L. Minster (Ryan); A. Moayyeri (Alireza); L. Vandenput (Liesbeth); D. Willner (Dana); S.-M. Xiao (Su-Mei); L.M. Yerges-Armstrong (Laura); H.-F. Zheng (Hou-Feng); N. Alonso (Nerea); J. Eriksson (Joel); C.M. Kammerer (Candace); S. Kaptoge (Stephen); P.J. Leo (Paul); G. Thorleifsson (Gudmar); S.G. Wilson (Scott); J.F. Wilson (James F); V. Aalto (Ville); M. Alen (Markku); A.K. Aragaki (Aaron); T. Aspelund (Thor); J.R. Center (Jacqueline); Z. Dailiana (Zoe); C. Duggan; M. Garcia (Melissa); N. Garcia-Giralt (Natàlia); S. Giroux (Sylvie); G. Hallmans (Göran); L.J. Hocking (Lynne); L.B. Husted (Lise Bjerre); K. Jameson (Karen); R. Khusainova (Rita); G.S. Kim (Ghi Su); C. Kooperberg (Charles); T. Koromila (Theodora); M. Kruk (Marcin); M. Laaksonen (Marika); A.Z. Lacroix (Andrea Z.); S.H. Lee (Seung Hun); P.C. Leung (Ping C.); J.R. Lewis (Joshua); L. Masi (Laura); S. Mencej-Bedrac (Simona); T.V. Nguyen (Tuan); X. Nogues (Xavier); M.S. Patel (Millan); J. Prezelj (Janez); L.M. Rose (Lynda); S. Scollen (Serena); K. Siggeirsdottir (Kristin); G.D. Smith; O. Svensson (Olle); S. Trompet (Stella); O. Trummer (Olivia); N.M. van Schoor (Natasja); J. Woo (Jean); K. Zhu (Kun); S. Balcells (Susana); M.L. Brandi; B.M. Buckley (Brendan M.); S. Cheng (Sulin); C. Christiansen; C. Cooper (Charles); G.V. Dedoussis (George); I. Ford (Ian); M. Frost (Morten); D. Goltzman (David); J. González-Macías (Jesús); M. Kähönen (Mika); M. Karlsson (Magnus); E.K. Khusnutdinova (Elza); J.-M. Koh (Jung-Min); P. Kollia (Panagoula); B.L. Langdahl (Bente); W.D. Leslie (William D.); P. Lips (Paul); O. Ljunggren (Östen); R. Lorenc (Roman); J. Marc (Janja); D. Mellström (Dan); B. Obermayer-Pietsch (Barbara); D. Olmos (David); U. Pettersson-Kymmer (Ulrika); D.M. Reid (David); J.A. Riancho (José); P.M. Ridker (Paul); M.F. Rousseau (Francois); P.E. Slagboom (Eline); N.L.S. Tang (Nelson L.S.); R. Urreizti (Roser); W. Van Hul (Wim); J. Viikari (Jorma); M.T. Zarrabeitia (María); Y.S. Aulchenko (Yurii); M.C. Castaño Betancourt (Martha); E. Grundberg (Elin); L. Herrera (Lizbeth); T. Ingvarsson (Torvaldur); H. Johannsdottir (Hrefna); T. Kwan (Tony); R. Li (Rui); R.N. Luben (Robert); M.C. Medina-Gomez (Carolina); S.T. Palsson (Stefan Th); J.I. Rotter (Jerome I.); G. Sigurdsson (Gunnar); J.B.J. van Meurs (Joyce); D.J. Verlaan (Dominique); F.M. Williams (Frances); A.R. Wood (Andrew); Y. Zhou (Yanhua); T. Pastinen (Tomi); S. Raychaudhuri (Soumya); J.A. Cauley (Jane); D.I. Chasman (Daniel); G.R. Clark (Graeme); S.R. Cummings (Steven R.); P. Danoy (Patrick); E.M. Dennison (Elaine); R. Eastell (Richard); J.A. Eisman (John); V. Gudnason (Vilmundur); A. Hofman (Albert); R.D. Jackson (Rebecca); G. Jones (Graeme); J.W. Jukema (Jan Wouter); K.T. Khaw; T. Lehtimäki (Terho); Y. Liu (YongMei); M. Lorentzon (Mattias); E. McCloskey (Eugene); B.D. Mitchell (Braxton); K. Nandakumar (Kannabiran); G.C. Nicholson (Geoffrey); B.A. Oostra (Ben); M. Peacock (Munro); H.A.P. Pols (Huib); R.L. Prince (Richard); O. Raitakari (Olli); I.R. Reid (Ian); J. Robbins (John); P.N. Sambrook (Philip); P.C. Sham (Pak Chung); A.R. Shuldiner (Alan); F.A. Tylavsky (Frances); C.M. van Duijn (Cornelia); N.J. Wareham (Nicholas J.); L.A. Cupples (Adrienne); M.J. Econs (Michael); D.M. Evans (David); T.B. Harris (Tamara B.); A.W.C. Kung (Annie Wai Chee); B.M. Psaty (Bruce); J. Reeve (Jonathan); T.D. Spector (Timothy); E.A. Streeten (Elizabeth); M.C. Zillikens (Carola); U. Thorsteinsdottir (Unnur); C. Ohlsson (Claes); D. Karasik (David); J.B. Richards (Brent); M.A. Brown (Matthew); J-A. Zwart (John-Anker); A.G. Uitterlinden (André); S.H. Ralston (Stuart); J.P.A. Ioannidis (John P.A.); D.P. Kiel (Douglas P.); F. Rivadeneira Ramirez (Fernando)

    2015-01-01

    textabstractBone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown.

  7. The MHC locus and genetic susceptibility to autoimmune and infectious diseases

    NARCIS (Netherlands)

    Matzaraki, Vasiliki; Kumar, Vinod; Wijmenga, Cisca; Zhernakova, Alexandra

    2017-01-01

    In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic

  8. Host genetics and outcome in meningococcal disease: a systematic review and meta-analysis

    NARCIS (Netherlands)

    Brouwer, Matthijs C.; Read, Robert C.; van de Beek, Diederik

    2010-01-01

    Various genes regulate the intensity of the inflammatory and coagulation response to infection and therefore might determine the severity and outcome of meningococcal disease. We systematically reviewed the published work for case control studies on the influence of host genetics on severity and

  9. Eleven loci with new reproducible genetic associations with allergic disease risk

    NARCIS (Netherlands)

    Ferreira, Manuel A.R.; Vonk, Judith M; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua D; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; Lu, Yi; Rüschendorf, Franz; Hinds, David A; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik Ke; Jorgenson, Eric; Lee, Young-Ae; Boomsma, Dorret I; Karlsson, Robert; Almqvist, Catarina; Koppelman, Gerard H; Paternoster, Lavinia

    2018-01-01

    BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.

  10. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology

    NARCIS (Netherlands)

    Ferreira, Manuel A; Vonk, Judith M; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua D; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; van Dongen, Jenny; Lu, Yi; Rüschendorf, Franz; Esparza-Gordillo, Jorge; Medway, Chris W; Mountjoy, Edward; Burrows, Kimberley; Hummel, Oliver; Grosche, Sarah; Brumpton, Ben M; Witte, John S; Hottenga, Jouke-Jan; Willemsen, Gonneke; Zheng, Jie; Rodríguez, Elke; Hotze, Melanie; Franke, Andre; Revez, Joana A; Beesley, Jonathan; Matheson, Melanie C; Dharmage, Shyamali C; Bain, Lisa M; Fritsche, Lars G; Gabrielsen, Maiken E; Balliu, Brunilda; Nielsen, Jonas B; Zhou, Wei; Hveem, Kristian; Langhammer, Arnulf; Holmen, Oddgeir L; Løset, Mari; Abecasis, Gonçalo R; Willer, Cristen J; Arnold, Andreas; Homuth, Georg; Schmidt, Carsten O; Thompson, Philip J; Martin, Nicholas G; Duffy, David L; Novak, Natalija; Boomsma, Dorret I

    2017-01-01

    Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that

  11. RESEARCH HIGHLIGHTS IN IAS

    Directory of Open Access Journals (Sweden)

    Marko Kreft

    2017-03-01

    Full Text Available We are reviewing and commenting highlights of the research published in Image Analysis and Stereology journal (IAS, volume 35, where 16 original research papers on image analysis, computer vision, modelling, and other approaches were published. We have reported on the precision of curve length estimation in the plane. Further, a focus was on a robust estimation technique for 3D point cloud registration. Next contribution in computer vision was on the accuracy of stereo matching algorithm based on illumination control. An attempt was also made to automatically diagnose prenatal cleft lip with representative key points and identify the type of defect in three-dimensional ultrasonography. Similarly, a new report is presenting estimation of torsion of digital curves in 3D images and next, the nuchal translucency by ultrasound is being analyzed. Also in ophthalmology, image analysis may help physicians to establish a correct diagnosis, which is supported by a new approach to measure tortuosity of retinal vessel. Another report of medical significance analyzed correlation of the shape parameters for characterization of images of corneal endothelium cells. Shape analysis is also an important topic in material science, e.g. in analyzing fine aggregates in concrete. As in concrete, in fiber reinforced composites image analysis may aid in improved quality, where the direction of fibers have decisive impact on properties. Automatic defect detection using a computer vision system improves productivity quality in industrial production, hence we report of a new Haar wavelet-based approach.

  12. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

    Directory of Open Access Journals (Sweden)

    Tobias Eisenberger

    Full Text Available Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs. Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

  13. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

    Science.gov (United States)

    Eisenberger, Tobias; Decker, Christian; Hiersche, Milan; Hamann, Ruben C; Decker, Eva; Neuber, Steffen; Frank, Valeska; Bolz, Hanno J; Fehrenbach, Henry; Pape, Lars; Toenshoff, Burkhard; Mache, Christoph; Latta, Kay; Bergmann, Carsten

    2015-01-01

    Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs). Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

  14. Genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel rescues the disease phenotypes of genetic models of Parkinson's disease.

    Science.gov (United States)

    Ng, Chee-Hoe; Basil, Adeline H; Hang, Liting; Tan, Royston; Goh, Kian-Leong; O'Neill, Sharon; Zhang, Xiaodong; Yu, Fengwei; Lim, Kah-Leong

    2017-07-01

    Despite intensive research, the etiology of Parkinson's disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1α, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. Here, we showed that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seem to negate the effects of AMPK activation, which we have previously demonstrated to be neuroprotective, that is, AMPK-mediated neuroprotection appears to require PGC-1α. Importantly, we further showed that genetic or pharmacological activation of the Drosophila PGC-1α ortholog spargel is sufficient to rescue the disease phenotypes of Parkin and LRRK2 genetic fly models of PD, thus supporting the proposed use of PGC-1α-related strategies for neuroprotection in PD. Copyright © 2017 National Neuroscience Institute. Published by Elsevier Inc. All rights reserved.

  15. Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases.

    Directory of Open Access Journals (Sweden)

    Hariklia Eleftherohorinou

    2009-11-01

    Full Text Available Although the introduction of genome-wide association studies (GWAS have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD, rheumatoid arthritis (RA and type 1 diabetes (T1D with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC. The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3-10(-20 with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes for T1D, 350 SNPs (189 genes for RA and 493 SNPs (277 genes for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC and RA (85% AUC, and weakly predictive of CD (60% AUC. The predictive ability of the T1D model (without any parameter refitting had good predictive ability (79% AUC in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.

  16. Genetic Association of , and - with Behcet's Disease in Saudi Patients

    Directory of Open Access Journals (Sweden)

    Fahda Al-Okaily

    2016-01-01

    Full Text Available Background HLA-B*51 has been universally associated with Behcet's disease (BD susceptibility, while different alleles of HLA-A have also been identified as independent BD susceptibility loci in various ethnic populations. The objective of this study was to investigate associations of HLA-A and - B alleles with BD in Saudi patients. Materials and Methods Genotyping for HLA-A and HLA-B was performed using HLA genotyping kit (Lab type (R SSO in 120 Saudi subjects, including 60 BD patients and 60 matched healthy controls. Results Our results revealed that frequencies of HLA-A*26, -A*31 , and - B*51 were significantly higher in BD patients than in controls, suggesting that HLA-A*26, -A*31 , and - B*51 are associated with BD. The frequency of HLA-B*15 was significantly lower in BD patients than in controls. Stratification of genotyping results into active and nonactive forms of BD revealed that the frequency of HLA-A*31 was significantly higher in the nonactive form than in the active form of BD, while there was no significant difference in the distribution of other alleles between the two forms of BD. Conclusion This study suggests that HLA-A*26, -A*31 , and - B*51 are associated with susceptibility risk to BD, while HLA-B*15 may be protective in Saudi patients. However, larger scale studies are needed to confirm these findings.

  17. Public attitudes towards preventive genomics and personal interest in genetic testing to prevent disease: a survey study

    NARCIS (Netherlands)

    Vermeulen, E.; Henneman, L.; van El, C.G.; Cornel, M.C.

    2014-01-01

    Background: Genetic testing and family history assessment can be used as an aid in the prevention of common chronic diseases. The aim of this study was to determine public attitudes and interests towards offering genetic testing and family history-based risk assessment for common chronic disease

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

    DEFF Research Database (Denmark)

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

    2006-01-01

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

  19. "Well, good luck with that": reactions to learning of increased genetic risk for Alzheimer disease.

    Science.gov (United States)

    Zallen, Doris T

    2018-03-08

    PurposeApolipoprotein-E (APOE) genetic testing to estimate risk for developing late-onset Alzheimer disease is increasingly being offered without prior genetic counseling or preparation. Consumer interest continues to grow, raising the question of how best to conduct such testing.MethodsTwenty-six semistructured interviews were carried out to study the reactions of individuals who had already learned of their higher risk after APOE testing had been done because of a family history of Alzheimer disease, or from genetic tests done for other health-related or general-interest reasons.ResultsAdverse psychological reactions were reported by a substantial fraction of the participants, including those who had specifically sought testing, those for whom the information came as a surprise, those with a family history, and those with no known history. Still, nearly all of those interviewed said that they had benefited in the long term from lifestyle changes, often learned from online sources, that they subsequently made.ConclusionThe results show that people should be prepared prior to any genetic testing and allowed to opt out of particular tests. If testing is carried out and a higher risk is revealed, they should be actively assisted in deciding how to proceed.GENETICS in MEDICINE advance online publication, 8 March 2018; doi:10.1038/gim.2018.13.

  20. Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

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    Sjur Reppe

    Full Text Available Bone Mineral Density (BMD is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR method to identify single nucleotide polymorphisms (SNPs associated with BMD by leveraging cardiovascular disease (CVD associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.