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Sample records for highlights genetic risk

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

    PubMed

    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; B K, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

    2015-09-01

    Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry 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 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations. PMID:26192919

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

    PubMed Central

    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; Dayani, 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 Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Alizadeh, Behrooz Z; Parkes, Miles; BK, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

    2016-01-01

    Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here, we report the first trans-ethnic 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 individuals of East-Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of IBD risk loci, the direction and magnitude of effect is consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by a combination of differences in allele frequencies (NOD2), effect sizes (TNFSF15, ATG16L1) or a combination of both (IL23R, IRGM). Our results provide biological insights into the pathogenesis of IBD, and demonstrate the utility of trans-ethnic association studies for mapping complex disease loci and understanding genetic architecture across diverse populations. PMID:26192919

  3. Genetic risks and genetic model specification.

    PubMed

    Zheng, Gang; Zhang, Wei; Xu, Jinfeng; Yuan, Ao; Li, Qizhai; Gastwirth, Joseph L

    2016-08-21

    Genetic risks and genetic models are often used in design and analysis of genetic epidemiology studies. A genetic model is defined in terms of two genetic risk measures: genotype relative risk and odds ratio. The impacts of choosing a risk measure on the resulting genetic models are studied in the power to detect association and deviation from Hardy-Weinberg equilibrium in cases using genetic relative risk. Extensive simulations demonstrate that the power of a study to detect associations using odds ratio is lower than that using relative risk with the same value when other parameters are fixed. When the Hardy-Weinberg equilibrium holds in the general population, the genetic model can be inferred by the deviation from Hardy-Weinberg equilibrium in only cases. Furthermore, it is more efficient than that based on the deviation from Hardy-Weinberg equilibrium in all cases and controls. PMID:27181372

  4. Interpreting genetic risks.

    PubMed

    Pearn, J

    2016-01-01

    Prof. Peter Beighton has given a professional lifetime to helping patients and their families who have been afflicted by inherited disease. His clinical skills have brought certainty, confidence and support to those confronted with some of the most difficult decisions in life's progress. Prof. Beighton's research has led to the discovery of new syndromes and the elucidation of accurate genetic risks in many diseases. This in turn has empowered patients and their families to make informed decisions and has provided doctors with the scientific knowledge to help patients. On the occasion of this festschrift, I join with so many members of Peter's international professional family to pay tribute to his leadership and service - not only in medical genetics - but also in the broadest domains of healthcare. PMID:27245536

  5. Genetic association analyses highlight biological pathways underlying mitral valve prolapse

    PubMed Central

    Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan; Delling, Francesca N.; Toomer, Katelynn; Durst, Ronen; Perrocheau, Maelle; Fernandez-Friera, Leticia; Solis, Jorge; Le Tourneau, Thierry; Chen, Ming-Huei; Probst, Vincent; Bosse, Yohan; Pibarot, Philippe; Zelenika, Diana; Lathrop, Mark; Hercberg, Serge; Roussel, Ronan; Benjamin, Emelia J.; Bonnet, Fabrice; Su Hao, LO; Dolmatova, Elena; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Hervé; Froguel, Philippe; Ellinor, Patrick T.; Vasan, Ramachandran S.; Bruneval, Patrick; Norris, Russell A.; Milan, David J.; Slaugenhaupt, Susan A.; Levine, Robert A.; Schott, Jean-Jacques; Hagege, Albert A.; Jeunemaitre, Xavier

    2016-01-01

    Non-syndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown aetiology that predisposes to mitral regurgitation, heart failure and sudden death1. Previous family and pathophysiological studies suggest a complex pattern of inheritance2–5. We performed a meta-analysis of two genome-wide association studies in 1,442 cases and 2,439 controls. We identified and replicated in 1,422 cases and 6,779 controls six loci and provide functional evidence for candidate genes. We highlight LMCD1 encoding a transcription factor6, for which morpholino knockdown in zebrafish results in atrioventricular (AV) valve regurgitation. A similar zebrafish phenotype was obtained for tensin1 (TNS1), a focal adhesion protein involved in cytoskeleton organization. We also show the expression of tensin1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair7. PMID:26301497

  6. Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

    PubMed

    Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan; Delling, Francesca N; Toomer, Katelynn; Durst, Ronen; Perrocheau, Maelle; Fernandez-Friera, Leticia; Solis, Jorge; Le Tourneau, Thierry; Chen, Ming-Huei; Probst, Vincent; Bosse, Yohan; Pibarot, Philippe; Zelenika, Diana; Lathrop, Mark; Hercberg, Serge; Roussel, Ronan; Benjamin, Emelia J; Bonnet, Fabrice; Lo, Su Hao; Dolmatova, Elena; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Hervé; Froguel, Philippe; Ellinor, Patrick T; Vasan, Ramachandran S; Bruneval, Patrick; Markwald, Roger R; Norris, Russell A; Milan, David J; Slaugenhaupt, Susan A; Levine, Robert A; Schott, Jean-Jacques; Hagege, Albert A; Jeunemaitre, Xavier

    2015-10-01

    Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1(-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair. PMID:26301497

  7. Etiology of Obesity Over the Life Span: Ecological and Genetic Highlights from Asian Countries.

    PubMed

    Chong, Pei Nee; Teh, Christinal Pey Wen; Poh, Bee Koon; Noor, Mohd Ismail

    2014-03-01

    Obesity is a worldwide pandemic, and the prevalence rate has doubled since the 1980s. Asian countries are also experiencing the global epidemic of obesity with its related health consequences. The prevalence of overweight and obesity are increasing at an alarming rate across all age groups in Asia. These increases are mainly attributed to rapid economic growth, which leads to socio-economic, nutrition and lifestyle transitions, resulting in a positive energy balance. In addition, fat mass and obesity-associated gene variants, copy number variants in chromosomes and epigenetic modifications have shown positive associations with the risk of obesity among Asians. In this review highlights of prevalence and related ecological and genetic factors that could influence the rapid rise in obesity among Asian populations are discussed. PMID:26626465

  8. Genetic testing for cancer risk.

    PubMed

    Ponder, B

    1997-11-01

    Genetic testing for cancer susceptibility is already part of the clinical management of families with some of the well-defined (but uncommon) inherited cancer syndromes. In cases where the risks associated with a predisposing mutation are less certain, or where there is no clearly effective intervention to offer those with a positive result, its use is more controversial. Careful evaluation of costs and benefits, and of the efficacy of interventions in those found to be at risk, is essential and is only just beginning. An immediate challenge is to ensure that both health professionals and the public understand clearly the issues involved. PMID:9353178

  9. Coal-ash spills highlight ongoing risk to ecosystems

    SciTech Connect

    Chatterjee, R.

    2009-05-01

    Two recent large-scale spills of coal combustion waste have highlighted the old problem of handling the enormous quantity of solid waste produced by coal. Both spills happened at power plants run by the Tennessee Valley Authority (TVA). In December 2008 a holding pond for coal ash collapsed at a power plant in Kingstom, Tenn., releasing coal-ash sludge onto farmland and into rivers: in January 2009 a break in a pipe removing water from a holding pond for gypsum caused a spill at Widows Creek Fossil Plant in Stevenson, Ala. The article discusses the toxic outcome of such disasters on ecosystems, quoting work by Willaim Hopkins at Virginia Polytechnic Institute and State University and recommendations and reports of the US EPA. 2 photos.

  10. The genetics of cancer risk.

    PubMed

    Pomerantz, Mark M; Freedman, Matthew L

    2011-01-01

    One hundred years ago, decades before the discovery of the structure of DNA, debate raged regarding how human traits were passed from one generation to the next. Phenotypes, including risk of disease, had long been recognized as having a familial component. Yet it was difficult to reconcile genetic segregation as described by Mendel with observations exhaustively documented by Karl Pearson and others regarding the normal distribution of human characteristics. In 1918, R. A. Fisher published his landmark article, "The Correlation Between Relatives on the Supposition of Mendelian Inheritance," bridging this divide and demonstrating that multiple alleles, all individually obeying Mendel's laws, account for the phenotypic variation observed in nature.Since that time, geneticists have sought to identify the link between genotype and phenotype. Trait-associated alleles vary in their frequency and degree of penetrance. Some minor alleles may approach a frequency of 50% in the human population, whereas others are present within only a few individuals. The spectrum for penetrance is similarly wide. These characteristics jointly determine the segregation pattern of a given trait, which, in turn, determine the method used to map the trait. Until recently, identification of rare, highly penetrant alleles was most practical. Revolutionary studies in genomics reported over the past decade have made interrogation of most of the spectrum of genetic variation feasible.The following article reviews recent discoveries in the genetic basis of inherited cancer risk and how these discoveries inform cancer biology and patient management. Although this article focuses on prostate cancer, the principles are generic for any cancer and, indeed, for any trait. PMID:22157285

  11. Genetic testing and your cancer risk

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000842.htm Genetic testing and your cancer risk To use the ... before you get tested. Which Cancers May Be Genetic Today, we know specific gene mutations that can ...

  12. What Are the Risks and Limitations of Genetic Testing?

    MedlinePlus

    ... testing? What are the risks and limitations of genetic testing? The physical risks associated with most genetic ... more information about the risks and limitations of genetic testing: The American College of Medical Genetics and ...

  13. Genetic predisposition, non-genetic risk factors and coronary infarct

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Using a genetic predisposition score (GPS), additively integrating the associations of 11 polymorphisms with coronary heart disease (CHD), we examined the consequences of joint presence of high GPS and non-genetic CHD risk factors. Methods: Within the European Prospective Investigation i...

  14. Genetic risk, risk perception, and decision making

    SciTech Connect

    Evers-Kiebooms, G.; Cassiman, J.J.; VanDenBerghe, H.; D'Ydewalle, G. )

    1987-01-01

    This book covers the proceedings of a conference held by March of Dimes Birth Defects Foundation. Topics presented include: Diagnosis of Genetic disease by linkage analysis and DNA diagnosis of autosomal dominant and recessive diseases.

  15. Integrating Genetics and Social Science: Genetic Risk Scores

    PubMed Central

    Belsky, Daniel W.; Israel, Salomon

    2014-01-01

    The sequencing of the human genome and the advent of low-cost genome-wide assays that generate millions of observations of individual genomes in a matter of hours constitute a disruptive innovation for social science. Many public-use social science datasets have or will soon add genome-wide genetic data. With these new data come technical challenges, but also new possibilities. Among these, the lowest hanging fruit and the most potentially disruptive to existing research programs is the ability to measure previously invisible contours of health and disease risk within populations. In this article, we outline why now is the time for social scientists to bring genetics into their research programs. We discuss how to select genetic variants to study. We explain how the polygenic architecture of complex traits and the low penetrance of individual genetic loci pose challenges to research integrating genetics and social science. We introduce genetic risk scores as a method of addressing these challenges and provide guidance on how genetic risk scores can be constructed. We conclude by outlining research questions that are ripe for social science inquiry. PMID:25343363

  16. Non-disclosure of genetic risks

    PubMed Central

    2016-01-01

    In ABC v. St Georges Healthcare NHS Trust, the High Court of England and Wales rejected the argument that doctors have a legal duty to disclose actionable genetic risks to a patient’s relatives. This article reconsiders the concept of a duty to disclose actionable genetic risks in the context of widening perceptions of legal harm and developing professional and public perceptions of corresponding wrongs.

  17. Genetic Research on Biospecimens Poses Minimal Risk

    PubMed Central

    Wendler, David S.; Rid, Annette

    2014-01-01

    Genetic research on human biospecimens is increasingly common. Yet, debate continues over the level of risk that this research poses to sample donors. Some argue that genetic research on biospecimens poses minimal risk; others argue that it poses greater than minimal risk and therefore needs additional requirements and limitations. This debate raises concern that some donors are not receiving appropriate protection or, conversely, that valuable research is being subject to unnecessary requirements and limitations. The present paper attempts to address this concern using the widely-endorsed ‘risks of daily life’ standard. The three extant versions of this standard all suggest that, with proper measures in place to protect donor confidentiality, most genetic research on human biospecimens poses minimal risk to donors. PMID:25530152

  18. Genetic research on biospecimens poses minimal risk.

    PubMed

    Wendler, David S; Rid, Annette

    2015-01-01

    Genetic research on human biospecimens is increasingly common. However, debate continues over the level of risk that this research poses to sample donors. Some argue that genetic research on biospecimens poses minimal risk; others argue that it poses greater than minimal risk and therefore needs additional requirements and limitations. This debate raises concern that some donors are not receiving appropriate protection or, conversely, that valuable research is being subject to unnecessary requirements and limitations. The present paper attempts to resolve this debate using the widely-endorsed 'risks of daily life' standard. The three extant versions of this standard all suggest that, with proper measures in place to protect confidentiality, most genetic research on human biospecimens poses minimal risk to donors. PMID:25530152

  19. Environmental chemical mutagens and genetic risks: Lessons from radiation genetics

    SciTech Connect

    Sankaranarayanan, K.

    1996-12-31

    The last three decades have witnessed substantial progress in the development and use of a variety of in vitro and in vivo assay systems for the testing of environmental chemicals which may pose a mutagenic hazard to humans. This is also true of basic studies in chemical mutagenesis on mechanisms, DNA repair, molecular dosimetry, structure-activity relationships, etc. However, the field of quantitative evaluation of genetic risks of environmental chemicals to humans is still in it infancy. This commentary addresses the question of how our experience in estimating genetic risks of exposure to ionizing radiation can be helpful in similar endeavors with environmental chemical mutagens. 24 refs., 3 tabs.

  20. On the Need for Rethinking Current Practice that Highlights Goal Achievement Risk in an Enterprise Context.

    PubMed

    Aven, Eyvind; Aven, Terje

    2015-09-01

    This article addresses the issue of how performance and risk management can complement each other in order to enhance the management of an enterprise. Often, we see that risk management focuses on goal achievements and not the enterprise risk related to its activities in the value chain. The statement "no goal, no risk" is a common misconception. The main aim of the article is to present a normative model for describing the links between performance and risk, and to use this model to give recommendations on how to best structure and plan the management of an enterprise in situations involving risk and uncertainties. The model, which has several novel features, is based on the interaction between different types of risk management (enterprise risk management, task risk management, and personal risk management) and a structure where the enterprise risk management overrules both the task and personal risk management. To illustrate the model we use the metaphor of a ship, where the ship is loaded with cash-generating activities and has a direction over time determined by the overall strategic objectives. Compared to the current enterprise risk management practice, the model and related analysis are founded on a new perspective on risk, highlighting knowledge and uncertainties beyond probabilities. PMID:25930689

  1. Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson's Disease Susceptibility.

    PubMed

    Liu, Guiyou; Liu, Yongquan; Jiang, Qinghua; Jiang, Yongshuai; Feng, Rennan; Zhang, Liangcai; Chen, Zugen; Li, Keshen; Liu, Jiafeng

    2016-09-01

    A rare TREM2 missense mutation (rs75932628-T) was reported to confer a significant Alzheimer's disease (AD) risk. A recent study indicated no evidence of the involvement of this variant in Parkinson's disease (PD). Here, we used the genetic and expression data to reinvestigate the potential association between TREM2 and PD susceptibility. In stage 1, using 10 independent studies (N = 89,157; 8787 cases and 80,370 controls), we conducted a subgroup meta-analysis. We identified a significant association between rs75932628 and PD (P = 3.10E-03, odds ratio (OR) = 3.88, 95 % confidence interval (CI) 1.58-9.54) in No-Northern Europe subgroup, and significantly increased PD risks (P = 0.01 for Mann-Whitney test) in No-Northern Europe subgroup than in Northern Europe subgroup. In stage 2, we used the summary results from a large-scale PD genome-wide association study (GWAS; N = 108,990; 13,708 cases and 95,282 controls) to search for other TREM2 variants contributing to PD susceptibility. We identified 14 single-nucleotide polymorphisms (SNPs) associated with PD within 50-kb upstream and downstream range of TREM2. In stage 3, using two brain expression GWAS datasets (N = 773), we identified 6 of the 14 SNPs regulating increased expression of TREM2. In stage 4, using the whole human genome microarray data (N = 50), we further identified significantly increased expression of TREM2 in PD cases compared with controls in human prefrontal cortex. In summary, convergent genetic and expression datasets demonstrate that TREM2 is a potent risk factor for PD and may be a therapeutic target in PD and other neurodegenerative diseases. PMID:26365049

  2. Healthy Living May Offset Genetic Breast Cancer Risk

    MedlinePlus

    ... news/fullstory_159053.html Healthy Living May Offset Genetic Breast Cancer Risk Lifestyle may matter even more ... be especially powerful for women at relatively high genetic risk of breast cancer, researchers found. "Those genetic ...

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

    PubMed Central

    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

  4. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.

    PubMed

    Scott, Robert A; Fall, Tove; Pasko, Dorota; Barker, Adam; Sharp, Stephen J; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Boeing, Heiner; Clavel-Chapelon, Françoise; Crowe, Francesca L; Dekker, Jacqueline M; Fagherazzi, Guy; Ferrannini, Ele; Forouhi, Nita G; Franks, Paul W; Gavrila, Diana; Giedraitis, Vilmantas; Grioni, Sara; Groop, Leif C; Kaaks, Rudolf; Key, Timothy J; Kühn, Tilman; Lotta, Luca A; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J Ramón; Rolandsson, Olov; Roswall, Nina; Sacerdote, Carlotta; Sala, Núria; Sánchez, María-José; Schulze, Matthias B; Siddiq, Afshan; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke M W; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; Yaghootkar, Hanieh; McCarthy, Mark I; Semple, Robert K; Riboli, Elio; Walker, Mark; Ingelsson, Erik; Frayling, Tim M; Savage, David B; Langenberg, Claudia; Wareham, Nicholas J

    2014-12-01

    We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size. PMID:24947364

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

    PubMed

    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

    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 in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. PMID:26831199

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

    PubMed Central

    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.; Abecasis, Goncalo R.; Adair, Linda S.; Alexander, Myriam; Altshuler, David; Amin, Najaf; Arking, Dan E.; Arora, Pankaj; Aulchenko, Yurii; Bakker, Stephan J. L.; Bandinelli, Stefania; Barroso, Ines; Beckmann, Jacques S.; Beilby, John P.; Bergman, Richard N.; Bergmann, Sven; Bis, Joshua C.; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Bots, Michiel L.; Bragg-Gresham, Jennifer L.; Brand, Stefan-Martin; Brand, Eva; Braund, Peter S.; Brown, Morris J.; Burton, Paul R.; Casas, Juan P.; Caulfield, Mark J.; Chakravarti, Aravinda; Chambers, John C.; Chandak, Giriraj R.; Chang, Yen-Pei C.; Charchar, Fadi J.; Chaturvedi, Nish; Shin Cho, Yoon; Clarke, Robert; Collins, Francis S.; Collins, Rory; Connell, John M.; Cooper, Jackie A.; Cooper, Matthew N.; Cooper, Richard S.; Corsi, Anna Maria; Dörr, Marcus; Dahgam, Santosh; Danesh, John; Smith, George Davey; Day, Ian N. M.; Deloukas, Panos; Denniff, Matthew; Dominiczak, Anna F.; Dong, Yanbin; Doumatey, Ayo; Elliott, Paul; Elosua, Roberto; Erdmann, Jeanette; Eyheramendy, Susana; Farrall, Martin; Fava, Cristiano; Forrester, Terrence; Fowkes, F. Gerald R.; Fox, Ervin R.; Frayling, Timothy M.; Galan, Pilar

    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 in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. PMID:26831199

  7. Experimental separation of genetic and demographic factors on extinction risk in wild populations.

    PubMed

    Wootton, J Timothy; Pfister, Catherine A

    2013-10-01

    When populations reach small size, an extinction risk vortex may arise from genetic (inbreeding depression, genetic drift) and ecological (demographic stochasticity, Allee effects, environmental fluctuation) processes. The relative contribution of these processes to extinction in wild populations is unknown, but important for conserving endangered species. In experimental field populations of a harvested kelp (Postelsia palmaeformis), in which we independently varied initial genetic diversity (completely inbred, control, outbred) and population size, ecological processes dominated the risk of extinction, whereas the contribution of genetic diversity was slight. Our results match theoretical predictions that demographic processes will generally doom small populations to extinction before genetic effects act strongly, prioritize detailed ecological analysis over descriptions of genetic structure in assessing conservation of at-risk species, and highlight the need for field experiments manipulating both demographics and genetic structure on long-term extinction risk. PMID:24358695

  8. [Quantification of radiation-induced genetic risk].

    PubMed

    Ehling, U H

    1987-05-01

    Associated with technical advances of our civilization is a radiation- and chemically-induced increase in the germ cell mutation rate in man. This would result in an increase in the frequency of genetic diseases and would be detrimental to future generations. It is the duty of our generation to keep this risk as low as possible. The estimation of the radiation-induced genetic risk of human populations is based on the extrapolation of results from animal experiments. Radiation-induced mutations are stochastic events. The probability of the event depends on the dose; the degree of the damage does not. The different methods to estimate the radiation-induced genetic risk will be discussed. The accuracy of the predicted results will be evaluated by a comparison with the observed incidence of dominant mutations in offspring born to radiation exposed survivors of the Hiroshima and Nagasaki atomic bombings. These methods will be used to predict the genetic damage from the fallout of the reactor accident at Chernobyl. For the exposure dose we used the upper limits of the mean effective life time equivalent dose from the fallout values in the Munich region. According to the direct method for the risk estimation we will expect for each 100 to 500 spontaneous dominant mutations one radiation-induced mutation in the first generation. With the indirect method we estimate a ratio of 100 dominant spontaneous mutations to one radiation-induced dominant mutation. The possibilities and the limitations of the different methods to estimate the genetic risk will be discussed. The discrepancy between the high safety standards for radiation protection and the low level of knowledge for the toxicological evaluation of chemical mutagens will be emphasized. PMID:3589954

  9. Genetic Insights into Cardiometabolic Risk Factors

    PubMed Central

    Whitfield, John B

    2014-01-01

    Many biochemical traits are recognised as risk factors, which contribute to or predict the development of disease. Only a few are in widespread use, usually to assist with treatment decisions and motivate behavioural change. The greatest effort has gone into evaluation of risk factors for cardiovascular disease and/or diabetes, with substantial overlap as ‘cardiometabolic’ risk. Over the past few years many genome-wide association studies (GWAS) have sought to account for variation in risk factors, with the expectation that identifying relevant polymorphisms would improve our understanding or prediction of disease; others have taken the direct approach of genomic case-control studies for the corresponding diseases. Large GWAS have been published for coronary heart disease and Type 2 diabetes, and also for associated biomarkers or risk factors including body mass index, lipids, C-reactive protein, urate, liver function tests, glucose and insulin. Results are not encouraging for personal risk prediction based on genotyping, mainly because known risk loci only account for a small proportion of risk. Overlap of allelic associations between disease and marker, as found for low density lipoprotein cholesterol and heart disease, supports a causal association, but in other cases genetic studies have cast doubt on accepted risk factors. Some loci show unexpected effects on multiple markers or diseases. An intriguing feature of risk factors is the blurring of categories shown by the correlation between them and the genetic overlap between diseases previously thought of as distinct. GWAS can provide insight into relationships between risk factors, biomarkers and diseases, with potential for new approaches to disease classification. PMID:24659834

  10. Identifying Common Genetic Risk Factors of Diabetic Neuropathies

    PubMed Central

    Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

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

    PubMed

    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; Meyer Zu Schwabedissen, Henriette; 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; 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; del Greco M, Fabiola; 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; Mateo Leach, Irene; 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 D; 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 M; 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

    2014-08-01

    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 loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD. PMID:24952745

  12. Body Mass Index Genetic Risk Score and Endometrial Cancer Risk

    PubMed Central

    Prescott, Jennifer; Setiawan, Veronica W.; Wentzensen, Nicolas; Schumacher, Fredrick; Yu, Herbert; Delahanty, Ryan; Bernstein, Leslie; Chanock, Stephen J.; Chen, Chu; Cook, Linda S.; Friedenreich, Christine; Garcia-Closas, Monserrat; Haiman, Christopher A.; Le Marchand, Loic; Liang, Xiaolin; Lissowska, Jolanta; Lu, Lingeng; Magliocco, Anthony M.; Olson, Sara H.; Risch, Harvey A.; Shu, Xiao-Ou; Ursin, Giske; Yang, Hannah P.; Kraft, Peter; De Vivo, Immaculata

    2015-01-01

    Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10−5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk. PMID:26606540

  13. Genetic risk factors in Alzheimer's disease.

    PubMed Central

    Tilley, L; Morgan, K; Kalsheker, N

    1998-01-01

    Following a brief introduction and discussion of the pathological features of Alzheimer's disease, the main emphasis of this review article will be the genetic factors that have been implicated in this disease. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial Alzheimer's disease will be discussed. These are well characterised but account for only a small proportion of Alzheimer's disease cases. Late onset, sporadic Alzheimer's disease is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease. Many of these are controversial and studies have shown conflicting results, which are discussed in this section. Finally, a brief discussion of some of the mechanisms suggested to play a role in the pathogenesis of Alzheimer's disease is included. It is hoped that this will show why particular genes have been implicated in Alzheimer's disease and how they might be able to influence the development of the disease. PMID:10193509

  14. Multivariate genetic analysis of academic skills of the Queensland core skills test and IQ highlight the importance of genetic g.

    PubMed

    Wainwright, Mark A; Wright, Margaret J; Luciano, Michelle; Geffen, Gina M; Martin, Nicholas G

    2005-12-01

    This study examined the genetic and environmental relationships among 5 academic achievement skills of a standardized test of academic achievement, the Queensland Core Skills Test (QCST; Queensland Studies Authority, 2003a). QCST participants included 182 monozygotic pairs and 208 dizygotic pairs (mean 17 years +/- 0.4 standard deviation). IQ data were included in the analysis to correct for ascertainment bias. A genetic general factor explained virtually all genetic variance in the component academic skills scores, and accounted for 32% to 73% of their phenotypic variances. It also explained 56% and 42% of variation in Verbal IQ and Performance IQ respectively, suggesting that this factor is genetic g. Modest specific genetic effects were evident for achievement in mathematical problem solving and written expression. A single common factor adequately explained common environmental effects, which were also modest, and possibly due to assortative mating. The results suggest that general academic ability, derived from genetic influences and to a lesser extent common environmental influences, is the primary source of variation in component skills of the QCST. PMID:16354502

  15. Genetic polymorphisms and esophageal cancer risk.

    PubMed

    Hiyama, Toru; Yoshihara, Masaharu; Tanaka, Shinji; Chayama, Kazuaki

    2007-10-15

    The aim of this paper is to review and evaluate, in a comprehensive manner, the published data regarding the contribution of genetic polymorphisms to risk of esophageal cancer, including squamous cell carcinoma (SCC) and adenocarcinoma, in humans. All relevant studies available in MEDLINE and published before February 2007 were identified. Studies carried out in humans and that compared esophageal cancer patients with at least 1 standard control group were considered for analysis. One-hundred studies and 3 meta-analyses were identified. Eighty (80%) studies were conducted in Asian countries, particularly China including Taiwan (60 (60%) studies). The most intensively examined genes were those encoding carcinogen metabolic enzymes. The most widely studied gene was GSTM1 (15 studies), followed by ALDH2 (11 studies). ALDH2, MTHFR C677T, CYP1A1 Ile/Val, CYP1A1MspI, CYP2E1, GSTP1, GSTM1 and GSTT1 were examined by meta-analyses and significant relations were found between ALDH2*1*2 and the CYP1A1 Val allele and increased risk of esophageal cancer. In addition, increased risk of esophageal SCC was consistently associated with the ADH2*1*2 and the p53 codon 72 Pro/Pro genotypes. Cohort studies that simultaneously consider multiple genetic and environmental factors possibly involved in esophageal carcinogenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contributions of their putative interactions. PMID:17674367

  16. Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity.

    PubMed

    Pinto, Pedro; Paulo, Paula; Santos, Catarina; Rocha, Patrícia; Pinto, Carla; Veiga, Isabel; Pinheiro, Manuela; Peixoto, Ana; Teixeira, Manuel R

    2016-09-01

    Molecular diagnosis of hereditary breast and ovarian cancer (HBOC) by standard methodologies has been limited to the BRCA1 and BRCA2 genes. With the recent development of new sequencing methodologies, the speed and efficiency of DNA testing have dramatically improved. The aim of this work was to validate the use of next-generation sequencing (NGS) for the detection of BRCA1/BRCA2 point mutations in a diagnostic setting and to study the role of other genes associated with HBOC in Portuguese families. A cohort of 94 high-risk families was included in the study, and they were initially screened for the two common founder mutations with variant-specific methods. Fourteen index patients were shown to carry the Portuguese founder mutation BRCA2 c.156_157insAlu, and the remaining 80 were analyzed in parallel by Sanger sequencing for the BRCA1/BRCA2 genes and by NGS for a panel of 17 genes that have been described as involved in predisposition to breast and/or ovarian cancer. A total of 506 variants in the BRCA1/BRCA2 genes were detected by both methodologies, with a 100 % concordance between them. This strategy allowed the detection of a total of 39 deleterious mutations in the 94 index patients, namely 10 in BRCA1 (25.6 %), 21 in BRCA2 (53.8 %), four in PALB2 (10.3 %), two in ATM (5.1 %), one in CHEK2 (2.6 %), and one in TP53 (2.6 %), with 20.5 % of the deleterious mutations being found in genes other than BRCA1/BRCA2. These results demonstrate the efficiency of NGS for the detection of BRCA1/BRCA2 point mutations and highlight the genetic heterogeneity of HBOC. PMID:27553368

  17. Adiposity significantly modifies genetic risk for dyslipidemia.

    PubMed

    Cole, Christopher B; Nikpay, Majid; Lau, Paulina; Stewart, Alexandre F R; Davies, Robert W; Wells, George A; Dent, Robert; McPherson, Ruth

    2014-11-01

    Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (P(Interaction) = 2.87 × 10(-4)) and HDLc (P(Interaction) = 1.05 × 10(-3)). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (P(Interaction) = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability. PMID:25225679

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

    MedlinePlus

    ... 20, 2014 Common gene variants account for most genetic risk for autism Roles of heritability, mutations, environment ... ASD) was traced to inherited variations in the genetic code shared by many people. These and other ( ...

  19. A Genetic Risk Score Combining Ten Psoriasis Risk Loci Improves Disease Prediction

    PubMed Central

    Chen, Haoyan; Poon, Annie; Yeung, Celestine; Helms, Cynthia; Pons, Jennifer; Bowcock, Anne M.; Kwok, Pui-Yan; Liao, Wilson

    2011-01-01

    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 only11.6% 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. PMID:21559375

  20. Genetic Vulnerability as a Distal Risk Factor for Suicidal Behaviour: Historical Perspective and Current Knowledge

    PubMed Central

    ANDRIESSEN, Karl; VIDETIC-PASKA, Alja

    2015-01-01

    Introduction Suicide is a multidimensional problem. Observations of family history of suicide suggest the existence of a genetic vulnerability to suicidal behaviour. Aim Starting with a historical perspective, the article reviews current knowledge of a genetic vulnerability to suicidal behaviour, distinct from the genetic vulnerability to psychiatric disorders, focused on clinical and population-based studies, and findings from recent molecular genetics association studies. Method The review includes peer-reviewed research articles and review papers from the professional literature in English language, retrieved from PubMed/Medline and PsycINFO. Results The research literature confirms a existence of a genetic vulnerability to suicidal behaviour. Even though the results of individual studies are difficult to compare, genetic influences could explain up to half of the variance of the occurrence of suicide. Conclusion Genetic vulnerability could be a distal risk factor for suicide, which helps us to understand the occurrence of suicide among vulnerable people. Ethical implications of such vulnerability are highlighted.

  1. Recent Enhancements to the Genetic Risk Prediction Model BRCAPRO

    PubMed Central

    Mazzola, Emanuele; Blackford, Amanda; Parmigiani, Giovanni; Biswas, Swati

    2015-01-01

    BRCAPRO is a widely used model for genetic risk prediction of breast cancer. It is a function within the R package BayesMendel and is used to calculate the probabilities of being a carrier of a deleterious mutation in one or both of the BRCA genes, as well as the probability of being affected with breast and ovarian cancer within a defined time window. Both predictions are based on information contained in the counselee’s family history of cancer. During the last decade, BRCAPRO has undergone several rounds of successive refinements: the current version is part of release 2.1 of BayesMendel. In this review, we showcase some of the most notable features of the software resulting from these recent changes. We provide examples highlighting each feature, using artificial pedigrees motivated by complex clinical examples. We illustrate how BRCAPRO is a comprehensive software for genetic risk prediction with many useful features that allow users the flexibility to incorporate varying amounts of available information. PMID:25983549

  2. Healthy Living May Offset Genetic Breast Cancer Risk

    MedlinePlus

    ... fullstory_159053.html Healthy Living May Offset Genetic Breast Cancer Risk Lifestyle may matter even more when your ... Women who carry common gene variants linked to breast cancer can still cut their risk of the disease ...

  3. Ciguatera fish poisoning: a first epidemic in Germany highlights an increasing risk for European countries.

    PubMed

    Mattei, César; Vetter, Irina; Eisenblätter, Anneka; Krock, Bernd; Ebbecke, Martin; Desel, Herbert; Zimmermann, Katharina

    2014-12-01

    Toxin-producing microalgae are thriving worldwide due to coral reef destruction and global warming with major consequences on ecosystems, international trade and human health. Microalgae belonging to the family of flagellate protists, in particular dinoflagellates, secrete a variety of high-molecular-weight polyether toxins that accumulate through the marine food chain to cause disease in humans by acting as sodium channel activator toxins; ciguatera is the most frequent seafood-borne illness worldwide with 50,000 to 500,000 global incidences per annum and is usually limited to endemic areas located between 35° northern and 35° southern latitude. The rising global incidence frequency renders it a major human health problem, because no curative treatment is available yet and reliable detection assays are lacking. During the last decade ciguatera has increasingly become endemic in previously unaffected areas for two reasons: first global warming has contributed to the emergence of dinoflagellate species in subtropical and even temperate regions that previously had been constrained to tropical areas and second: in Europe globalization of fishing industry and tourism has led to a progressive increase in the number of ciguatera cases and a lack of awareness among medical personnel contributes to under-reporting. We review, through a recent ciguatera outbreak in Germany, the risk for ciguatera poisoning in Europe and highlight characteristic symptoms, current knowledge about disease pathomechanisms and treatment options. PMID:25448771

  4. Explanatory Models of Genetics and Genetic Risk among a Selected Group of Students.

    PubMed

    Goltz, Heather Honoré; Bergman, Margo; Goodson, Patricia

    2016-01-01

    This exploratory qualitative study focuses on how college students conceptualize genetics and genetic risk, concepts essential for genetic literacy (GL) and genetic numeracy (GN), components of overall health literacy (HL). HL is dependent on both the background knowledge and culture of a patient, and lower HL is linked to increased morbidity and mortality for a number of chronic health conditions (e.g., diabetes and cancer). A purposive sample of 86 students from three Southwestern universities participated in eight focus groups. The sample ranged in age from 18 to 54 years, and comprised primarily of female (67.4%), single (74.4%), and non-White (57%) participants, none of whom were genetics/biology majors. A holistic-content approach revealed broad categories concerning participants' explanatory models (EMs) of genetics and genetic risk. Participants' EMs were grounded in highly contextualized narratives that only partially overlapped with biomedical models. While higher education levels should be associated with predominately knowledge-based EM of genetic risk, this study shows that even in well-educated populations cultural factors can dominate. Study findings reveal gaps in how this sample of young adults obtains, processes, and understands genetic/genomic concepts. Future studies should assess how individuals with low GL and GN obtain and process genetics and genetic risk information and incorporate this information into health decision making. Future work should also address the interaction of communication between health educators, providers, and genetic counselors, to increase patient understanding of genetic risk. PMID:27376052

  5. Explanatory Models of Genetics and Genetic Risk among a Selected Group of Students

    PubMed Central

    Goltz, Heather Honoré; Bergman, Margo; Goodson, Patricia

    2016-01-01

    This exploratory qualitative study focuses on how college students conceptualize genetics and genetic risk, concepts essential for genetic literacy (GL) and genetic numeracy (GN), components of overall health literacy (HL). HL is dependent on both the background knowledge and culture of a patient, and lower HL is linked to increased morbidity and mortality for a number of chronic health conditions (e.g., diabetes and cancer). A purposive sample of 86 students from three Southwestern universities participated in eight focus groups. The sample ranged in age from 18 to 54 years, and comprised primarily of female (67.4%), single (74.4%), and non-White (57%) participants, none of whom were genetics/biology majors. A holistic-content approach revealed broad categories concerning participants’ explanatory models (EMs) of genetics and genetic risk. Participants’ EMs were grounded in highly contextualized narratives that only partially overlapped with biomedical models. While higher education levels should be associated with predominately knowledge-based EM of genetic risk, this study shows that even in well-educated populations cultural factors can dominate. Study findings reveal gaps in how this sample of young adults obtains, processes, and understands genetic/genomic concepts. Future studies should assess how individuals with low GL and GN obtain and process genetics and genetic risk information and incorporate this information into health decision making. Future work should also address the interaction of communication between health educators, providers, and genetic counselors, to increase patient understanding of genetic risk. PMID:27376052

  6. Genetic 'risk carriers' and lifestyle 'risk takers'. Which risks deserve our legal protection in insurance?

    PubMed

    Van Hoyweghen, Ine; Horstman, Klasien; Schepers, Rita

    2007-09-01

    Over the past years, one of the most contentious topics in policy debates on genetics has been the use of genetic testing in insurance. In the rush to confront concerns about potential abuses of genetic information, most countries throughout Europe and the US have enacted genetics-specific legislation for insurance. Drawing on current debates on the pros and cons of a genetics-specific legislative approach, this article offers empirical insight into how such legislation works out in insurance practice. To this end, ethnographic fieldwork was done in the underwriting departments of Belgian insurance companies. Belgium was one of the first European countries introducing genetics-specific legislation in insurance. Although this approach does not allow us to speak in terms of ' the causal effects of the law', it enables us to point to some developments in insurance practice that are quite different than the law's original intentions. It will not only become clear that the Belgian genetics-specific legislation does not offer adequate solutions to the underlying issues it was intended for. We will also show that, while the legislation's focus has been on the inadmissibility of genetic discrimination, at the same time differences are made in the insurance appraisal within the group of the asymptomatic ill. In other words, by giving exclusive legal protection to the group of genetic risks, other non-genetic risk groups are unintendedly being under-protected. From a policy point of view, studying genetics-specific legislation is especially valuable because it forces us to return to first principles: Which risks deserve our legal protection in insurance? Who do we declare our solidarity with? PMID:17922196

  7. Pathway analysis of body mass index genome-wide association study highlights risk pathways in cardiovascular disease

    PubMed Central

    Zhao, Xin; Gu, Jinxia; Li, Ming; Xi, Jie; Sun, Wenyu; Song, Guangmin; Liu, Guiyou

    2015-01-01

    Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. It is reported that body mass index (BMI) is risk factor for CVD. Genome-wide association studies (GWAS) have recently provided rapid insights into genetics of CVD and its risk factors. However, the specific mechanisms how BMI influences CVD risk are largely unknown. We think that BMI may influences CVD risk by shared genetic pathways. In order to confirm this view, we conducted a pathway analysis of BMI GWAS, which examined approximately 329,091 single nucleotide polymorphisms from 4763 samples. We identified 31 significant KEGG pathways. There is literature evidence supporting the involvement of GnRH signaling, vascular smooth muscle contraction, dilated cardiomyopathy, Gap junction, Wnt signaling, Calcium signaling and Chemokine signaling in CVD. Collectively, our study supports the potential role of the CVD risk pathways in BMI. BMI may influence CVD risk by the shared genetic pathways. We believe that our results may advance our understanding of BMI mechanisms in CVD. PMID:26264282

  8. The Effect of Genetic Risk Information and Health Risk Assessment on Compliance with Preventive Behaviors.

    ERIC Educational Resources Information Center

    Bamberg, Richard; And Others

    1990-01-01

    Results from a study of 82 males provide no statistical support and limited encouragement that genetic risk information may motivate persons to make positive changes in preventive health behaviors. Health risk assessments were used to identify subjects at risk for coronary heart disease or lung cancer because of genetic factors. (IAH)

  9. Decision-making about inherited cancer risk: exploring dimensions of genetic responsibility.

    PubMed

    Etchegary, Holly; Miller, Fiona; deLaat, Sonya; Wilson, Brenda; Carroll, June; Cappelli, Mario

    2009-06-01

    Since genetic information has implications for family members, some choices about genetic risk may be influenced by perceptions of responsibility to relatives. Drawing upon 25 semi-structured interviews with test recipients in Canada, this study explored decisions about inherited breast-ovarian and colon cancer. Qualitative data analysis revealed the pervasive significance of genetic responsibility in test decisions. We highlight three dimensions of genetic responsibility: 1) to know about the self for self; 2) to know about the self for others; 3) to know about the self to oblige others to know. It is argued that these dimensions of genetic responsibility have implications for test decisions, family relationships and other family members' desire to know (or not know) and to act (or not act) with respect to their own genetic risk. In particular, genetic responsibility may play out as a framing of a relative's moral obligation to know their risk that could obviate any interest they might have in not knowing. We conclude that perceptions of responsibility to-and of-other family members be thoroughly explored in genetic counseling sessions. PMID:19294336

  10. Multi-locus models of genetic risk of disease

    PubMed Central

    2010-01-01

    Background Evidence for genetic contribution to complex diseases is described by recurrence risks to relatives of diseased individuals. Genome-wide association studies allow a description of the genetics of the same diseases in terms of risk loci, their effects and allele frequencies. To reconcile the two descriptions requires a model of how risks from individual loci combine to determine an individual's overall risk. Methods We derive predictions of risk to relatives from risks at individual loci under a number of models and compare them with published data on disease risk. Results The model in which risks are multiplicative on the risk scale implies equality between the recurrence risk to monozygotic twins and the square of the recurrence risk to sibs, a relationship often not observed, especially for low prevalence diseases. We show that this theoretical equality is achieved by allowing impossible probabilities of disease. Other models, in which probabilities of disease are constrained to a maximum of one, generate results more consistent with empirical estimates for a range of diseases. Conclusions The unconstrained multiplicative model, often used in theoretical studies because of its mathematical tractability, is not a realistic model. We find three models, the constrained multiplicative, Odds (or Logit) and Probit (or liability threshold) models, all fit the data on risk to relatives. Currently, in practice it would be difficult to differentiate between these models, but this may become possible if genetic variants that explain the majority of the genetic variance are identified. PMID:20181060

  11. Generating natural hazard risk maps for Styria to highlight differences in the social vulnerability

    NASA Astrophysics Data System (ADS)

    Heß, Vincent

    2016-04-01

    Costs of natural hazards are commonly classified as either damage costs or risk mitigation costs. These categories are not independent, as risk mitigation aims at reducing damage costs. However, the factors that influence the risk of damage costs are still not completely understood. Commonly, the risk is defined as a function of hazard, exposure and vulnerability and we want to produce risk maps that combine existing information about these factors under a common framework. Because of good data availability, the risk maps will be produced for Styria, Austria, where detailed hazard and land-use maps are available on a municipality level and the costs can be verified with private damage data from the Austrian disaster fond. A key issue is the generation of a social vulnerability map by the use of demographic and socio-economic data. We use a statistical model to analyze how much of the variance in the damage data are explainable by considering social characteristics across municipalities. The combination of the aforementioned maps results in a risk map, which can not only display areas of high risks, but also the underlying reasons. Knowledge about risk increasing factors consequently allow for better suited risk mitigation measures. Especially soft measures need to be clearly targeted towards local needs to increase the resilience and adaptive capacity of municipalities.

  12. Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.

    PubMed

    Robinson, C L; Jouni, H; Kruisselbrink, T M; Austin, E E; Christensen, K D; Green, R C; Kullo, I J

    2016-02-01

    We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation. PMID:25708169

  13. Cumulative genetic risk and prefrontal activity in patients with schizophrenia.

    PubMed

    Walton, Esther; Turner, Jessica; Gollub, Randy L; Manoach, Dara S; Yendiki, Anastasia; Ho, Beng-Choon; Sponheim, Scott R; Calhoun, Vince D; Ehrlich, Stefan

    2013-05-01

    The lack of consistency of genetic associations in highly heritable mental illnesses, such as schizophrenia, remains a challenge in molecular psychiatry. Because clinical phenotypes for psychiatric disorders are often ill defined, considerable effort has been made to relate genetic polymorphisms to underlying physiological aspects of schizophrenia (so called intermediate phenotypes), that may be more reliable. Given the polygenic etiology of schizophrenia, the aim of this work was to form a measure of cumulative genetic risk and study its effect on neural activity during working memory (WM) using functional magnetic resonance imaging. Neural activity during the Sternberg Item Recognition Paradigm was measured in 79 schizophrenia patients and 99 healthy controls. Participants were genotyped, and a genetic risk score (GRS), which combined the additive effects of 41 single-nucleotide polymorphisms (SNPs) from 34 risk genes for schizophrenia, was calculated. These risk SNPs were chosen according to the continuously updated meta-analysis of genetic studies on schizophrenia available at www.schizophreniaresearchforum.org. We found a positive relationship between GRS and left dorsolateral prefrontal cortex inefficiency during WM processing. GRS was not correlated with age, performance, intelligence, or medication effects and did not differ between acquisition sites, gender, or diagnostic groups. Our study suggests that cumulative genetic risk, combining the impact of many genes with small effects, is associated with a known brain-based intermediate phenotype for schizophrenia. The GRS approach could provide an advantage over studying single genes in studies focusing on the genetic basis of polygenic conditions such as neuropsychiatric disorders. PMID:22267534

  14. Highlight report: Launch of a large integrated European in vitro toxicology project: EU-ToxRisk.

    PubMed

    Daneshian, Mardas; Kamp, Hennicke; Hengstler, Jan; Leist, Marcel; van de Water, Bob

    2016-05-01

    The integrated European project, EU-ToxRisk, proudly sees itself as "flagship" exploring new alternative-to-animal approaches to chemical safety evaluation. It promotes mechanism-based toxicity testing and risk assessment according to the principles laid down for toxicology for the twenty-first century. The project was officially launched in January 2016 with a kickoff meeting in Egmond aan Zee, the Netherlands. Over 100 scientists representing academia and industry as well as regulatory authorities attended the inaugural meeting. The project will integrate advances in in vitro and in silico toxicology, read-across methods, and adverse outcome pathways. EU-ToxRisk will continue to make use of the case study strategy deployed in SEURAT-1, a FP7 initiative ended in December 2015. Even though the development of new non-animal methods is one target of EU-ToxRisk, the project puts special emphasis on their acceptance and implementation in regulatory contexts. This €30 million Horizon 2020 project involves 38 European partners and one from the USA. EU-ToxRisk aims at the "development of a new way of risk assessment." PMID:27017488

  15. Highlights 1993

    SciTech Connect

    Not Available

    1993-11-01

    Current research programs at Lawrence Berkeley Laboratory are presented. The topics include: the genetic basis for breast cancer, the Advanced Light Source, selenium characterization in soils via x-ray absorption spectroscopy, automated colony sorting in efforts of map the human genome, cancer drugs, the Sudbury Neutrino Observatory (SNO), atomic force microscopes (AFM), mapping the radon risk in homes, ketene research, tracking B mesons and the search for the top quark, computerized scientific visualization, technology transfer efforts, and astronomy in the classroom.

  16. Adaptive genetic variation and heart disease risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose of review: Obesity, dyslipidemia and cardiovascular disease are complex and determined by both genetic and environmental factors and their interrelationships. Many associations from genome-wide association studies (GWAS) and candidate gene approaches have described a multitude of polymorphis...

  17. Breast cancer risk assessment using genetic variants and risk factors in a Singapore Chinese population

    PubMed Central

    2014-01-01

    Introduction Genetic variants for breast cancer risk identified in genome-wide association studies (GWAS) in Western populations require further testing in Asian populations. A risk assessment model incorporating both validated genetic variants and established risk factors may improve its performance in risk prediction of Asian women. Methods A nested case-control study of female breast cancer (411 cases and 1,212 controls) within the Singapore Chinese Health Study was conducted to investigate the effects of 51 genetic variants identified in previous GWAS on breast cancer risk. The independent effect of these genetic variants was assessed by creating a summed genetic risk score (GRS) after adjustment for body mass index and the Gail model risk factors for breast cancer. Results The GRS was an independent predictor of breast cancer risk in Chinese women. The multivariate-adjusted odds ratios (95% confidence intervals) of breast cancer for the second, third, and fourth quartiles of the GRS were 1.26 (0.90 to 1.76), 1.47 (1.06 to 2.04) and 1.75 (1.27 to 2.41) respectively (P for trend <0.001). In addition to established risk factors, the GRS improved the classification of 6.2% of women for their absolute risk of breast cancer in the next five years. Conclusions Genetic variants on top of conventional risk factors can improve the risk prediction of breast cancer in Chinese women. PMID:24941967

  18. Occupational and genetic risk factors for osteoarthritis: A review

    PubMed Central

    Yucesoy, Berran; Charles, Luenda E.; Baker, Brent; Burchfiel, Cecil M.

    2015-01-01

    BACKGROUND Osteoarthritis (OA) is a multifactorial disease with strong genetic and occupational components. Although published studies have described several risk factors for OA, very few studies have investigated the occupational and genetic factors that contribute to this debilitating condition. OBJECTIVE To describe occupational and genetic factors that may contribute to the risk of developing (OA). METHODS A literature search was conducted in PubMed using the search terms osteoarthritis, occupation, work, and genetics. RESULTS Heavy physical work load was the most common occupational risk factor for OA in several anatomical locations. Other factors include kneeling and regular stair climbing, crawling, bending and whole body vibration, and repetitive movements. Numerous studies have also shown the influence of genetic variability in the pathogenesis of OA. Genetic variants of several groups of genes e.g., cartilage extracellular matrix structural genes and the genes related to bone density have been implicated in disease pathogenesis. CONCLUSION This review shows that occupational factors were extensively studied in knee OA unlike OA of other anatomical regions. Although genetic association studies performed to date identified a number of risk variants, some of these associations have not been consistently replicated across different studies and populations. Therefore, more research is needed. PMID:24004806

  19. Applying Personal Genetic Data to Injury Risk Assessment in Athletes

    PubMed Central

    Goodlin, Gabrielle T.; Roos, Andrew K.; Roos, Thomas R.; Hawkins, Claire; Beache, Sydney; Baur, Stephen; Kim, Stuart K.

    2015-01-01

    Recent studies have identified genetic markers associated with risk for certain sports-related injuries and performance-related conditions, with the hope that these markers could be used by individual athletes to personalize their training and diet regimens. We found that we could greatly expand the knowledge base of sports genetic information by using published data originally found in health and disease studies. For example, the results from large genome-wide association studies for low bone mineral density in elderly women can be re-purposed for low bone mineral density in young endurance athletes. In total, we found 124 single-nucleotide polymorphisms associated with: anterior cruciate ligament tear, Achilles tendon injury, low bone mineral density and stress fracture, osteoarthritis, vitamin/mineral deficiencies, and sickle cell trait. Of these single nucleotide polymorphisms, 91% have not previously been used in sports genetics. We conducted a pilot program on fourteen triathletes using this expanded knowledge base of genetic variants associated with sports injury. These athletes were genotyped and educated about how their individual genetic make-up affected their personal risk profile during an hour-long personal consultation. Overall, participants were favorable of the program, found it informative, and most acted upon their genetic results. This pilot program shows that recent genetic research provides valuable information to help reduce sports injuries and to optimize nutrition. There are many genetic studies for health and disease that can be mined to provide useful information to athletes about their individual risk for relevant injuries. PMID:25919592

  20. Genetic tests to identify risk for breast cancer

    PubMed Central

    Lynch, Julie; Venne, Vickie; Berse, Brygida

    2016-01-01

    Objectives To describe the currently available genetic tests that identify hereditary risk for breast cancer. Data sources Systematic review of scientific literature, clinical practice guidelines, and data published by test manufacturers. Conclusion Changes in gene patent laws and advances in sequencing technologies have resulted in rapid expansion of genetic testing. While BRCA1/2 are the most recognized genes linked to breast cancer, several laboratories now offer multi-gene panels to detect many risk-related mutations. Implication for Nursing Practice Genetic testing will be increasingly important in the prevention, diagnosis, and treatment of breast cancer. Oncology and advanced practice nurses need to understand risk factors, significance of various genetic tests, and patient counseling. PMID:25951739

  1. Bridge: a GUI package for genetic risk prediction

    PubMed Central

    2013-01-01

    Background Risk prediction models capitalizing on genetic and environmental information hold great promise for individualized disease prediction and prevention. Nevertheless, linking the genetic and environmental risk predictors into a useful risk prediction model remains a great challenge. To facilitate risk prediction analyses, we have developed a graphical user interface package, Bridge. Results The package is built for both designing and analyzing a risk prediction model. In the design stage, it provides an estimated classification accuracy of the model using essential genetic and environmental information gained from public resources and/or previous studies, and determines the sample size required to verify this accuracy. In the analysis stage, it adopts a robust and powerful algorithm to form the risk prediction model. Conclusions The package is developed based on the optimality theory of the likelihood ratio and therefore theoretically could form a model with high performance. It can be used to handle a relatively large number of genetic and environmental predictors, with consideration of their possible interactions, and so is particularly useful for studying risk prediction models for common complex diseases. PMID:24359333

  2. Quantification of the genetic risk of environmental mutagens

    SciTech Connect

    Ehling, U.H.

    1988-03-01

    Screening methods are used for hazard identification. Assays for heritable mutations in mammals are used for the confirmation of short-term test results and for the quantification of the genetic risk. There are two main approaches in making genetic risk estimates. One of these, termed the direct method, expresses risk in terms of the expected frequency of genetic changes induced per unit. The other, referred to as the doubling dose method or the indirect method, expresses risk in relation to the observed incidence of genetic disorders now present in man. The indirect method uses experimental data only for the calculation of the doubling dose. The quality of the risk estimation depends on the assumption of persistence of the induced mutations and the ability to determine the current incidence of genetic diseases. The difficulties of improving the estimates of current incidences of genetic diseases or the persistence of the genes in the population led them to the development of an alternative method, the direct estimation of the genetic risk. The direct estimation uses experimental data for the induced frequency for dominant mutations in mice. For the verification of these quantifications one can use the data of Hiroshima and Nagasaki. According to the estimation with the direct method, one would expect less than 1 radiation-induced dominant cataract in 19,000 children with one or both parents exposed. The expected overall frequency of dominant mutations in the first generation would be 20-25, based on radiation-induced dominant cataract mutations. It is estimated that 10 times more recessive than dominant mutations are induced. The same approaches can be used to determine the impact of chemical mutagens.

  3. Single-gene association between GATA-2 and autoimmune hepatitis: A novel genetic insight highlighting immunologic pathways to disease

    PubMed Central

    Webb, Gwilym; Chen, Yung-Yi; Li, Ka-Kit; Neil, Desley; Oo, Ye Htun; Richter, Alex; Bigley, Venetia; Collin, Matthew; Adams, David H.; Hirschfield, Gideon M.

    2016-01-01

    Background & Aims Autoimmune hepatitis (AIH), an immune-mediated liver disease, originates as a consequence of interacting genetic and environmental risk factors. Treatment remains non-specific and prone to side effects. Deficiencies in regulatory T cell (Treg) function are hypothesized to contribute to the pathogenesis of AIH. Methods We describe an adult patient who presented with AIH in the context of monocytopenia. The patient was characterized by GATA2 gene sequencing, flow cytometry of peripheral blood for leucocyte subsets, ELISA for serum Flt-3 ligand, and immunohistochemistry of liver biopsy tissue. Results Sequencing confirmed a GATA2 mutation. Peripheral Treg were absent in the context of a preserved total T cell count. Immunostaining for the Treg transcription factor FOXP3 was reduced in liver tissue as compared to a control AIH specimen. There were marked deficiencies in multiple antigen-presenting cell subsets and Flt-3 ligand was elevated. These findings are consistent with previous reports of GATA2 dysfunction. Conclusions The association of a GATA2 mutation with AIH is previously unrecognized. GATA2 encodes a hematopoietic cell transcription factor, and mutations may manifest as monocytopenia, dendritic and B cell deficiencies, myelodysplasia, and immunodeficiency. Tregs may be depleted as in this case. Our findings provide support for the role of Tregs in AIH, complement reports of other deficiencies in T cell regulation causing AIH-like syndromes, and support the rationale of attempting to modulate the Treg axis for the therapeutic benefit of AIH patients. PMID:26812071

  4. Risk estimations, risk factors, and genetic variants associated with Alzheimer's disease in selected publications from the Framingham Heart Study.

    PubMed

    Weinstein, Galit; Wolf, Philip A; Beiser, Alexa S; Au, Rhoda; Seshadri, Sudha

    2013-01-01

    The study of Alzheimer's disease (AD) in the Framingham Heart Study (FHS), a multi-generational, community-based population study, began nearly four decades ago. In this overview, we highlight findings from seven prior publications that examined lifetime risk estimates for AD, environmental risk factors for AD, circulating and imaging markers of aging-related brain injury, and explorations on the genetics underlying AD. First, we describe estimations of the lifetime risk of AD. These estimates are distinguished from other measures of disease burden and have substantial public health implications. We then describe prospective studies of environmental AD risk factors: one examined the association between plasma levels of omega-3 fatty-acid and risk of incident AD, the other explored the association of diabetes to this risk in subsamples with specific characteristics. With evidence of inflammation as an underlying mechanism, we also describe findings from a study that compared the effects of serum cytokines and spontaneous production of peripheral blood mononuclear cell cytokines on AD risk. Investigating AD related endophenotypes increases sensitivity in identifying risk factors and can be used to explore pathophysiologic pathways between a risk factor and the disease. We describe findings of an association between large volume of white matter hyperintensities and a specific pattern of cognitive deficits in non-demented participants. Finally, we summarize our findings from two genetic studies: The first used genome-wide association (GWA) and family-based association methods to explore the genetic basis of cognitive and structural brain traits. The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD. PMID:22796871

  5. Do Environmental Factors Modify the Genetic Risk of Prostate Cancer?

    PubMed Central

    Loeb, Stacy; Peskoe, Sarah B.; Joshu, Corinne E.; Huang, Wen-Yi; Hayes, Richard B.; Carter, H. Ballentine; Isaacs, William B.; Platz, Elizabeth A.

    2015-01-01

    Background Many SNPs influence prostate cancer risk. To what extent genetic risk can be reduced by environmental factors is unknown. Methods We evaluated effect modification by environmental factors of the association between susceptibility SNPs and prostate cancer in 1,230 incident prostate cancer cases and 1,361 controls, all white and similar ages, nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Trial. Genetic risk scores were calculated as number of risk alleles for 20 validated SNPs. We estimated the association between higher genetic risk (≥ 12 SNPs) and prostate cancer within environmental factor strata and tested for interaction. Results Men with ≥12 risk alleles had 1.98, 2.04, and 1.91 times the odds of total, advanced, and nonadvanced prostate cancer, respectively. These associations were attenuated with the use of selenium supplements, aspirin, ibuprofen, and higher vegetable intake. For selenium, the attenuation was most striking for advanced prostate cancer: compared with <12 alleles and no selenium, the OR for ≥12 alleles was 2.06 [95% confidence interval (CI), 1.67–2.55] in nonusers and 0.99 (0.38–2.58) in users (Pinteraction = 0.031). Aspirin had the most marked attenuation for nonadvanced prostate cancer: compared with <12 alleles and nonusers, the OR for ≥12 alleles was 2.25 (1.69–3.00) in nonusers and 1.70 (1.25–2.32) in users (Pinteraction = 0.009). This pattern was similar for ibuprofen (Pinteraction = 0.023) and vegetables (Pinteraction = 0.010). Conclusions This study suggests that selenium supplements may reduce genetic risk of advanced prostate cancer, whereas aspirin, ibuprofen, and vegetables may reduce genetic risk of nonadvanced prostate cancer. PMID:25342390

  6. Electrophysiological markers of genetic risk for attention deficit hyperactivity disorder

    PubMed Central

    Tye, Charlotte; McLoughlin, Gráinne; Kuntsi, Jonna; Asherson, Philip

    2014-01-01

    Electroencephalography (EEG) is an ideal neuroscientific approach, providing a direct measurement of neural activity that demonstrates reliability, developmental stability and high heritability. This systematic review of a subset of domains evaluates the utility of electrophysiological measures as potential intermediate phenotypes for ADHD in the domains of quantitative EEG indices of arousal and intra-individual variability, and functional investigations of inhibitory and error processing using the event-related potential (ERP) technique. Each domain demonstrates consistent and meaningful associations with ADHD, a degree of genetic overlap with ADHD and potential links to specific genetic variants. Investigations of the genetic and environmental contributions to EEG/ERP and shared genetic overlap with ADHD may enhance molecular genetic studies and provide novel insights into aetiology. Such research will aid in the precise characterisation of the clinical deficits seen in ADHD and guide the development of novel intervention and prevention strategies for those at risk. PMID:21426626

  7. Disparities in Cancer Genetic Risk Assessment and Testing.

    PubMed

    Underhill, Meghan L; Jones, Tarsha; Habin, Karleen

    2016-07-01

    Scientific and technologic advances in genomics have revolutionized genetic counseling and testing, targeted therapy, and cancer screening and prevention. Among younger women, African American and Hispanic women have a higher rate of cancers that are associated with hereditary cancer risk, such as triple-negative breast cancer, which is linked to poorer outcomes. Therefore, genetic testing is particularly important in diverse populations. Unfortunately, all races and ethnic groups are not well represented in current genetic testing practices, leading to disparities in cancer prevention and early detection. PMID:27314195

  8. Telomere shortening as genetic risk factor of liver cirrhosis.

    PubMed

    Carulli, Lucia

    2015-01-14

    Cirrhosis is the main complication of chronic liver disease, leads to progressive liver function impairment and is the main risk factor for the development of liver cancer. Liver failure at endstage cirrhosis is associated with increased mortality with liver transplantation as the only possible treatment at this stage. The pathogenesis of liver cirrhosis is not completely elucidated. Although the common factors leading to liver injury, such as viral hepatitis, alcohol consume or fatty liver disease can be identified in the majority of patients a small percentage of patients have no apparent risk factors. Moreover given the same risk factors, some patients progress to cirrhosis whereas others have a benign course, the reason remains unclear. In order to develop new diagnostic and therapeutic tools, it is s essential to understand the pathogenesis of cirrhosis. The identification of genetic risk factors associated with cirrhosis is one of the possible approach to achieve these goal. In the past years several studies have supported the role of telomere shortening and cirrhosis. In the recent year several studies on the relation between several single nucleotide polymorphism (SNPs) and cirrhosis have been published; it has been proposed also a cirrhosis risk score based on seven SNPs. Also epidemiological studies on identical twins and in different ethnic groups have been supporting the importance of the role of genetic risk factors. Finally in the very recent years it has been suggested that telomere shortening may represent a genetic risk factor for the development of cirrhosis. PMID:25593453

  9. Genetic Variants Related to Height and Risk of Atrial Fibrillation

    PubMed Central

    Rosenberg, Michael A.; Kaplan, Robert C.; Siscovick, David S.; Psaty, Bruce M.; Heckbert, Susan R.; Newton-Cheh, Christopher; Mukamal, Kenneth J.

    2014-01-01

    Increased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥65 years) enrolled in 1989–1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10−8). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets. PMID:24944287

  10. [Recommendations for genetic testing and management of individuals genetically at-risk of cutaneous melanoma].

    PubMed

    Avril, M-F; Bahadoran, P; Cabaret, O; Caron, O; de la Fouchardière, A; Demenais, F; Desjardins, L; Frébourg, T; Hammel, P; Leccia, M-T; Lesueur, F; Mahé, E; Martin, L; Maubec, E; Remenieras, A; Richard, S; Robert, C; Soufir, N; Stoppa-Lyonnet, D; Thomas, L; Vabres, P; Bressac-de Paillerets, B

    2015-01-01

    Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly. PMID:25600792

  11. An animal model of differential genetic risk for methamphetamine intake

    PubMed Central

    Phillips, Tamara J.; Shabani, Shkelzen

    2015-01-01

    The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a

  12. [Environmental and genetic risk factors for endometrial carcinoma].

    PubMed

    Sénéchal, Claire; Cottereau, Edouard; de Pauw, Antoine; Elan, Camille; Dagousset, Isabelle; Fourchotte, Virginie; Gauthier-Villars, Marion; Lae, Marick; Stoppa-Lyonnet, Dominique; Buecher, Bruno

    2015-03-01

    In France, endometrial cancer is at the first rank of gynecological cancers for cancer incidence, before ovarian and cervical cancers. In fact, the number of incident cases has been estimated to 7275 for the year 2012; the number of death due to endometrial cancer to 2025. This cancer is hormone-dependent and endogenous (reproductive factors) or exogenous (oral combined contraceptives, hormone replacement therapy) causes of exposition to estrogens are the major environmental risk factors for both types of endometrial cancers: type I or well-differentiated endometrioid adenocarcinomas; and type II including all other histological types: papillary serous adenocarcinomas, clear cell adenocarcinomas and carcinosarcomas, also known as malignant mixed Mullerian tumor, MMMT. Obesity, diabetes mellitus and adjuvant treatment of breast cancer with tamoxifen are also associated with an increased risk of endometrial cancer. Genetic factors may also be implicated in the pathogenesis of endometrial cancer either as "minor genetic factors" (susceptibility factors), which remain largely unknown and are responsible for the increased observed risk in relatives of women affected with endometrial cancer; or as major genetic factors responsible for hereditary forms and namely for Lynch syndrome whose genetic transmission is of autosomic dominant type. The appropriate recognition of Lynch syndrome is of critical importance because affected patients and their relatives should benefit from specific care. The aims of this review is to describe major environmental and genetic risk factors for endometrial cancer with specific attention to most recent advances in this field and to describe recommendations for care of at-risk women. PMID:25725922

  13. Epidemiology, major risk factors and genetic predisposition for breast cancer in the Pakistani population.

    PubMed

    Shaukat, Uzma; Ismail, Muhammad; Mehmood, Nasir

    2013-01-01

    Occurrence of breast cancer is related to genetic as well as cultural, environmental and life-style factors. Variations in diversity of these factors among different ethnic groups and geographical areas emphasize the immense need for studies in all racial-ethnic populations. The incidence of breast cancer in Pakistan is highest in Asians after Jews in Israel and 2.5 times higher than that in neighboring countries like Iran and India, accounting for 34.6% of female cancers. The Pakistani population is deficient in information regarding breast cancer etiology and epidemiology, but efforts done so far had suggested consanguinity as a major risk factor for frequent mutations leading to breast cancer and has also shed light on genetic origins in different ethnic groups within Pakistan. World-wide research efforts on different ethnicities have enhanced our understanding of genetic predisposition to breast cancer but despite these discoveries, 75% of the familial risk of breast cancer remains unexplained, highlighting the fact that the majority of breast cancer susceptibility genes remain unidentified. For this purpose Pakistani population provides a strong genetic pool to elucidate the genetic etiology of breast cancer because of cousin marriages. In this review, we describe the known breast cancer predisposition factors found in the local Pakistani population and the epidemiological research work done to emphasize the importance of exploring factors/variants contributing to breast cance, in order to prevent, cure and decrease its incidence in our country. PMID:24289553

  14. Environmental Adversity Increases Genetic Risk for Externalizing Disorders

    PubMed Central

    Hicks, Brian M.; South, Susan C.; DiRago, Ana C.; Iacono, William G.; McGue, Matt

    2008-01-01

    Background Studies of gene-environment (G-E) interplay in the development of psychiatric and substance use disorders are rapidly accumulating. However, few attempts have been made to integrate findings and articulate general mechanisms of G-E influence in the emergence of psychopathology. Objective Identify patterns of G-E interplay between externalizing (EXT; antisocial behavior and substance use) disorders and several environmental risk factors. Design We used quantitative genetic models to examine how genetic and environmental risk for EXT disorders changes as a function of environmental context. Setting Participants were recruited from the community and took part in a day-long assessment at a university laboratory. Participants The sample consisted of 1315 male and female twin pairs participating in the age 17 assessment of the Minnesota Twin Family Study. Main Outcome Measures Multiple measures and informants were employed to construct a composite of EXT disorders and composite measures of 6 environmental risk factors including academic achievement and engagement, antisocial and prosocial peer affiliation, mother-child and father-child relationship problems, and stressful life events. Results A significant G × E interaction was detected between each environmental risk factor and EXT such that greater environmental adversity was associated with increased genetic risk in EXT. Conclusion Our findings demonstrate that in the context of environmental adversity, genetic factors become more important in the etiology of EXT disorders. The consistency of the results further suggests a general mechanism of environmental influence on EXT disorders regardless of the specific form of the environmental risk. PMID:19487629

  15. Assessment of the value of a genetic risk score in improving the estimation of coronary risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS ...

  16. Aquaculture: Incorporating risk assessment and risk management into public policies on genetically modified finfish and shellfish

    SciTech Connect

    Hallerman, E.M.; Kapuscinski, A.R.

    1995-12-31

    Genetically modified finfish and shellfish pose economic benefits to aquaculture, but also pose ecological and genetic risks to ecosystems receiving such organisms. Realization of benefits with minimization of risks posed by a new technology can be addressed through the processes of risk assessment and risk management. Public policies adopted by individual countries will reflect differences in the outocme of risk assessment and risk management processes resulting from differences among the receiving ecosystems and sets of human values at issue. A number of countries and international institutions have begun development of policies for oversight of genetically modified aquatic organisms. In the United States, a working group commissioned by the U.S. Department of Agriculture incorporated risk assessment and risk management principles into draft performance standards for safely conducting research with genetically modified finfish and shellfish. The performance standards address research with a broad range of aquatic GMO`s and compliance is intended to be voluntary. In contrast, the Canadian policy mandates adherence to specified guidelines for experiments with transgenic aquatic organisms; establishment as national policy is expended soon.

  17. Environmental risk assessment for medicinal products containing genetically modified organisms.

    PubMed

    Anliker, B; Longhurst, S; Buchholz, C J

    2010-01-01

    Many gene therapy medicinal products and also some vaccines consist of, or contain, genetically modified organisms (GMOs), which require specific consideration in the environmental risk assessment (ERA) before marketing authorisation or clinical trial applications. The ERA is performed in order to identify the potential risks for public health and the environment, which may arise due to the clinical use of these medicinal products. If such environmental risks are identified and considered as not acceptable, the ERA should go on to propose appropriate risk management strategies capable to reduce these risks. This article will provide an overview of the legal basis and requirements for the ERA of GMO-containing medicinal products in the context of marketing authorisation in the EU and clinical trials in Germany. Furthermore, the scientific principles and methodology that generally need to be followed when preparing an ERA for GMOs are discussed. PMID:19940966

  18. Shared Genetic Factors Influence Amygdala Volumes and Risk for Alcoholism

    PubMed Central

    Dager, Alecia D; McKay, D Reese; Kent, Jack W; Curran, Joanne E; Knowles, Emma; Sprooten, Emma; Göring, Harald HH; Dyer, Thomas D; Pearlson, Godfrey D; Olvera, Rene L; Fox, Peter T; Lovallo, William R; Duggirala, Ravi; Almasy, Laura; Blangero, John; Glahn, David C

    2015-01-01

    Alcohol abuse and dependence (alcohol use disorders, AUDs) are associated with brain shrinkage. Subcortical structures including the amygdala, hippocampus, ventral striatum, dorsal striatum, and thalamus subserve reward functioning and may be particularly vulnerable to alcohol-related damage. These structures may also show pre-existing deficits impacting the development and maintenance of AUD. It remains unclear whether there are common genetic features underlying both subcortical volumes and AUD. In this study, structural brain images were acquired from 872 Mexican-American individuals from extended pedigrees. Subcortical volumes were obtained using FreeSurfer, and quantitative genetic analyses were performed in SOLAR. We hypothesized the following: (1) reduced subcortical volumes in individuals with lifetime AUD relative to unrelated controls; (2) reduced subcortical volumes in individuals with current relative to past AUD; (3) in non-AUD individuals, reduced subcortical volumes in those with a family history of AUD compared to those without; and (4) evidence for common genetic underpinnings (pleiotropy) between AUD risk and subcortical volumes. Results showed that individuals with lifetime AUD showed larger ventricular and smaller amygdala volumes compared to non-AUD individuals. For the amygdala, there were no differences in volume between current vs past AUD, and non-AUD individuals with a family history of AUD demonstrated reductions compared to those with no such family history. Finally, amygdala volume was genetically correlated with the risk for AUD. Together, these results suggest that reduced amygdala volume reflects a pre-existing difference rather than alcohol-induced neurotoxic damage. Our genetic correlation analysis provides evidence for a common genetic factor underlying both reduced amygdala volumes and AUD risk. PMID:25079289

  19. Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand

    PubMed Central

    Miwa, Masanao; Honjo, Satoshi; You, Gyokukou; Tanaka, Masakazu; Uchida, Kazuhiko; Srivatanakul, Petcharin; Khuhaprema, Thiravud; Loilome, Watcharin; Techasen, Anchalee; Wongkham, Chaisiri; Limpaiboon, Temduang; Yongvanit, Puangrat; Wongkham, Sopit

    2014-01-01

    Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients’ lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA. PMID:25401000

  20. Assessing dietary patterns in Barbados highlights the need for nutritional intervention to reduce risk of chronic disease

    PubMed Central

    Sharma, S.; Cao, X.; Harris, R.; Hennis, A. J. M.; Wu, S.-Y.; Leske, M. C.

    2009-01-01

    Background The dietary habits of the Caribbean have been changing to include more fast foods and a less nutrient dense diet. The aims of this study are to examine dietary patterns in Barbados and highlight foods for a nutritional intervention. Methods Four-day food diaries collected from control participants in the population-based, case-control Barbados National Cancer Study (BNCS). Results Forty-nine adult participants (91% response) completed the diaries providing 191 days of dietary data. Total energy intake was almost identical to data collected 5-years earlier in the Barbados Food Consumption and Anthropometric Survey 2000, but the percent energy derived from fat was from 2.1% to 5.2% higher. Sugar intake exceeded the Caribbean recommendation almost four-fold, while intakes of calcium, iron (women only), zinc and dietary fibre were below recommendations. Fish and chicken dishes were the two largest sources of energy and fat. Sweetened drinks and juices provided over 40% of total sugar intake. Conclusions These data provide existing dietary patterns and strongly justify a nutritional intervention program to reduce dietary risk factors for chronic disease. The intervention could focus on the specific foods highlighted, both regarding frequency and amount of consumption. Effectiveness can be evaluated pre- and post-intervention using our Food Frequency Questionnaire developed for BNCS. PMID:18339055

  1. "Electro-clinical syndromes" with onset in paediatric age: the highlights of the clinical-EEG, genetic and therapeutic advances

    PubMed Central

    2011-01-01

    The genetic causes underlying epilepsy remain largely unknown, and the impact of available genetic data on the nosology of epilepsy is still limited. Thus, at present, classification of epileptic disorders should be mainly based on electroclinical features. Electro-clinical syndrome is a term used to identify a group of clinical entities showing a cluster of electro-clinical characteristics, with signs and symptoms that together define a distinctive, recognizable, clinical disorder. These often become the focus of treatment trials as well as of genetic, neuropsychological, and neuroimaging investigations. They are distinctive disorders identifiable on the basis of a typical age onset, specific EEG characteristics, seizure types, and often other features which, when taken together, permit a specific diagnosis which, in turn, often has implications for treatment, management, and prognosis. Each electro-clinical syndrome can be classified according to age at onset, cognitive and developmental antecedents and consequences, motor and sensory examinations, EEG features, provoking or triggering factors, and patterns of seizure occurrence with respect to sleep. Therefore, according to the age at onset, here we review the more frequently observed paediatric electro-clinical syndrome from their clinical-EEG, genetic and therapeutic point of views. PMID:22182677

  2. Increased genetic risk for obesity in premature coronary artery disease

    PubMed Central

    Cole, Christopher B; Nikpay, Majid; Stewart, Alexandre FR; McPherson, Ruth

    2016-01-01

    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. PMID:26220701

  3. Multi-locus genetic risk score predicts risk for Crohn’s disease in Slovenian population

    PubMed Central

    Zupančič, Katarina; Skok, Kristijan; Repnik, Katja; Weersma, Rinse K; Potočnik, Uroš; Skok, Pavel

    2016-01-01

    AIM: To develop a risk model for Crohn’s disease (CD) based on homogeneous population. METHODS: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study was performed for 112 single nucleotide polymorphisms (SNPs). We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC). For risk evaluation, we divided individuals according to positive and negative likelihood ratios (LR) of a test, with LR > 5 for high risk group and LR < 0.20 for low risk group. RESULTS: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. Individuals with the highest risk (GRS > 5.54) showed significantly increased odds of developing CD (OR = 26.65, 95%CI: 11.25-63.15) compared to the individuals with the lowest risk (GRS < 4.57) which is a considerably greater risk captured than in one SNP with the highest effect size (OR = 3.24). When more than 33 SNPs were included in GRS, discriminatory ability was not improved significantly; AUC of all 74 SNPs was 0.76. CONCLUSION: The authors proved the possibility of building accurate genetic risk score based on 33 risk variants on Slovenian CD patients which may serve as a screening tool in the targeted population. PMID:27076762

  4. Creating a genetic risk score for coronary artery disease.

    PubMed

    Dandona, Sonny; Roberts, Robert

    2009-05-01

    Coronary artery disease (CAD) and its sequelae represent a significant health burden. Over the past two decades, numerous studies have attempted to link DNA sequence variation with the risk of CAD and related phenotypes. There has been significant evolution in technology from the early linkage studies within kindreds, and now we are able to use high-density genotyping to facilitate large-scale genome-wide association studies. The first novel genetic risk factor for CAD, 9p21.3, has been confirmed, and other loci are awaiting replication studies. The relative importance of each locus from a global standpoint and the incremental information conferred by testing for genetic variants remain to be determined. PMID:19361348

  5. Genetic polymorphisms as a risk factor for dyslipidemia in children

    PubMed Central

    Santos, Izabela R.; Fernandes, Ana Paula; Sousa, Marinez O.; Ferreira, Cláudia N.; Gomes, Karina B.

    2013-01-01

    Dyslipidemia is an important etiological factor for development of cardiovascular disease, which is the leading cause of deaths in adults. Given the growing global epidemic of dyslipidemia, lipoprotein metabolism disorders have become an important health problem not only in adulthood, but have also emerged as an increasingly risk factor in childhood. Although several genome-wide association studies in multiple large population-based cohorts of adults and meta-analyses have identified susceptibility genes or loci, especially in lipid-related traits, it is of great importance to evaluate genetic predisposition at an early age. Recent findings suggest that the identification of polymorphisms in the metabolism of lipids in childhood may help fight subclinical atherosclerosis and its progression to cardiovascular complications in adulthood. Therefore, the aim of this study was to review genetic polymorphisms as risk factors associated with dyslipidemia in children and adolescents.

  6. Genetic risks and familial associations of small bowel carcinoma

    PubMed Central

    Shenoy, Santosh

    2016-01-01

    Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn’s disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases “small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease”. Figures, tables and schematic diagram to illustrate pathways are included in the review. PMID:27326320

  7. Genetic risks and familial associations of small bowel carcinoma.

    PubMed

    Shenoy, Santosh

    2016-06-15

    Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn's disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases "small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease". Figures, tables and schematic diagram to illustrate pathways are included in the review. PMID:27326320

  8. APOL1 Kidney Risk Alleles: Population Genetics and Disease Associations

    PubMed Central

    Limou, Sophie; Nelson, George W.; Kopp, Jeffrey B.; Winkler, Cheryl A.

    2014-01-01

    APOL1 kidney disease is a unique case in the field of the genetics of common disease: 2 variants (termed G1 and G2) with high population frequency have been repeatedly associated with nondiabetic CKDs, with very strong effect size (odds ratios 3–29) in populations of sub-Saharan African descent. This review provides an update on the spectrum of APOL1 kidney disease and on the worldwide distribution of these kidney risk variants. We also summarize the proper way to run a recessive analysis on joint and independent effects of APOL1 G1 and G2 kidney risk variants. PMID:25168832

  9. A Family-Centered Model for Sharing Genetic Risk.

    PubMed

    Daly, Mary B

    2015-01-01

    The successes of the Human Genome Project have ushered in a new era of genomic science. To effectively translate these discoveries, it will be critical to improve the communication of genetic risk within families. This will require a systematic approach that accounts for the nature of family relationships and sociocultural beliefs. This paper proposes the application of the Family Systems Illness Model, used in the setting of cancer care, to the evolving field of genomics. PMID:26479564

  10. Genetic Differentiation of the Western Capercaillie Highlights the Importance of South-Eastern Europe for Understanding the Species Phylogeography

    PubMed Central

    Ballian, Dalibor; Kunovac, Saša; Zubić, Goran; Grubešić, Marijan; Zhelev, Petar; Paule, Ladislav; Grebenc, Tine; Kraigher, Hojka

    2011-01-01

    The Western Capercaillie (Tetrao urogallus L.) is a grouse species of open boreal or high altitude forests of Eurasia. It is endangered throughout most mountain range habitat areas in Europe. Two major genetically identifiable lineages of Western Capercaillie have been described to date: the southern lineage at the species' southernmost range of distribution in Europe, and the boreal lineage. We address the question of genetic differentiation of capercaillie populations from the Rhodope and Rila Mountains in Bulgaria, across the Dinaric Mountains to the Slovenian Alps. The two lineages' contact zone and resulting conservation strategies in this so-far understudied area of distribution have not been previously determined. The results of analysis of mitochondrial DNA control region sequences of 319 samples from the studied populations show that Alpine populations were composed exclusively of boreal lineage; Dinaric populations of both, but predominantly (96%) of boreal lineage; and Rhodope-Rila populations predominantly (>90%) of southern lineage individuals. The Bulgarian mountains were identified as the core area of the southern lineage, and the Dinaric Mountains as the western contact zone between both lineages in the Balkans. Bulgarian populations appeared genetically distinct from Alpine and Dinaric populations and exhibited characteristics of a long-term stationary population, suggesting that they should be considered as a glacial relict and probably a distinct subspecies. Although all of the studied populations suffered a decline in the past, the significantly lower level of genetic diversity when compared with the neighbouring Alpine and Bulgarian populations suggests that the isolated Dinaric capercaillie is particularly vulnerable to continuing population decline. The results are discussed in the context of conservation of the species in the Balkans, its principal threats and legal protection status. Potential conservation strategies should consider the

  11. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

    PubMed Central

    Lucarelli, Marco; Bruno, Sabina Maria; Pierandrei, Silvia; Ferraguti, Giampiero; Stamato, Antonella; Narzi, Fabiana; Amato, Annalisa; Cimino, Giuseppe; Bertasi, Serenella; Quattrucci, Serena; Strom, Roberto

    2015-01-01

    Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype–phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype–phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype–phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway. PMID:25910067

  12. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

    PubMed Central

    Szatmari, Peter; Paterson, Andrew; Zwaigenbaum, Lonnie; Roberts, Wendy; Brian, Jessica; Liu, Xiao-Qing; Vincent, John; Skaug, Jennifer; Thompson, Ann; Senman, Lili; Feuk, Lars; Qian, Cheng; Bryson, Susan; Jones, Marshall; Marshall, Christian; Scherer, Stephen; Vieland, Veronica; Bartlett, Christopher; Mangin, La Vonne; Goedken, Rhinda; Segre, Alberto; Pericak-Vance, Margaret; Cuccaro, Michael; Gilbert, John; Wright, Harry; Abramson, Ruth; Betancur, Catalina; Bourgeron, Thomas; Gillberg, Christopher; Leboyer, Marion; Buxbaum, Joseph; Davis, Kenneth; Hollander, Eric; Silverman, Jeremy; Hallmayer, Joachim; Lotspeich, Linda; Sutcliffe, James; Haines, Jonathan; Folstein, Susan; Piven, Joseph; Wassink, Thomas; Sheffield, Val; Geschwind, Daniel; Bucan, Maja; Brown, Ted; Cantor, Rita; Constantino, John; Gilliam, Conrad; Herbert, Martha; Lajonchere, Clara; Ledbetter, David; Lese-Martin, Christa; Miller, Janet; Nelson, Stan; Samango-Sprouse, Carol; Spence, Sarah; State, Matthew; Tanzi, Rudolph; Coon, Hilary; Dawson, Geraldine; Devlin, Bernie; Estes, Annette; Flodman, Pamela; Klei, Lambertus; Mcmahon, William; Minshew, Nancy; Munson, Jeff; Korvatska, Elena; Rodier, Patricia; Schellenberg, Gerard; Smith, Moyra; Spence, Anne; Stodgell, Chris; Tepper, Ping Guo; Wijsman, Ellen; Yu, Chang-En; Rogé, Bernadette; Mantoulan, Carine; Wittemeyer, Kerstin; Poustka, Annemarie; Felder, Bärbel; Klauck, Sabine; Schuster, Claudia; Poustka, Fritz; Bölte, Sven; Feineis-Matthews, Sabine; Herbrecht, Evelyn; Schmötzer, Gabi; Tsiantis, John; Papanikolaou, Katerina; Maestrini, Elena; Bacchelli, Elena; Blasi, Francesca; Carone, Simona; Toma, Claudio; Van Engeland, Herman; De Jonge, Maretha; Kemner, Chantal; Koop, Frederieke; Langemeijer, Marjolein; Hijmans, Channa; Staal, Wouter; Baird, Gillian; Bolton, Patrick; Rutter, Michael; Weisblatt, Emma; Green, Jonathan; Aldred, Catherine; Wilkinson, Julie-Anne; Pickles, Andrew; Le Couteur, Ann; Berney, Tom; Mcconachie, Helen; Bailey, Anthony; Francis, Kostas; Honeyman, Gemma; Hutchinson, Aislinn; Parr, Jeremy; Wallace, Simon; Monaco, Anthony; Barnby, Gabrielle; Kobayashi, Kazuhiro; Lamb, Janine; Sousa, Ines; Sykes, Nuala; Cook, Edwin; Guter, Stephen; Leventhal, Bennett; Salt, Jeff; Lord, Catherine; Corsello, Christina; Hus, Vanessa; Weeks, Daniel; Volkmar, Fred; Tauber, Maïté; Fombonne, Eric; Shih, Andy; Meyer, Kacie

    2007-01-01

    Autism spectrum disorders (ASD) are common, heritable neurodevelopmental conditions. The genetic architecture of ASD is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASD by using Affymetrix 10K single nucleotide polymorphism (SNP) arrays and 1168 families with ≥ 2 affected individuals to perform the largest linkage scan to date, while also analyzing copy number variation (CNV) in these families. Linkage and CNV analyses implicate chromosome 11p12-p13 and neurexins, respectively, amongst other candidate loci. Neurexins team with previously-implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for ASD. PMID:17322880

  13. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk.

    PubMed

    Hu, Dong Gui; Mackenzie, Peter I; McKinnon, Ross A; Meech, Robyn

    2016-01-01

    Identification of genetic polymorphisms that contribute to the risk of developing cancers is important for cancer prevention. The most recent human genome GRCh38/hg38 assembly (2013) reveals thousands of genetic polymorphisms in human uridine diphosphoglucuronosyltransferase (UGT) genes. Among these, a large number of polymorphisms at the UGT1A and UGT2B genes have been shown to modulate UGT gene promoter activity or enzymatic activity. Glucuronidation plays an important role in the metabolism and clearance of endogenous and exogenous carcinogenic compounds, and this reaction is primarily catalyzed by the UGT1A and UGT2B enzymes. Therefore, it has long been hypothesized that UGT polymorphisms that reduce the capacity to glucuronidate carcinogens and other types of cancer-promoting molecules (e.g. sex hormones) are associated with an increased risk of developing cancers. A large number of case-control studies have investigated this hypothesis and these studies identified numerous UGT polymorphisms in UGT1A and UGT2B genes as genetic risk factors for a wide variety of cancers, including bladder, breast, colorectal, endometrial, esophageal, head and neck, liver, lung, prostate, and thyroid. These UGT polymorphisms may be cancer causative polymorphisms, or be linked to as yet undefined causative polymorphisms, either in UGT genes or neighboring genes. This article presents a comprehensive review of these case-control studies, discusses current areas of uncertainty, and highlights future research directions in this field. PMID:26828111

  14. Genetic risk factors and age-related macular degeneration (AMD)

    PubMed Central

    Mousavi, Maryam; Armstrong, Richard A.

    2013-01-01

    Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make lifestyle choices that may reduce the risk of disease. Collaboration between geneticists, ophthalmologists, and optometrists suggests that genetic risk factors play a more significant role in AMD than previously thought. The most important genes are associated with immune system modulation and the complement system, e.g., complement factor H (CFH), factor B (CFB), factor C3, and serpin peptidase inhibitor (SERPING1). Genes associated with membrane transport, e.g., ATP-binding cassette protein (ABCR) and voltage-dependent calcium channel gamma 3 (CACNG3), the vascular system, e.g., fibroblast growth factor 2 (FGF2), fibulin-5, lysyl oxidase-like gene (LOXL1) and selectin-P (SELP), and with lipid metabolism, e.g., apolipoprotein E (APOE) and hepatic lipase (LIPC) have also been implicated. In addition, several other genes exhibit some statistical association with AMD, e.g., age-related maculopathy susceptibility protein 2 (ARMS2) and DNA excision repair protein gene (ERCC6) but more research is needed to establish their significance. Modifiable risk factors for AMD should be discussed with patients whose lifestyle and/or family history place them in an increased risk category. Furthermore, calculation of AMD risk using current models should be recommended as a tool for patient education. It is likely that AMD management in future will be increasingly influenced by assessment of genetic risk as such screening methods become more widely available.

  15. Performance of an Adipokine Pathway-Based Multilocus Genetic Risk Score for Prostate Cancer Risk Prediction

    PubMed Central

    Ribeiro, Ricardo J. T.; Monteiro, Cátia P. D.; Azevedo, Andreia S. M.; Cunha, Virgínia F. M.; Ramanakumar, Agnihotram V.; Fraga, Avelino M.; Pina, Francisco M.; Lopes, Carlos M. S.; Medeiros, Rui M.; Franco, Eduardo L.

    2012-01-01

    Few biomarkers are available to predict prostate cancer risk. Single nucleotide polymorphisms (SNPs) tend to have weak individual effects but, in combination, they have stronger predictive value. Adipokine pathways have been implicated in the pathogenesis. We used a candidate pathway approach to investigate 29 functional SNPs in key genes from relevant adipokine pathways in a sample of 1006 men eligible for prostate biopsy. We used stepwise multivariate logistic regression and bootstrapping to develop a multilocus genetic risk score by weighting each risk SNP empirically based on its association with disease. Seven common functional polymorphisms were associated with overall and high-grade prostate cancer (Gleason≥7), whereas three variants were associated with high metastatic-risk prostate cancer (PSA≥20 ng/mL and/or Gleason≥8). The addition of genetic variants to age and PSA improved the predictive accuracy for overall and high-grade prostate cancer, using either the area under the receiver-operating characteristics curves (P<0.02), the net reclassification improvement (P<0.001) and integrated discrimination improvement (P<0.001) measures. These results suggest that functional polymorphisms in adipokine pathways may act individually and cumulatively to affect risk and severity of prostate cancer, supporting the influence of adipokine pathways in the pathogenesis of prostate cancer. Use of such adipokine multilocus genetic risk score can enhance the predictive value of PSA and age in estimating absolute risk, which supports further evaluation of its clinical significance. PMID:22792137

  16. Generalized and Specific Cognitive Performance in Clinical High-Risk Cohorts: A Review Highlighting Potential Vulnerability Markers for Psychosis

    PubMed Central

    Brewer, Warrick J.; Wood, Stephen J.; Phillips, Lisa J.; Francey, Shona M.; Pantelis, Christos; Yung, Alison R.; Cornblatt, Barbara; McGorry, Patrick D.

    2006-01-01

    Cognitive deficits are a core feature of established psychotic illnesses. However, the association between cognition and emerging psychosis is less understood. While there is some evidence that cognitive deficits are present prior to the onset of psychosis, findings are not consistent. In this article we provide an overview of the more general cognitive findings available from genetic high-risk studies, retrospective studies, and birth cohort studies. We then focus the review on neuropsychological performance in clinically “at-risk” groups. Overall, general cognitive ability as assessed by established batteries appears to remain relatively intact in these ultra-high risk cohorts and is a poor predictor close to illness onset relative to other vulnerability factors. Further decline may occur with illness progression, more consistent with state relative to trait factors. In addition, most established cognitive tasks involve several relatively discrete cognitive subprocesses, where findings from general batteries of subtests may mask specific deficits. In this context, our review suggests that relatively specific olfactory identification and spatial working memory deficits exist prior to illness onset and may be more potent trait markers for psychosis than cognitively dense tasks such as verbal memory. Suggestions for further research address the importance of standardization of inclusion criteria and the maintenance of basic neuropsychological assessment to allow better comparison of findings across centers. Further, in order to better understand the aetiopathology of cognitive dysfunction in psychosis, more experimental, hypothesis-driven measures of discrete cognitive processes are required. Delineation of the relationship between specific cognitive ability and symptoms from data-driven approaches may improve our understanding of the role of cognition during psychosis onset. PMID:16782759

  17. A comparison of genetic risk score with family history for estimating prostate cancer risk

    PubMed Central

    Helfand, Brian T

    2016-01-01

    Prostate cancer (PCa) testing is recommended by most authoritative groups for high-risk men including those with a family history of the disease. However, family history information is often limited by patient knowledge and clinician intake, and thus, many men are incorrectly assigned to different risk groups. Alternate methods to assess PCa risk are required. In this review, we discuss how genetic variants, referred to as PCa-risk single-nucleotide polymorphisms, can be used to calculate a genetic risk score (GRS). GRS assigns a relatively unique value to all men based on the number of PCa-risk SNPs that an individual carries. This GRS value can provide a more precise estimate of a man's PCa risk. This is particularly relevant in situations when an individual is unaware of his family history. In addition, GRS has utility and can provide a more precise estimate of risk even among men with a positive family history. It can even distinguish risk among relatives with the same degree of family relationships. Taken together, this review serves to provide support for the clinical utility of GRS as an independent test to provide supplemental information to family history. As such, GRS can serve as a platform to help guide-shared decision-making processes regarding the timing and frequency of PCa testing and biopsies. PMID:27004541

  18. Novel genetic predictors of venous thromboembolism risk in African Americans

    PubMed Central

    Hernandez, Wenndy; Gamazon, Eric R.; Smithberger, Erin; O’Brien, Travis J.; Harralson, Arthur F.; Tuck, Matthew; Barbour, April; Kittles, Rick A.; Cavallari, Larisa H.

    2016-01-01

    Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 578 subjects, followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals, we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P < 6 × 10−7). These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD), and the expression of THBD is lower among VTE cases compared with controls (P = 9.87 × 10−6). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants that increase the risk of VTE in AAs, a population disproportionately affected by this disease. PMID:26888256

  19. Convergent synaptic and circuit substrates underlying autism genetic risks

    PubMed Central

    McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

    2014-01-01

    There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development. PMID:24999357

  20. Association between OPN genetic variations and nephrolithiasis risk

    PubMed Central

    Xiao, Xu; Dong, Zhenjia; Ye, Xianqing; Yan, Yao; Chen, Xuehua; Pan, Qin; Xie, Yongfeng; Xie, Jie; Wang, Qiangdong; Yuan, Qinbo

    2016-01-01

    Osteopontin (OPN) has an important role in urolithiasis. However, few studies have explored the association between OPN genetic variants and urolithiasis risk. In the present study, three single-nucleotide polymorphisms (SNPs) (rs28357094, rs11439060 and rs11730582) located on the promoter of OPN were genotyped in a total of 480 individuals, including 230 nephrolithiasis patients and 250 matched healthy controls, and the associations between these SNPs and nephrolithiasis risk in different genetic models was assessed. No significant differences were identified in the genotype and allele frequencies of OPN rs28357094 or rs11730582 (P=0.805 for rs28357094; P=0.577 for rs11730582, respectively). However, carriers with the OPN rs11439060 insertion (ins) types (ins/deletion and ins/ins) were overrepresented in urolithiasis patients compared with the controls [odds ratio (OR), 1.55; 95% confidence interval (CI), 1.08–2.22]. In the stratified analysis, the increased risk was more evident among younger subjects (adjusted OR, 1.68; 95% CI, 1.01–2.81), females (2.15; 1.14–4.08), overweight subjects (1.80; 1.07–3.05), normotensive subjects (2.48; 1.02–6.00), abnormal blood sugar subjects (1.58; 1.08–2.30), smokers (1.63; 1.02–2.60), and ever-drinkers (1.98; 1.10–3.60).. These findings revealed that the OPN rs11439060 polymorphism may act as genetic biomarker for the detection of high-risk nephrolithiasis patients. PMID:27602211

  1. Psychosocial and ethical implications of defining genetic risk for cancers.

    PubMed

    Kash, K M

    1995-09-30

    In summary, we need to provide fully informed consent regarding the hazards and the benefits of genetic testing and defining risk. This reflects the first ethical principle of autonomy. It is the responsibility of the counseling team to make sure that the individual is psychologically equipped to deal with the emotional distress that may result from testing. An undue burden must not be placed on someone and harm must not be inflicted. This is the second ethical principle of beneficence. Third, awareness of the potential problems of testing is extremely important. These issues are those of disclosure, insurance problems, and employment problems--the third ethical principle of confidentiality. Recommendations for screening guidelines, regardless of testing results, should be provided. It is important for women who are not gene carriers to know that they still need to go for screening. Lastly, we need to find ways to help individuals cope with their risk status, whether it is actual high risk or perceived high risk. Helping women to develop positive coping strategies and to adhere to screening is extremely important. As the Huntington's data indicated, over time, regardless of their risk levels, individuals do learn how to cope and adapt with the outcome of testing. Women and men need to learn how to live with their risk status so that the negative psychological sequelae will be minimized. PMID:8526383

  2. Disclosing Pleiotropic Effects during Genetic Risk Assessment for Alzheimer’s Disease: A Randomized, Controlled Trial

    PubMed Central

    Christensen, Kurt D.; Roberts, J. Scott; Whitehouse, Peter J.; Royal, Charmaine D. M.; Obisesan, Thomas O.; Cupples, L. Adrienne; Vernarelli, Jacqueline A.; Bhatt, Deepak L.; Linnenbringer, Erin; Butson, Melissa B.; Fasaye, Grace-Ann; Uhlmann, Wendy R.; Hiraki, Susan; Wang, Na; Cook-Deegan, Robert; Green, Robert C.

    2016-01-01

    Background Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information. Objective To determine the safety and behavioral impact of disclosing modest associations between APOE genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer’s disease (AD). Design Randomized, multicenter equivalence clinical trial Setting Four teaching hospitals Participants 257 asymptomatic adults enrolled, 69% with one AD-affected first degree relative Intervention Disclosing AD and CAD genetic risk information (AD+CAD) versus disclosing only AD genetic risk (AD-only) Measurements Co-primary outcomes were Beck Anxiety Index (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes included test-related distress at 12 months, all measures at 6 weeks and 6 months, and health behavior changes at 12 months. Results 12 months after disclosure, mean BAI scores were 3.5 and 3.5 in AD-only and AD+CAD arms (Δ=0.0, 95%CI: −1.0 to 1.0), and mean CES-D scores were 6.4 and 7.1 in AD-only and AD+CAD arms (Δ=0.7, 95%CI: −1.0 to 2.4). Both confidence bounds fell within the equivalence margin of +/−5 points. Among ε4-positive participants, distress was lower in AD+CAD arms than AD-only arms (Δ=−4.8, 95%CI: −8.6 to −1.0) (p=0.031 for disclosure arm x APOE genotype). AD+CAD participants also reported more health behavior changes, regardless of APOE genotype. Limitations Outcomes were self-reported from volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomized participants. Conclusion Disclosing pleiotropic information did not increase anxiety or depression, and may have decreased distress among those at increased risk for two conditions. Providing risk modification information regarding CAD improved health behaviors. Findings highlight potential benefits of secondary genetic findings

  3. Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

    PubMed Central

    Smith, Shad B.; Maixner, Dylan; Greenspan, Joel; Dubner, Ron; Fillingim, Roger; Ohrbach, Richard; Knott, Charles; Slade, Gary; Bair, Eric; Gibson, Dustin G.; Zaykin, Dmitri V.; Weir, Bruce; Maixner, William; Diatchenko, Luda

    2011-01-01

    Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously-reported associations between TMD and two genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD and they identify potential targets for therapeutic intervention. PMID:22074755

  4. Benefits and risks associated with genetically modified food products.

    PubMed

    Kramkowska, Marta; Grzelak, Teresa; Czyżewska, Krystyna

    2013-01-01

    Scientists employing methods of genetic engineering have developed a new group of living organisms, termed 'modified organisms', which found application in, among others, medicine, the pharmaceutical industry and food distribution. The introduction of transgenic products to the food market resulted in them becoming a controversial topic, with their proponents and contestants. The presented study aims to systematize objective data on the potential benefits and risks resulting from the consumption of transgenic food. Genetic modifications of plants and animals are justified by the potential for improvement of the food situation worldwide, an increase in yield crops, an increase in the nutritional value of food, and the development of pharmaceutical preparations of proven clinical significance. In the opinions of critics, however, transgenic food may unfavourably affect the health of consumers. Therefore, particular attention was devoted to the short- and long-lasting undesirable effects, such as alimentary allergies, synthesis of toxic agents or resistance to antibiotics. Examples arguing for the justified character of genetic modifications and cases proving that their use can be dangerous are innumerable. In view of the presented facts, however, complex studies are indispensable which, in a reliable way, evaluate effects linked to the consumption of food produced with the application of genetic engineering techniques. Whether one backs up or negates transgenic products, the choice between traditional and non-conventional food remains to be decided exclusively by the consumers. PMID:24069841

  5. A developmental behavior-genetic perspective on alcoholism risk.

    PubMed

    Rose, R J

    1998-01-01

    Although behavioral problems associated with abuse of alcohol emerge during late adolescence and adulthood, some behavioral characteristics indicative of an increased risk of alcoholism may already be obvious during early childhood. Studies in several countries have demonstrated that children with high levels of novelty-seeking behavior and low levels of harm-avoidance behavior are more likely to develop alcohol-related problems during adolescence. Moreover, as early as age 3, children at high risk of future alcoholism because of a family history are more active, more impatient, and more aggressive than matched controls of low-risk children. Causal influences on the initiation of drinking must be distinguished from those that affect patterns of consumption once drinking is initiated. Studies of adolescent twins have demonstrated that initiation of drinking is primarily influenced by the drinking status of parents, siblings, and friends and by socioregional differences in the environments within which adolescent twins reside. The influence of genetic factors is negligible. Conversely, once initiated, differences in frequency and quantity of drinking are strongly influenced by genetic factors. However, these influences, too, are modulated by sibling and peer effects and by regional environmental variation. PMID:15706788

  6. Disparities and genetic risk factors in obstructive sleep apnea.

    PubMed

    Dudley, Katherine A; Patel, Sanjay R

    2016-02-01

    Obstructive sleep apnea (OSA) is an increasingly prevalent condition. A growing body of literature supports substantial racial disparities in the prevalence, risk factors, presentation, diagnosis, and treatment of this disease. Craniofacial structure among Asians appears to confer an elevated risk of OSA despite lower rates of obesity. Among African Americans, Native Americans, and Hispanics, OSA prevalence is increased, likely due in part to obesity. The burden of symptoms, particularly excessive daytime sleepiness, is higher among African Americans, although Hispanics more often report snoring. Limited data suggest that African Americans may be more susceptible to hypertension in the setting of OSA. While differences in genetic risk factors may explain disparities in OSA burden, no definitive genetic differences have yet been identified. In addition to disparities in OSA development, disparities in OSA diagnosis and treatment have also been identified. Increased severity of disease at diagnosis among African Americans suggests a delay in diagnosis. Treatment outcomes are also suboptimal among African Americans. In children, tonsillectomy is less likely to cure OSA and more commonly associated with complications in this group. Among adults, adherence to continuous positive airway pressure (CPAP) is substantially lower in African Americans. The reasons for these disparities, particularly in outcomes, are not well understood and should be a research priority. PMID:26428843

  7. Cancer Genetics Risk Assessment and Counseling (PDQ®)—Health Professional Version

    Cancer.gov

    Expert-reviewed information summary in which cancer risk perception, risk communication, and risk counseling are discussed. The summary also contains information about recording and analyzing a family history of cancer and factors to consider when offering genetic testing.

  8. Development and Evaluation of a Genetic Risk Score for Obesity

    PubMed Central

    Belsky, Daniel W.; Moffitt, Terrie E.; Sugden, Karen; Williams, Benjamin; Houts, Renate; McCarthy, Jeanette; Caspi, Avshalom

    2013-01-01

    Background Results from genome-wide association studies (GWAS) represent a potential resource for etiological and treatment research. GWAS of obesity-related phenotypes have been especially successful. To translate this success into a research tool, we developed and tested a “genetic risk score” (GRS) that summarizes an individual’s genetic predisposition to obesity. Methods Different GWAS of obesity-related phenotypes report different sets of single nucleotide polymorphisms (SNPs) as the best genomic markers of obesity risk. Therefore, we applied a 3-stage approach that pooled results from multiple GWAS to select SNPs to include in our GRS: The 3 stages are (1) Extraction. SNPs with evidence of association are compiled from published GWAS; (2) Clustering. SNPs are grouped according to patterns of linkage disequilibrium; (3) Selection. Tag SNPs are selected from clusters that meet specific criteria. We applied this 3-stage approach to results from 16 GWAS of obesity-related phenotypes in European-descent samples to create a GRS. We then tested the GRS in the Atherosclerosis Risk in the Communities (ARIC) Study cohort (N=10,745, 55% female, 77% white, 23% African American). Results Our 32-locus GRS was a statistically significant predictor of body mass index (BMI) and obesity among ARIC whites (for BMI, r=0.13, p<1×10−30; for obesity, area under the receiver operating characteristic curve (AUC)=0.57 [95% CI 0.55–0.58]). The GRS improved prediction of obesity (as measured by delta-AUC and integrated discrimination index) when added to models that included demographic and geographic information. FTO- and MC4R-linked SNPs, and a non-genetic risk assessment consisting of a socioeconomic index (p<0.01 for all comparisons). The GRS also predicted increased mortality risk over 17 years of follow-up. The GRS performed less well among African Americans. Conclusions The obesity GRS derived using our 3-stage approach is not useful for clinical risk prediction, but

  9. Class II HLA interactions modulate genetic risk for multiple sclerosis

    PubMed Central

    Dilthey, Alexander T; Xifara, Dionysia K; Ban, Maria; Shah, Tejas S; Patsopoulos, Nikolaos A; Alfredsson, Lars; Anderson, Carl A; Attfield, Katherine E; Baranzini, Sergio E; Barrett, Jeffrey; Binder, Thomas M C; Booth, David; Buck, Dorothea; Celius, Elisabeth G; Cotsapas, Chris; D’Alfonso, Sandra; Dendrou, Calliope A; Donnelly, Peter; Dubois, Bénédicte; Fontaine, Bertrand; Fugger, Lars; Goris, An; Gourraud, Pierre-Antoine; Graetz, Christiane; Hemmer, Bernhard; Hillert, Jan; Kockum, Ingrid; Leslie, Stephen; Lill, Christina M; Martinelli-Boneschi, Filippo; Oksenberg, Jorge R; Olsson, Tomas; Oturai, Annette; Saarela, Janna; Søndergaard, Helle Bach; Spurkland, Anne; Taylor, Bruce; Winkelmann, Juliane; Zipp, Frauke; Haines, Jonathan L; Pericak-Vance, Margaret A; Spencer, Chris C A; Stewart, Graeme; Hafler, David A; Ivinson, Adrian J; Harbo, Hanne F; Hauser, Stephen L; De Jager, Philip L; Compston, Alastair; McCauley, Jacob L; Sawcer, Stephen; McVean, Gil

    2016-01-01

    Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles. PMID:26343388

  10. Simplifying clinical use of the genetic risk prediction model BRCAPRO.

    PubMed

    Biswas, Swati; Atienza, Philamer; Chipman, Jonathan; Hughes, Kevin; Barrera, Angelica M Gutierrez; Amos, Christopher I; Arun, Banu; Parmigiani, Giovanni

    2013-06-01

    Health care providers need simple tools to identify patients at genetic risk of breast and ovarian cancers. Genetic risk prediction models such as BRCAPRO could fill this gap if incorporated into Electronic Medical Records or other Health Information Technology solutions. However, BRCAPRO requires potentially extensive information on the counselee and her family history. Thus, it may be useful to provide simplified version(s) of BRCAPRO for use in settings that do not require exhaustive genetic counseling. We explore four simplified versions of BRCAPRO, each using less complete information than the original model. BRCAPROLYTE uses information on affected relatives only up to second degree. It is in clinical use but has not been evaluated. BRCAPROLYTE-Plus extends BRCAPROLYTE by imputing the ages of unaffected relatives. BRCAPROLYTE-Simple reduces the data collection burden associated with BRCAPROLYTE and BRCAPROLYTE-Plus by not collecting the family structure. BRCAPRO-1Degree only uses first-degree affected relatives. We use data on 2,713 individuals from seven sites of the Cancer Genetics Network and MD Anderson Cancer Center to compare these simplified tools with the Family History Assessment Tool (FHAT) and BRCAPRO, with the latter serving as the benchmark. BRCAPROLYTE retains high discrimination; however, because it ignores information on unaffected relatives, it overestimates carrier probabilities. BRCAPROLYTE-Plus and BRCAPROLYTE-Simple provide better calibration than BRCAPROLYTE, so they have higher specificity for similar values of sensitivity. BRCAPROLYTE-Plus performs slightly better than BRCAPROLYTE-Simple. The Areas Under the ROC curve are 0.783 (BRCAPRO), 0.763 (BRCAPROLYTE), 0.772 (BRCAPROLYTE-Plus), 0.773 (BRCAPROLYTE-Simple), 0.728 (BRCAPRO-1Degree), and 0.745 (FHAT). The simpler versions, especially BRCAPROLYTE-Plus and BRCAPROLYTE-Simple, lead to only modest loss in overall discrimination compared to BRCAPRO in this dataset. Thus, we conclude that

  11. Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

    PubMed Central

    2014-01-01

    Introduction We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. Methods Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRSs). Results Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRSs. GRSs were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10−16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10−7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. Conclusion Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women. PMID:24946689

  12. [Epidemiology of schizophrenic disorders, genetic and environmental risk factors].

    PubMed

    Szoke, Andrei

    2013-03-01

    Schizophrenia is a relatively common pathology with onset at adolescence or early adulthood, more frequent in men than women. By describing distribution of cases in different populations and the factors that influence this distribution, epidemiology contributes to our understanding of the disease. Several risk factors for schizophrenia have been uncovered both genetic and environmental. The environmental factors can act at individual level (obstetric complications, season of birth, urbanicity, childhood trauma, cannabis, migration) or at population/area levels (socio-economic level, social fragmentation and social capital, ethnic density, etc.). An integrative and dynamic model based on the "vulnerability-persistence-impairment" paradigm is useful in integrating the findings about the risk factors and their complex relationships. PMID:23687754

  13. Risk assessment of genetically modified crops for nutrition and health.

    PubMed

    Magaña-Gómez, Javier A; de la Barca, Ana M Calderón

    2009-01-01

    The risk assessment of genetically modified (GM) crops for human nutrition and health has not been systematic. Evaluations for each GM crop or trait have been conducted using different feeding periods, animal models, and parameters. The most common result is that GM and conventional sources induce similar nutritional performance and growth in animals. However, adverse microscopic and molecular effects of some GM foods in different organs or tissues have been reported. Diversity among the methods and results of the risk assessments reflects the complexity of the subject. While there are currently no standardized methods to evaluate the safety of GM foods, attempts towards harmonization are on the way. More scientific effort is necessary in order to build confidence in the evaluation and acceptance of GM foods. PMID:19146501

  14. Structured Parenting of Toddlers at High versus Low Genetic Risk: Two Pathways to Child Problems

    ERIC Educational Resources Information Center

    Leve, Leslie D.; Harold, Gordon T.; Ge, Xiaojia; Neiderhiser, Jenae M.; Shaw, Daniel; Scaramella, Laura V.; Reiss, David

    2009-01-01

    Objective: Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for…

  15. Genetic Determinants of Cardio-Metabolic Risk: A Proposed Model for Phenotype Association and Interaction

    PubMed Central

    Blackett, Piers R; Sanghera, Dharambir K

    2012-01-01

    This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes and β cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus it follows that the genetics of dyslipidemia, obesity, and non-alcoholic fatty liver (NAFLD) disease are central in triggering progression of the syndrome to overt expression of disease traits, and have become a key focus of interest for early detection and for designing prevention and treatments. To support the “birds’ eye view” approach we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacological targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance. PMID:23351585

  16. Genetic risk variants in African Americans with multiple sclerosis

    PubMed Central

    Isobe, Noriko; Gourraud, Pierre-Antoine; Harbo, Hanne F.; Caillier, Stacy J.; Santaniello, Adam; Khankhanian, Pouya; Maiers, Martin; Spellman, Stephen; Cereb, Nezih; Yang, SooYoung; Pando, Marcelo J.; Piccio, Laura; Cross, Anne H.; De Jager, Philip L.; Cree, Bruce A.C.; Hauser, Stephen L.

    2013-01-01

    Objectives: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls). Methods: Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations. Results: The following major histocompatibility complex risk alleles were replicated: HLA-DRB1*15:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54–2.63], p = 2.50e-07), HLA-DRB1*03:01 (OR = 1.58 [1.29–1.94], p = 1.11e-05), as well as HLA-DRB1*04:05 (OR = 2.35 [1.26–4.37], p = 0.007) and the African-specific risk allele of HLA-DRB1*15:03 (OR = 1.26 [1.05–1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55–0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p < 0.01, outside the major histocompatibility complex region, 8 MS SNPs were also found to be associated with MS in African Americans. Conclusion: MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations. PMID:23771490

  17. Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

    PubMed

    Ukraintseva, Svetlana; Yashin, Anatoliy; Arbeev, Konstantin; Kulminski, Alexander; Akushevich, Igor; Wu, Deqing; Joshi, Gaurang; Land, Kenneth C; Stallard, Eric

    2016-02-01

    Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention. PMID:26306600

  18. Genetic instability in epithelial tissues at risk for cancer.

    PubMed

    Hittelman, W N

    2001-12-01

    Epithelial tumors develop through a multistep process driven by genomic instability frequently associated with etiologic agents such as prolonged tobacco smoke exposure or human papilloma virus (HPV) infection. The purpose of the studies reported here was to examine the nature of genomic instability in epithelial tissues at cancer risk in order to identify tissue genetic biomarkers that might be used to assess an individual's cancer risk and response to chemopreventive intervention. As part of several chemoprevention trials, biopsies were obtained from risk tissues (i.e., bronchial biopsies from chronic smokers, oral or laryngeal biopsies from individuals with premalignancy) and examined for chromosome instability using in situ hybridization. Nearly all biopsy specimens show evidence for chromosome instability throughout the exposed tissue. Increased chromosome instability was observed with histologic progression in the normal to tumor transition of head and neck squamous cell carcinomas. Chromosome instability was also seen in premalignant head and neck lesions, and high levels were associated with subsequent tumor development. In bronchial biopsies of current smokers, the level of ongoing chromosome instability correlated with smoking intensity (e.g., packs/day), whereas the chromosome index (average number of chromosome copies per cell) correlated with cumulative tobacco exposure (i.e., pack-years). Spatial chromosome analyses of the epithelium demonstrated multifocal clonal outgrowths. In former smokers, random chromosome instability was reduced; however, clonal populations appeared to persist for many years, perhaps accounting for continued lung cancer risk following smoking cessation. PMID:11795428

  19. Analysis of genetics and risk factors of Alzheimer's Disease.

    PubMed

    Panpalli Ates, M; Karaman, Y; Guntekin, S; Ergun, M A

    2016-06-14

    Alzheimer's Disease is the leading neurodegenerative cause of dementia. The pathogenesis is not clearly understood yet, is believed to be the complex interaction between genetic and environmental factors. Consequently vascular risk factors and Apolipoprotein E genotyping are increasingly gaining importance. This study aimed at assessing the relationships between Alzheimer's Disease and Apolipoprotein E phenotype and vascular risk factors. Patients diagnosed with "possible Alzheimer's Disease" in the Gazi University, Department of Neurology, were included in the study and age-matched volunteer patients who attended the polyclinic were included as a control group. In this study, the risk factors including low education level, smoking, hyperlipidemia, higher serum total cholesterol levels, and hyperhomocysteinemia were found to be statistically significantly more common in the Alzheimer's Disease group in comparison to the Control Group, while all Apolipoprotein E ε4/ε4 genotypes were found in the Alzheimer's Disease group. The presence of the Apolipoprotein E ε4 allele is believed to increase vascular risk factors as well as to affect Alzheimer's Disease directly. The biological indicators which are used in identifying the patients' genes will be probably used in the treatment plan of the patients in the future. PMID:27026590

  20. Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding

    PubMed Central

    Schott, B H; Assmann, A; Schmierer, P; Soch, J; Erk, S; Garbusow, M; Mohnke, S; Pöhland, L; Romanczuk-Seiferth, N; Barman, A; Wüstenberg, T; Haddad, L; Grimm, O; Witt, S; Richter, S; Klein, M; Schütze, H; Mühleisen, T W; Cichon, S; Rietschel, M; Noethen, M M; Tost, H; Gundelfinger, E D; Düzel, E; Heinz, A; Meyer-Lindenberg, A; Seidenbecher, C I; Walter, H

    2014-01-01

    Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the ‘missing heritability' of complex phenotypes. PMID:24643163

  1. What risk assessments of genetically modified organisms can learn from institutional analyses of public health risks.

    PubMed

    Rajan, S Ravi; Letourneau, Deborah K

    2012-01-01

    The risks of genetically modified organisms (GMOs) are evaluated traditionally by combining hazard identification and exposure estimates to provide decision support for regulatory agencies. We question the utility of the classical risk paradigm and discuss its evolution in GMO risk assessment. First, we consider the problem of uncertainty, by comparing risk assessment for environmental toxins in the public health domain with genetically modified organisms in the environment; we use the specific comparison of an insecticide to a transgenic, insecticidal food crop. Next, we examine normal accident theory (NAT) as a heuristic to consider runaway effects of GMOs, such as negative community level consequences of gene flow from transgenic, insecticidal crops. These examples illustrate how risk assessments are made more complex and contentious by both their inherent uncertainty and the inevitability of failure beyond expectation in complex systems. We emphasize the value of conducting decision-support research, embracing uncertainty, increasing transparency, and building interdisciplinary institutions that can address the complex interactions between ecosystems and society. In particular, we argue against black boxing risk analysis, and for a program to educate policy makers about uncertainty and complexity, so that eventually, decision making is not the burden that falls upon scientists but is assumed by the public at large. PMID:23193357

  2. What Risk Assessments of Genetically Modified Organisms Can Learn from Institutional Analyses of Public Health Risks

    PubMed Central

    Rajan, S. Ravi; Letourneau, Deborah K.

    2012-01-01

    The risks of genetically modified organisms (GMOs) are evaluated traditionally by combining hazard identification and exposure estimates to provide decision support for regulatory agencies. We question the utility of the classical risk paradigm and discuss its evolution in GMO risk assessment. First, we consider the problem of uncertainty, by comparing risk assessment for environmental toxins in the public health domain with genetically modified organisms in the environment; we use the specific comparison of an insecticide to a transgenic, insecticidal food crop. Next, we examine normal accident theory (NAT) as a heuristic to consider runaway effects of GMOs, such as negative community level consequences of gene flow from transgenic, insecticidal crops. These examples illustrate how risk assessments are made more complex and contentious by both their inherent uncertainty and the inevitability of failure beyond expectation in complex systems. We emphasize the value of conducting decision-support research, embracing uncertainty, increasing transparency, and building interdisciplinary institutions that can address the complex interactions between ecosystems and society. In particular, we argue against black boxing risk analysis, and for a program to educate policy makers about uncertainty and complexity, so that eventually, decision making is not the burden that falls upon scientists but is assumed by the public at large. PMID:23193357

  3. Genetic variation modifies risk for neurodegeneration based on biomarker status

    PubMed Central

    Hohman, Timothy J.; Koran, Mary Ellen I.; Thornton-Wells, Tricia A.

    2014-01-01

    Background: While a great deal of work has gone into understanding the relationship between Cerebrospinal fluid (CSF) biomarkers, brain atrophy, and disease progression, less work has attempted to investigate how genetic variation modifies these relationships. The goal of this study was two-fold. First, we sought to identify high-risk vs. low-risk individuals based on their CSF tau and Aβ load and characterize these individuals with regard to brain atrophy in an AD-relevant region of interest. Next, we sought to identify genetic variants that modified the relationship between biomarker classification and neurodegeneration. Methods: Participants were categorized based on established cut-points for biomarker positivity. Mixed model regression was used to quantify longitudinal change in the left inferior lateral ventricle. Interaction analyses between single nucleotide polymorphisms (SNPs) and biomarker group status were performed using a genome wide association study (GWAS) approach. Correction for multiple comparisons was performed using the Bonferroni procedure. Results: One intergenic SNP (rs4866650) and one SNP within the SPTLC1 gene (rs7849530) modified the association between amyloid positivity and neurodegeneration. A transcript variant of WDR11-AS1 gene (rs12261764) modified the association between tau positivity and neurodegeneration. These effects were consistent across the two sub-datasets and explained approximately 3% of variance in ventricular dilation. One additional SNP (rs6887649) modified the association between amyloid positivity and baseline ventricular volume, but was not observed consistently across the sub-datasets. Conclusions: Genetic variation modifies the association between AD biomarkers and neurodegeneration. Genes that regulate the molecular response in the brain to oxidative stress may be particularly relevant to neural vulnerability to the damaging effects of amyloid-β. PMID:25140149

  4. Genetic scores based on risk-associated single nucleotide polymorphisms (SNPs) can reveal inherited risk of renal cell carcinoma

    PubMed Central

    Chen, Haitao; Lin, Xiaolin; Yu, Yang; Gou, Yuancheng; Hou, Jiangang; Jiang, Deke; Na, Rong; Wang, Xiang; Ding, Qiang; Xu, Jianfeng

    2016-01-01

    The objective of this study was to evaluate whether renal cell carcinoma (RCC) risk-associated single nucleotide polymorphisms (SNPs) could reflect the individual inherited risks of RCC. A total of 346 RCC patients and 1,130 controls were recruited in this case-control study. Genetic scores were calculated for each individual based on the odds ratios and frequencies of risk-associated SNPs. Four SNPs were significantly associated with RCC in Chinese population. Two genetic score models were established, genetic score 1 (rs10054504, rs7023329 and rs718314) and genetic score 2 (rs10054504, rs7023329 and rs1049380). For genetic score 1, the individual likelihood of RCC with low (<0.8), medium (0.8-1.2) and high (≥1.2) genetic score 1 was 15.61%, 22.25% and 33.92% respectively (P-trend=6.88×10−7). For genetic score 2, individual with low (<0.8), medium (0.8-1.2) and high (≥1.2) genetic score 2 would have likelihood of RCC as 14.39%, 24.54% and 36.48%, respectively (P-trend=1.27×10−10). The area under the receiver operating curve (AUC) of genetic score 1 was 0.626, and AUC of genetic score 2 was 0.658. We concluded that genetic score can reveal personal risk and inherited risk of RCC, especially when family history is not available. PMID:27229762

  5. Fine-mapping in the MHC region accounts for 18% additional genetic risk for celiac disease

    PubMed Central

    Gutierrez-Achury, Javier; Zhernakova, Alexandra; Pulit, Sara L.; Trynka, Gosia; Hunt, Karen A.; Romanos, Jihane; Raychaudhuri, Soumya; van Heel, David A.; Wijmenga, Cisca; de Bakker, Paul I.W.

    2015-01-01

    Although dietary gluten is the trigger, 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-DQ alleles and observed five novel associations that account for 18% of the genetic risk. Together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability. PMID:25894500

  6. Genetic risk prediction and neurobiological understanding of alcoholism.

    PubMed

    Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; Kiefer, F; Kiefe, F; Wodarz, N; Müller-Myhsok, B; Dahmen, N; Nöthen, M; Sherva, R; Farrer, L; Smith, A H; Kranzler, H R; Rietschel, M; Gelernter, J; Niculescu, A B

    2014-01-01

    We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress

  7. Research Highlights

    ERIC Educational Resources Information Center

    Australian Council for Educational Research, 2004

    2004-01-01

    This document is an annual publication documenting developments in the Australian Council for Educational Research (ACER)'s research programs for the previous year. The 2004 edition highlights research on the following themes: (1) Helping international schools measure achievement; (2) Evaluating Australian teachers; (3) Tests of reading…

  8. NEURAL PLASTICITY, HUMAN GENETICS, AND RISK FOR ALCOHOL DEPENDENCE

    PubMed Central

    Hill, Shirley Y.

    2013-01-01

    Opportunities for advances in the neurobiology of alcohol dependence have been facilitated by the development of sophisticated neurophysiological and neuroimaging techniques that allow us to have a window on developmental changes in brain structure and function. The search for genes that may increase susceptibility to alcohol dependence has been greatly facilitated by the recognition that intermediate phenotypes, sometimes referred to as endophenotypes. may be closer to the genetic variation than is the more complex alcohol dependence phenotype. This chapter will review the evidence that the brain is highly plastic, exhibiting major postnatal changes, especially during adolescence, in neural circuits that appear to influence addiction susceptibility. This chapter will suggest that heritable aspects of brain structure and function that are seen developmentally may be an important endophenotypic characteristic associated with familial risk for developing alcohol dependence. Finally, a review of studies showing associations between brain structural and functional characteristics and specific genes will be offered. PMID:20813240

  9. Preimplantation genetic diagnosis and rational choice under risk or uncertainty.

    PubMed

    Zuradzki, Tomasz

    2014-11-01

    In this paper I present an argument in favour of a parental duty to use preimplantation genetic diagnosis (PGD). I argue that if embryos created in vitro were able to decide for themselves in a rational manner, they would sometimes choose PGD as a method of selection. Couples, therefore, should respect their hypothetical choices on a principle similar to that of patient autonomy. My thesis shows that no matter which moral doctrine couples subscribe to, they ought to conduct the PGD procedure in the situations when it is impossible to implant all of the created embryos and if there is a significant risk for giving birth to a child with a serious condition. PMID:24835332

  10. Most genetic risk for autism resides with common variation

    PubMed Central

    Gaugler, Trent; Klei, Lambertus; Sanders, Stephan J.; Bodea, Corneliu A.; Goldberg, Arthur P.; Lee, Ann B.; Mahajan, Milind; Manaa, Dina; Pawitan, Yudi; Reichert, Jennifer; Ripke, Stephan; Sandin, Sven; Sklar, Pamela; Svantesson, Oscar; Reichenberg, Abraham; Hultman, Christina M.; Devlin, Bernie

    2014-01-01

    A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (henceforth autism) the nature of its allelic spectrum is uncertain. Individual risk genes have been identified from rare variation, especially de novo mutations1–8. From this evidence one might conclude that rare variation dominates its allelic spectrum, yet recent studies show that common variation, individually of small effect, has substantial impact en masse9,10. At issue is how much of an impact relative to rare variation. Using a unique epidemiological sample from Sweden, novel methods that distinguish total narrow-sense heritability from that due to common variation, and by synthesizing results from other studies, we reach several conclusions about autism’s genetic architecture: its narrow-sense heritability is ≈54% and most traces to common variation; rare de novo mutations contribute substantially to individuals’ liability; still their contribution to variance in liability, 2.6%, is modest compared to heritable variation. PMID:25038753

  11. Most genetic risk for autism resides with common variation.

    PubMed

    Gaugler, Trent; Klei, Lambertus; Sanders, Stephan J; Bodea, Corneliu A; Goldberg, Arthur P; Lee, Ann B; Mahajan, Milind; Manaa, Dina; Pawitan, Yudi; Reichert, Jennifer; Ripke, Stephan; Sandin, Sven; Sklar, Pamela; Svantesson, Oscar; Reichenberg, Abraham; Hultman, Christina M; Devlin, Bernie; Roeder, Kathryn; Buxbaum, Joseph D

    2014-08-01

    A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation. PMID:25038753

  12. Genetic risk factors of cisplatin induced ototoxicity in adult patients.

    PubMed

    Talach, T; Rottenberg, J; Gal, B; Kostrica, R; Jurajda, M; Kocak, I; Lakomy, R; Vogazianos, E

    2016-01-01

    Ototoxicity is an important adverse effect of using Cisplatin (cis-diamminedichloroplatinum) (CDDP) as a form of chemotherapy. The clinical picture of CDDP induced ototoxicity includes perceptive hearing impairment (reversible or permanent) and tinnitus. Ototoxicity manifests with considerable variability between patients. The objective of this prospective study was to investigate a possible genetic background to this variability. We assessed ototoxicity induced by therapeutic doses of CDDP in adult patients with germinative testicular tumors, or other tumors treated with an identical CDDP dosage scheme. Audiological examination before, during and after the treatment has shown deterioration in hearing; first in the high-frequencies and with increased CDDP cumulative doses, impairment in other frequencies as well. Occurrence of tinnitus was not dependent on the administered dose of CDDP, or the other risk factors examined in this study. The association of CDDP induced ototoxicity with genetic polymorphisms in candidate genes was examined. Our study has demonstrated an association of early onset of CDDP induced ototoxicity with the presence of two copies of GSTT1 gene (p=0,009) and with T allele of rs9332377 polymorphism in COMT gene (p=0,001). PMID:26774148

  13. Genetic risk profiles for cancer susceptibility and therapy response.

    PubMed

    Bartsch, Helmut; Dally, Heike; Popanda, Odilia; Risch, Angela; Schmezer, Peter

    2007-01-01

    Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored therapy regimens. Some of our attempts to define such risk profiles are presented. Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based lung cancer case-control study. When evaluating the risk associated with different genotypes for N-acetyltransferases (Wikman et al. 2001) and glutathione-S-transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung tumors. A promoter polymorphism of the myeloperoxidase gene MPO was shown to decrease lung cancer susceptibility mainly in small cell lung cancer (SCLC) (Dally et al. 2002). The CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004). Therapy response: Inter-individual differences in therapy response are consistently observed with cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of lung cancer. Stronger

  14. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis

    PubMed Central

    Obici, Laura; Kuks, Jan B.; Buades, Juan; Adams, David; Suhr, Ole B.; Coelho, Teresa; Kyriakides, Theodore

    2016-01-01

    Purpose of review These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene. Recent findings The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP. Summary Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP. PMID:26734953

  15. Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis

    PubMed Central

    Haller, Gabe; Alvarado, David M.; Willing, Marcia C.; Braverman, Alan C.; Bridwell, Keith H.; Kelly, Michael; Lenke, Lawrence G.; Luhmann, Scott J.; Gurnett, Christina A.; Dobbs, Matthew B.

    2015-01-01

    Background: Scoliosis is a feature of several genetic disorders that are also associated with aortic aneurysm, including Marfan syndrome, Loeys-Dietz syndrome, and type-IV Ehlers-Danlos syndrome. Life-threatening complications of aortic aneurysm can be decreased through early diagnosis. Genetic screening for mutations in populations at risk, such as patients with adolescent idiopathic scoliosis, may improve recognition of these disorders. Methods: The coding regions of five clinically actionable genes associated with scoliosis (COL3A1, FBN1, TGFBR1, TGFBR2, and SMAD3) and aortic aneurysm were sequenced in 343 adolescent idiopathic scoliosis cases. Gene variants that had minor allele frequencies of <0.0001 or were present in human disease mutation databases were identified. Variants were classified as pathogenic, likely pathogenic, or variants of unknown significance. Results: Pathogenic or likely pathogenic mutations were identified in 0.9% (three) of 343 adolescent idiopathic scoliosis cases. Two patients had pathogenic SMAD3 nonsense mutations consistent with type-III Loeys-Dietz syndrome and one patient had a pathogenic FBN1 mutation with subsequent confirmation of Marfan syndrome. Variants of unknown significance in COL3A1 and FBN1 were identified in 5.0% (seventeen) of 343 adolescent idiopathic scoliosis cases. Six FBN1 variants were previously reported in patients with Marfan syndrome, yet were considered variants of unknown significance based on the level of evidence. Variants of unknown significance occurred most frequently in FBN1 and were associated with greater curve severity, systemic features of Marfan syndrome, and joint hypermobility. Conclusions: Clinically actionable pathogenic mutations in genes associated with adolescent idiopathic scoliosis and aortic aneurysm are rare in patients with adolescent idiopathic scoliosis who are not suspected of having these disorders, although variants of unknown significance are relatively common. Clinical

  16. Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015.

    PubMed

    Daly, Mary B; Pilarski, Robert; Axilbund, Jennifer E; Berry, Michael; Buys, Saundra S; Crawford, Beth; Farmer, Meagan; Friedman, Susan; Garber, Judy E; Khan, Seema; Klein, Catherine; Kohlmann, Wendy; Kurian, Allison; Litton, Jennifer K; Madlensky, Lisa; Marcom, P Kelly; Merajver, Sofia D; Offit, Kenneth; Pal, Tuya; Rana, Huma; Reiser, Gwen; Robson, Mark E; Shannon, Kristen Mahoney; Swisher, Elizabeth; Voian, Nicoleta C; Weitzel, Jeffrey N; Whelan, Alison; Wick, Myra J; Wiesner, Georgia L; Dwyer, Mary; Kumar, Rashmi; Darlow, Susan

    2016-02-01

    The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer. PMID:26850485

  17. Tutorial dialogues and gist explanations of genetic breast cancer risk.

    PubMed

    Widmer, Colin L; Wolfe, Christopher R; Reyna, Valerie F; Cedillos-Whynott, Elizabeth M; Brust-Renck, Priscila G; Weil, Audrey M

    2015-09-01

    The intelligent tutoring system (ITS) BRCA Gist is a Web-based tutor developed using the Shareable Knowledge Objects (SKO) platform that uses latent semantic analysis to engage women in natural-language dialogues to teach about breast cancer risk. BRCA Gist appears to be the first ITS designed to assist patients' health decision making. Two studies provide fine-grained analyses of the verbal interactions between BRCA Gist and women responding to five questions pertaining to breast cancer and genetic risk. We examined how "gist explanations" generated by participants during natural-language dialogues related to outcomes. Using reliable rubrics, scripts of the participants' verbal interactions with BRCA Gist were rated for content and for the appropriateness of the tutor's responses. Human researchers' scores for the content covered by the participants were strongly correlated with the coverage scores generated by BRCA Gist, indicating that BRCA Gist accurately assesses the extent to which people respond appropriately. In Study 1, participants' performance during the dialogues was consistently associated with learning outcomes about breast cancer risk. Study 2 was a field study with a more diverse population. Participants with an undergraduate degree or less education who were randomly assigned to BRCA Gist scored higher on tests of knowledge than those assigned to the National Cancer Institute website or than a control group. We replicated findings that the more expected content that participants included in their gist explanations, the better they performed on outcome measures. As fuzzy-trace theory suggests, encouraging people to develop and elaborate upon gist explanations appears to improve learning, comprehension, and decision making. PMID:25921818

  18. Genetic factors influencing the risk of multiple myeloma bone disease

    PubMed Central

    Johnson, D C; Weinhold, N; Mitchell, J; Chen, B; Stephens, O W; Försti, A; Nickel, J; Kaiser, M; Gregory, W A; Cairns, D; Jackson, G H; Hoffmann, P; Noethen, M M; Hillengass, J; Bertsch, U; Barlogie, B; Davis, F E; Hemminki, K; Goldschmidt, H; Houlston, R S; Morgan, G J

    2016-01-01

    A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10–9) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10–7). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM. PMID:26669972

  19. Peer Smoking and the Nicotinic Receptor Genes: An Examination of Genetic and Environmental Risks for Nicotine Dependence

    PubMed Central

    Johnson, Eric O.; Chen, Li-Shiun; Breslau, Naomi; Hatsukami, Dorothy; Robbins, Tania; Saccone, Nancy L.; Grucza, Richard A.; Bierut, Laura J.

    2010-01-01

    Background Peer smoking provides a socially reinforcing context of friends’ encouragement and approval that contributes to smoking behavior. Twin studies show correlations and interactions between peer substance use and genetic liability for substance use. However, none examined specific genes. Here we test the hypothesis that the nicotinic receptor genes CHRNA5 (rs16969968), CHRNA3 (rs578776), CHRNB3 (rs13277254), and CHRND (rs12466358) modify the risk for nicotine dependence (ND) associated with peer smoking. Methods Cases of current nicotine dependence (FTND ≥ 4) and smoking-exposed (smoked 100+ cigarettes lifetime), but non-dependent controls (lifetime FTND = 0) came from the Collaborative Genetic Study of Nicotine Dependence (n=2,038). Peer smoking was retrospectively assessed for grades 9–12. Results Peer smoking and the four SNPs were associated with ND. A statistically significant interaction was found between peer smoking and rs16969968 (p = 0.0077). Overall risk of ND was highest for the rs16969968 AA genotype. However, variance in ND attributable to peer smoking was substantially lower among those with the AA genotype at rs16969968 than the lower risk genotypes: AA = 2.5%, GA/AG = 11.2%, GG = 14.2%; p ≤ 0.004. Conclusions Peer smoking had a substantially lower effect on ND among those with the high risk AA genotype at the functional SNP rs16969968 (CHRNA5) than among those with lower risk genotypes. Such results highlight the possibility that given drug exposure those with specific genetic risks may be less affected by social contexts and intervention strategies focused on social factors could have less influence on those at highest genetic risk. PMID:20840187

  20. Environmental and genetic risk factors for eating disorders: What the clinician needs to know

    PubMed Central

    Mazzeo, Suzanne E.; Bulik, Cynthia M.

    2008-01-01

    Synopsis Patients and families are often aware of research on genetic factors influencing eating disorders. Accurate interpretations of research on environmental and genetic risk factors can be empowering to patients and families; however, misinterpretations could prove detrimental. The clinician who is not versed in genetic research may feel ill-prepared to discuss the nuances of genetic research with patients and families. In this paper the authors discuss what is known about genetic and environmental risk factors with an emphasis on gene-environment interplay in order to increase clinicians’ comfort level with discussing these complex issues with their patients. PMID:19014858

  1. Genetic Risk by Experience Interaction for Childhood Internalizing Problems: Converging Evidence across Multiple Methods

    ERIC Educational Resources Information Center

    Vendlinski, Matthew K.; Lemery-Chalfant, Kathryn; Essex, Marilyn J.; Goldsmith, H. Hill

    2011-01-01

    Background: Identifying how genetic risk interacts with experience to predict psychopathology is an important step toward understanding the etiology of mental health problems. Few studies have examined genetic risk by experience interaction (GxE) in the development of childhood psychopathology. Methods: We used both co-twin and parent mental…

  2. Genetic epidemiology of cardiometabolic risk ractors and their clustering patterns in Mexican American children and adolescents: The SAFARI Study

    PubMed Central

    Fowler, Sharon P.; Puppala, Sobha; Arya, Rector; Chittoor, Geetha; Farook, Vidya S.; Schneider, Jennifer; Resendez, Roy G.; Upadhayay, Ram Prasad; VandeBerg, Jane; Hunt, Kelly J.; Bradshaw, Benjamin; Cersosimo, Eugenio; VandeBerg, John L.; Almasy, Laura; Curran, Joanne E.; Comuzzie, Anthony G.; Lehman, Donna M.; Jenkinson, Christopher P.; Lynch, Jane L.; DeFronzo, Ralph A.; Blangero, John; Hale, Daniel E.; Duggirala, Ravindranath

    2013-01-01

    Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6–17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth (SAFARI) study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, Texas, at increased risk of type 2 diabetes. MS was defined as ≥ 3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population. PMID:23736306

  3. Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings

    PubMed Central

    Sariaslan, A; Larsson, H; Fazel, S

    2016-01-01

    Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8–10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h2=53–71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30–0.33) than bipolar disorder (r=0.23; 0.21–0.25), and large proportions (51–67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21% 20–22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disorder<0.001; Pschizophrenia=0.55). These findings highlight the problems of not disentangling common and unique sources of covariance across genetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and

  4. Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings.

    PubMed

    Sariaslan, A; Larsson, H; Fazel, S

    2016-09-01

    Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8-10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h(2)=53-71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30-0.33) than bipolar disorder (r=0.23; 0.21-0.25), and large proportions (51-67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21%; 20-22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disorder<0.001; Pschizophrenia=0.55). These findings highlight the problems of not disentangling common and unique sources of covariance across genetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and violence

  5. Preferences for Genetic and Behavioral Health Information: The Impact of Risk Factors and Disease Attributions

    PubMed Central

    O'Neill, Suzanne C.; McBride, Colleen M.; Alford, Sharon Hensley; Kaphingst, Kimberly A.

    2012-01-01

    Background Increased availability of genetic risk information may lead the public to give precedence to genetic causation over behavioral/environmental factors, decreasing behavior change motivation. Few population-based data inform these concerns. Purpose We assess the association of family history, behavioral risks, and causal attributions for diseases and the perceived value of pursuing information emphasizing health habits or genes. Method 1959 healthy adults completed a survey that assessed behavioral risk factors, family history, causal attributions of eight diseases, and health information preferences. Results Participants’ causal beliefs favored health behaviors over genetics. Interest in behavioral information was higher than in genetic information. As behavioral risk factors increased, inclination toward genetic explanations increased; interest in how health habits affect disease risk decreased. Conclusions Those at greatest need for behavior change may hold attributions that diminish interest in behavior change information. Enhancing understanding of gene-environment influences could be explored to increase engagement with health information. PMID:20532842

  6. Fractal and Transgenerational Genetic Effects on Phenotypic Variation and Disease Risk

    NASA Astrophysics Data System (ADS)

    Nadeau, Joe

    To understand human biology and to manage heritable diseases, a complete picture of the genetic basis for phenotypic variation and disease risk is needed. Unexpectedly however, most of these genetic variants, even for highly heritable traits, continue to elude discovery for poorly understood reasons. The genetics community is actively exploring the usual explanations for missing heritability. But given the extraordinary work that has already been done and the exceptional magnitude of the problem, it seems likely that unconventional genetic properties are involved.

  7. Facial emotion perception differs in young persons at genetic and clinical high-risk for psychosis.

    PubMed

    Kohler, Christian G; Richard, Jan A; Brensinger, Colleen M; Borgmann-Winter, Karin E; Conroy, Catherine G; Moberg, Paul J; Gur, Ruben C; Gur, Raquel E; Calkins, Monica E

    2014-05-15

    A large body of literature has documented facial emotion perception impairments in schizophrenia. More recently, emotion perception has been investigated in persons at genetic and clinical high-risk for psychosis. This study compared emotion perception abilities in groups of young persons with schizophrenia, clinical high-risk, genetic risk and healthy controls. Groups, ages 13-25, included 24 persons at clinical high-risk, 52 first-degree relatives at genetic risk, 91 persons with schizophrenia and 90 low risk persons who completed computerized testing of emotion recognition and differentiation. Groups differed by overall emotion recognition abilities and recognition of happy, sad, anger and fear expressions. Pairwise comparisons revealed comparable impairments in recognition of happy, angry, and fearful expressions for persons at clinical high-risk and schizophrenia, while genetic risk participants were less impaired, showing reduced recognition of fearful expressions. Groups also differed for differentiation of happy and sad expressions, but differences were mainly between schizophrenia and control groups. Emotion perception impairments are observable in young persons at-risk for psychosis. Preliminary results with clinical high-risk participants, when considered along findings in genetic risk relatives, suggest social cognition abilities to reflect pathophysiological processes involved in risk of schizophrenia. PMID:24582775

  8. Genetically at-risk status and individual agency. A qualitative study on asymptomatic women living with genetic risk of breast/ovarian cancer.

    PubMed

    Caiata-Zufferey, Maria

    2015-05-01

    For the last 20 years, genetic tests have allowed unaffected women to determine whether they are predisposed to developing breast/ovarian cancer due to BRCA1/2 gene mutations. In the event of adverse results, women receive a specific label associated with a set of medical recommendations: the genetically at-risk status. This qualitative study adopted a life-course perspective to understand the impact of this status on women's agency. Following a grounded theory design, retrospective biographical interviews were conducted in Switzerland between 2011 and 2013 with 32 unaffected women at risk of developing genetic breast/ovarian cancer and aware of their predisposition for at least three years. The results show that the genetically at-risk status conveys an invitation to transform health into a project, i.e., into a set of planned activities realized in collaboration with the medical system in order to reduce the risk of developing cancer. This health project shapes women's agency in three ways: it enhances, constrains and questions it, thus creating a sense of disorientation about what is considered rational and appropriate in terms of genetic risk management. Based on these findings, the paper concludes by stressing the paradoxes of the genetically at-risk status and the limits of the medical system in managing women designated with it. The paper also suggests that because of the disorientation intrinsic to their situation, genetically at-risk women have to reflexively construct their own health project from a range of available options in ways that are coherent and viable for themselves and their significant others. This process of reflexive construction may be called legitimation. PMID:25813728

  9. KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

    PubMed Central

    Haghvirdizadeh, Polin; Mohamed, Zahurin; Abdullah, Nor Azizan; Haghvirdizadeh, Pantea; Haerian, Monir Sadat; Haerian, Batoul Sadat

    2015-01-01

    Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM. PMID:26448950

  10. The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

    PubMed Central

    Sailani, M. Reza; Makrythanasis, Periklis; Valsesia, Armand; Santoni, Federico A.; Deutsch, Samuel; Popadin, Konstantin; Borel, Christelle; Migliavacca, Eugenia; Sharp, Andrew J.; Duriaux Sail, Genevieve; Falconnet, Emilie; Rabionet, Kelly; Serra-Juhé, Clara; Vicari, Stefano; Laux, Daniela; Grattau, Yann; Dembour, Guy; Megarbane, Andre; Touraine, Renaud; Stora, Samantha; Kitsiou, Sofia; Fryssira, Helena; Chatzisevastou-Loukidou, Chariklia; Kanavakis, Emmanouel; Merla, Giuseppe; Bonnet, Damien; Pérez-Jurado, Luis A.; Estivill, Xavier; Delabar, Jean M.; Antonarakis, Stylianos E.

    2013-01-01

    Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21–specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture. PMID:23783273

  11. Genetic Risk by Experience Interaction for Childhood Internalizing Problems: Converging Evidence across Multiple Methods

    PubMed Central

    Vendlinski, Matthew K.; Lemery-Chalfant, Kathryn; Essex, Marilyn J.; Goldsmith, H. Hill

    2010-01-01

    Background Identifying how genetic risk interacts with experience to predict psychopathology is an important step toward understanding the etiology of mental health problems. Few studies have examined genetic risk by experience interaction (GxE) in the development of childhood psychopathology. Methods We used both co-twin and parent mental health as markers of genetic risk to test whether GxE predicted internalizing problems in a sample of 8-year-old twins. Multi-instrument composites were used to characterize both parent and child psychopathology, and five experiential risk factors (socioeconomic status, single parent upbringing, negative parent-child interactions, number of negative life events, negative impact of negative life events) composed a cumulative risk index. Results We found consistent evidence for GxE for child internalizing problems, with significant interaction effects emerging both when genetic risk was indexed by co-twin mental health and when it was based on parent mental health. When co-twin mental health was used to estimate genetic risk, child internalizing problems were more heritable for children at low rather than high experiential risk. When parent mental health was used to estimate genetic risk, the association between genetic risk and internalizing problems was stronger for children at elevated experiential risk. Consideration of the interaction effect sizes helps to reconcile these findings. Conclusions Our results suggest that the processes involved in both diathesis-stress and bioecological models of development may operate for child internalizing problems. Effect sizes indicated that the main effects of genetic and experiential risk were much better predictors of child internalizing problems than was their interaction. PMID:21198591

  12. Association of genetic and non-genetic risk factors with the development of prostate cancer in Malaysian men.

    PubMed

    Munretnam, Khamsigan; Alex, Livy; Ramzi, Nurul Hanis; Chahil, Jagdish Kaur; Kavitha, I S; Hashim, Nikman Adli Nor; Lye, Say Hean; Velapasamy, Sharmila; Ler, Lian Wee

    2014-01-01

    There is growing global interest to stratify men into different levels of risk to developing prostate cancer, thus it is important to identify common genetic variants that confer the risk. Although many studies have identified more than a dozen common genetic variants which are highly associated with prostate cancer, none have been done in Malaysian population. To determine the association of such variants in Malaysian men with prostate cancer, we evaluated a panel of 768 SNPs found previously associated with various cancers which also included the prostate specific SNPs in a population based case control study (51 case subjects with prostate cancer and 51 control subjects) in Malaysian men of Malay, Chinese and Indian ethnicity. We identified 21 SNPs significantly associated with prostate cancer. Among these, 12 SNPs were strongly associated with increased risk of prostate cancer while remaining nine SNPs were associated with reduced risk. However, data analysis based on ethnic stratification led to only five SNPs in Malays and 3 SNPs in Chinese which remained significant. This could be due to small sample size in each ethnic group. Significant non-genetic risk factors were also identified for their association with prostate cancer. Our study is the first to investigate the involvement of multiple variants towards susceptibility for PC in Malaysian men using genotyping approach. Identified SNPs and non-genetic risk factors have a significant association with prostate cancer. PMID:24443231

  13. Hereditary breast cancer: an update on risk assessment and genetic testing in 2015.

    PubMed

    Stuckey, Ashley R; Onstad, Michaela A

    2015-08-01

    The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals. PMID:25747548

  14. Pathways and barriers to genetic testing and screening: Molecular genetics meets the high-risk family. Final report

    SciTech Connect

    Duster, T.

    1998-11-01

    The proliferation of genetic screening and testing is requiring increasing numbers of Americans to integrate genetic knowledge and interventions into their family life and personal experience. This study examines the social processes that occur as families at risk for two of the most common autosomal recessive diseases, sickle cell disease (SC) and cystic fibrosis (CF), encounter genetic testing. Each of these diseases is found primarily in a different ethnic/racial group (CF in Americans of North European descent and SC in Americans of West African descent). This has permitted them to have a certain additional lens on the role of culture in integrating genetic testing into family life and reproductive planning. A third type of genetic disorder, the thalassemias was added to the sample in order to extent the comparative frame and to include other ethnic and racial groups.

  15. A conceptual model of geological risk in the Ischia Island (Italy): highlights on volcanic history, seismicity and flooding

    NASA Astrophysics Data System (ADS)

    Carlino, Stefano; Cubellis, Elena; Iannuzzi, Raffaello; Luongo, Giuseppe

    2010-05-01

    During the last eight centuries the island of Ischia was hit by earthquakes, volcanic eruptions and floods producing heavy damages and numerous fatalities. Since the last twenty century the Ischia population is grown very fast, nowadays more than 56.000 people live in the island and 4 million of people visit it during the year, thus this area is characterised as an high geological risk territory. The island is here presented as an interesting "laboratory" for volcanic, seismic and hydrogeological risks assessment, from which to draw lessons for planning in risk areas. Ischia is a volcanic field, formed by the succession of effusive and explosive eruptions which formed lavas, welded and loose pyroclastic rocks. The succession of rock layers, with different permeability, promotes, during heavy rainfall, the formation of flows with high kinetic energy, which can produce devastating landslides. In this context, the remarkable development of settlements in the island, occurred in recent times, and the lack of planning that bring attention to the vulnerability of the area, have produced an exponential risk increase. Eruptions, earthquakes, flooding occurred in the island of Ischia in the past, have produced a wealth literature about catastrophic natural events. In general, the accounts of the events were recorded by various means, such as: newspaper, property disputes, historical and sociological analysis, poetic or artistic works, scientific analysis. As regard volcanism, earthquakes, tsunamis, there are myths, legends, historical documents, archaeological findings and results of recent surveys. Documented descriptions of historical eruptive events are only available for the last eruption of 1301-1302, while there are records for eruptive events in the early centuries of the Christian Age. More comprehensive accounts are available about historical seismicity. Information and documentations are available since the 1228 earthquake. However, more detailed and useful

  16. Linking genetic and environmental factors in amphibian disease risk

    PubMed Central

    Savage, Anna E; Becker, Carlos G; Zamudio, Kelly R

    2015-01-01

    A central question in evolutionary biology is how interactions between organisms and the environment shape genetic differentiation. The pathogen Batrachochytrium dendrobatidis (Bd) has caused variable population declines in the lowland leopard frog (Lithobates yavapaiensis); thus, disease has potentially shaped, or been shaped by, host genetic diversity. Environmental factors can also influence both amphibian immunity and Bd virulence, confounding our ability to assess the genetic effects on disease dynamics. Here, we used genetics, pathogen dynamics, and environmental data to characterize L. yavapaiensis populations, estimate migration, and determine relative contributions of genetic and environmental factors in predicting Bd dynamics. We found that the two uninfected populations belonged to a single genetic deme, whereas each infected population was genetically unique. We detected an outlier locus that deviated from neutral expectations and was significantly correlated with mortality within populations. Across populations, only environmental variables predicted infection intensity, whereas environment and genetics predicted infection prevalence, and genetic diversity alone predicted mortality. At one locality with geothermally elevated water temperatures, migration estimates revealed source–sink dynamics that have likely prevented local adaptation. We conclude that integrating genetic and environmental variation among populations provides a better understanding of Bd spatial epidemiology, generating more effective conservation management strategies for mitigating amphibian declines. PMID:26136822

  17. Linking genetic and environmental factors in amphibian disease risk.

    PubMed

    Savage, Anna E; Becker, Carlos G; Zamudio, Kelly R

    2015-07-01

    A central question in evolutionary biology is how interactions between organisms and the environment shape genetic differentiation. The pathogen Batrachochytrium dendrobatidis (Bd) has caused variable population declines in the lowland leopard frog (Lithobates yavapaiensis); thus, disease has potentially shaped, or been shaped by, host genetic diversity. Environmental factors can also influence both amphibian immunity and Bd virulence, confounding our ability to assess the genetic effects on disease dynamics. Here, we used genetics, pathogen dynamics, and environmental data to characterize L. yavapaiensis populations, estimate migration, and determine relative contributions of genetic and environmental factors in predicting Bd dynamics. We found that the two uninfected populations belonged to a single genetic deme, whereas each infected population was genetically unique. We detected an outlier locus that deviated from neutral expectations and was significantly correlated with mortality within populations. Across populations, only environmental variables predicted infection intensity, whereas environment and genetics predicted infection prevalence, and genetic diversity alone predicted mortality. At one locality with geothermally elevated water temperatures, migration estimates revealed source-sink dynamics that have likely prevented local adaptation. We conclude that integrating genetic and environmental variation among populations provides a better understanding of Bd spatial epidemiology, generating more effective conservation management strategies for mitigating amphibian declines. PMID:26136822

  18. Combining genetic mapping with genome-wide expression in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and candidate genes regulating autoimmunity

    PubMed Central

    Thessen Hedreul, Melanie; Möller, Steffen; Stridh, Pernilla; Gupta, Yask; Gillett, Alan; Daniel Beyeen, Amennai; Öckinger, Johan; Flytzani, Sevasti; Diez, Margarita; Olsson, Tomas; Jagodic, Maja

    2013-01-01

    The experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system commonly used to study multiple sclerosis (MS). We combined clinical EAE phenotypes with genome-wide expression profiling in spleens from 150 backcross rats between susceptible DA and resistant PVG rat strains during the chronic EAE phase. This enabled correlation of transcripts with genotypes, other transcripts and clinical EAE phenotypes and implicated potential genetic causes and pathways in EAE. We detected 2285 expression quantitative trait loci (eQTLs). Sixty out of 599 cis-eQTLs overlapped well-known EAE QTLs and constitute positional candidate genes, including Ifit1 (Eae7), Atg7 (Eae20-22), Klrc3 (eEae22) and Mfsd4 (Eae17). A trans-eQTL that overlaps Eae23a regulated a large number of small RNAs and implicates a master regulator of transcription. We defined several disease-correlated networks enriched for pathways involved in cell-mediated immunity. They include C-type lectins, G protein coupled receptors, mitogen-activated protein kinases, transmembrane proteins, suppressors of transcription (Jundp2 and Nr1d1) and STAT transcription factors (Stat4) involved in interferon signaling. The most significant network was enriched for T cell functions, similar to genetic findings in MS, and revealed both established and novel gene interactions. Transcripts in the network have been associated with T cell proliferation and differentiation, the TCR signaling and regulation of regulatory T cells. A number of network genes and their family members have been associated with MS and/or other autoimmune diseases. Combining disease and genome-wide expression phenotypes provides a link between disease risk genes and distinct molecular pathways that are dysregulated during chronic autoimmune inflammation. PMID:23900079

  19. Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.

    PubMed

    Daly, Mary B; Pilarski, Robert; Axilbund, Jennifer E; Buys, Saundra S; Crawford, Beth; Friedman, Susan; Garber, Judy E; Horton, Carolyn; Kaklamani, Virginia; Klein, Catherine; Kohlmann, Wendy; Kurian, Allison; Litton, Jennifer; Madlensky, Lisa; Marcom, P Kelly; Merajver, Sofia D; Offit, Kenneth; Pal, Tuya; Pasche, Boris; Reiser, Gwen; Shannon, Kristen Mahoney; Swisher, Elizabeth; Voian, Nicoleta C; Weitzel, Jeffrey N; Whelan, Alison; Wiesner, Georgia L; Dwyer, Mary A; Kumar, Rashmi

    2014-09-01

    During the past few years, several genetic aberrations that may contribute to increased risks for development of breast and/or ovarian cancers have been identified. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian focus specifically on the assessment of genetic mutations in BRCA1/BRCA2, TP53, and PTEN, and recommend approaches to genetic testing/counseling and management strategies in individuals with these mutations. This portion of the NCCN Guidelines includes recommendations regarding diagnostic criteria and management of patients with Cowden Syndrome/PTEN hamartoma tumor syndrome. PMID:25190698

  20. Genetic risk factors in two Utah pedigrees at high risk for suicide

    PubMed Central

    Coon, H; Darlington, T; Pimentel, R; Smith, K R; Huff, C D; Hu, H; Jerominski, L; Hansen, J; Klein, M; Callor, W B; Byrd, J; Bakian, A; Crowell, S E; McMahon, W M; Rajamanickam, V; Camp, N J; McGlade, E; Yurgelun-Todd, D; Grey, T; Gray, D

    2013-01-01

    We have used unique population-based data resources to identify 22 high-risk extended pedigrees that show clustering of suicide over twice that expected from demographically adjusted incidence rates. In this initial study of genetic risk factors, we focused on two high-risk pedigrees. In the first of these (pedigree 12), 10/19 (53%) of the related suicides were female, and the average age at death was 30.95. In the second (pedigree 5), 7/51 (14%) of the suicides were female and the average age at death was 36.90. Six decedents in pedigree 12 and nine in pedigree 5 were genotyped with the Illumina HumanExome BeadChip. Genotypes were analyzed using the Variant Annotation, Analysis, and Search program package that computes likelihoods of risk variants using the functional impact of the DNA variation, aggregative scoring of multiple variants across each gene and pedigree structure. We prioritized variants that were: (1) shared across pedigree members, (2) rare in other Utah suicides not related to these pedigrees, (3) ⩽ 5% in genotyping data from 398 other Utah population controls and (4) ⩽5% frequency in publicly available sequence data from 1358 controls and/or in dbSNP. Results included several membrane protein genes (ANO5, and TMEM141 for pedigree 12 and FAM38A and HRCT1 for pedigree 5). Other genes with known neuronal involvement and/or previous associations with psychiatric conditions were also identified, including NFKB1, CASP9, PLXNB1 and PDE11A in pedigree 12, and THOC1, and AUTS2 in pedigree 5. Although the study is limited to variants included on the HumanExome BeadChip, these findings warrant further exploration, and demonstrate the utility of this high-risk pedigree resource to identify potential genes or gene pathways for future development of targeted interventions. PMID:24252905

  1. Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes.

    PubMed

    Patel, Kashyap A; Oram, Richard A; Flanagan, Sarah E; De Franco, Elisa; Colclough, Kevin; Shepherd, Maggie; Ellard, Sian; Weedon, Michael N; Hattersley, Andrew T

    2016-07-01

    Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D. PMID:27207547

  2. Type 1 Diabetes Genetic Risk Score: a novel tool to discriminate monogenic and type 1 diabetes

    PubMed Central

    Patel, K A; Oram, R A; Flanagan, S E; De Franco, E; Colclough, K; shepherd, M; Ellard, S

    2016-01-01

    Distinguishing patients with monogenic diabetes from Type 1 diabetes (T1D) is important for correct diagnosis, treatment and to select patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven MODY (n=805) and T1D (n=1963) (ROC-AUC=0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS in 242 White-European patients with neonatal diabetes (NDM) who had been tested for all known neonatal diabetes genes. Monogenic NDM was confirmed in 90%, 59% and 8% in patients with GRS <5th T1D centile, 50-75th T1D centile and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cut-off in 48 NDM patients with no known genetic cause, identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later, had less syndromic presentation but had additional autoimmune features compared to proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D. PMID:27207547

  3. Clinical validity and utility of genetic risk scores in prostate cancer

    PubMed Central

    Helfand, Brian T; Kearns, James; Conran, Carly; Xu, Jianfeng

    2016-01-01

    Current issues related to prostate cancer (PCa) clinical care (e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa) call for risk assessment tools that can be combined with family history (FH) to stratify disease risk among men in the general population. Since 2007, genome-wide association studies (GWASs) have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss (1) the validity of these PCa risk-associated SNPs, individually and collectively; (2) the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score (GRS); (3) the adequate number of SNPs needed for risk assessment; (4) reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, (5) risk assessment for men from various racial groups, and (6) the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians. PMID:27297129

  4. Clinical validity and utility of genetic risk scores in prostate cancer.

    PubMed

    Helfand, Brian T; Kearns, James; Conran, Carly; Xu, Jianfeng

    2016-01-01

    Current issues related to prostate cancer (PCa) clinical care (e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa) call for risk assessment tools that can be combined with family history (FH) to stratify disease risk among men in the general population. Since 2007, genome-wide association studies (GWASs) have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss (1) the validity of these PCa risk-associated SNPs, individually and collectively; (2) the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score (GRS); (3) the adequate number of SNPs needed for risk assessment; (4) reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, (5) risk assessment for men from various racial groups, and (6) the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians. PMID:27297129

  5. Parents' and children's communication about genetic risk: a qualitative study, learning from families' experiences

    PubMed Central

    Metcalfe, Alison; Plumridge, Gill; Coad, Jane; Shanks, Andrew; Gill, Paramjit

    2011-01-01

    Little is known about how parents explain to their children their risk of inheriting a gene that may cause disease in the child or in the child's future progeny. This study explored how genetic risk information is shared between family members and the factors affecting it, to ascertain the implications for children, young people and their parents to inform future service development and provision. A volunteer group of parents, children (8–11 years) and young people (12+ years) in families affected by or at risk of one of six inherited genetic conditions was interviewed. The semi-structured interviews explored the roles of family members, the language used and the self-reported psychological outcomes in a discussion on genetic risk information. The findings were analysed using grounded theory. A total of 33 families participated, which included 79 individuals. Parents often found discussing genetic risk information very difficult and emotionally painful. Discussions were not usually planned and often a major event prompted parents to finally explain genetic risks to their children; however, children usually preferred to learn about the genetic condition gradually throughout childhood. Parents identified a number of challenges they faced related to talking to children, and many thought health professionals should provide more advice to assist them in providing developmentally appropriate information. We therefore conclude that greater emphasis is required in supporting parents and children in discussing genetic risk information throughout their child's development. Open communication about genetic risks throughout childhood seemed to help children and parents cope better and come to terms with the implications of the genetic condition. PMID:21326287

  6. Integration of genetic and epigenetic markers for risk stratification: opportunities and challenges

    PubMed Central

    Pashayan, Nora; Reisel, Daniel; Widschwendter, Martin

    2016-01-01

    Summary Common genetic susceptibility variants could be used for risk stratification in risk-tailored cancer screening and prevention programmes. Combining genetic variants with environmental risk factors would improve risk stratification. Epigenetic changes are surrogate markers of environmental exposures during individual’s lifetime. Integrating epigenetic markers, in lieu of environmental exposure data, with genetic markers would potentially improve risk stratification. Epigenetic changes are reversible and acquired gradually, providing potentials for prevention and early detection strategies. The epigenetic changes are tissue-specific and stage-of-development-specific, raising challenges in choice of sample and timing for evaluation of cancer-associated changes. The Horizon 2020 funded research programme, FORECEE, using empirical data, will investigate the value of integration of epigenomics with genomics for risk prediction and prevention of women-specific cancers. PMID:27053939

  7. An exposure-weighted score test for genetic associations integrating environmental risk factors.

    PubMed

    Han, Summer S; Rosenberg, Philip S; Ghosh, Arpita; Landi, Maria Teresa; Caporaso, Neil E; Chatterjee, Nilanjan

    2015-09-01

    Current methods for detecting genetic associations lack full consideration of the background effects of environmental exposures. Recently proposed methods to account for environmental exposures have focused on logistic regressions with gene-environment interactions. In this report, we developed a test for genetic association, encompassing a broad range of risk models, including linear, logistic and probit, for specifying joint effects of genetic and environmental exposures. We obtained the test statistics by maximizing over a class of score tests, each of which involves modified standard tests of genetic association through a weight function. This weight function reflects the potential heterogeneity of the genetic effects by levels of environmental exposures under a particular model. Simulation studies demonstrate the robust power of these methods for detecting genetic associations under a wide range of scenarios. Applications of these methods are further illustrated using data from genome-wide association studies of type 2 diabetes with body mass index and of lung cancer risk with smoking. PMID:26134142

  8. DEVELOPMENT OF AQUATIC MODELS FOR TESTING THE RELATIONSHIP BETWEEN GENETIC DIVERSITY AND POPULATION EXTINCTION RISK

    EPA Science Inventory

    The relationship between population adaptive potential and extinction risk in a changing environment is not well understood. Although the expectation is that genetic diversity is directly related to the capacity of populations to adapt, the statistical and predictive aspects of ...

  9. COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS

    EPA Science Inventory

    Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

  10. Measurement and Associations of Pregnancy Risk Factors with Genetic Influences, Postnatal Environmental Influences, and Toddler Behavior

    ERIC Educational Resources Information Center

    Marceau, Kristine; Hajal, Nastassia; Leve, Leslie D.; Reiss, David; Shaw, Daniel S.; Ganiban, Jody M.; Mayes, Linda C.; Neiderhiser, Jenae M.

    2013-01-01

    This study demonstrates the unique contributions of perinatal risk and genetic and environmental influences on child behavior using data from 561 domestic US adoption triads (birth mothers, adopted child, and adoptive parents). Findings show distinct patterns of associations among genetic (birth mother psychopathology), prenatal (six maternal…

  11. The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review

    PubMed Central

    Cooke Bailey, Jessica N.; Hoffman, Joshua D.; Sardell, Rebecca J.; Scott, William K.; Pericak-Vance, Margaret A.; Haines, Jonathan L.

    2016-01-01

    Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review the ability and utility of these numerous models for prediction of AMD and suggest additional risk factors to be incorporated into clinically useful predictive models of AMD. PMID:26959068

  12. The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review.

    PubMed

    Cooke Bailey, Jessica N; Hoffman, Joshua D; Sardell, Rebecca J; Scott, William K; Pericak-Vance, Margaret A; Haines, Jonathan L

    2016-01-01

    Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review the ability and utility of these numerous models for prediction of AMD and suggest additional risk factors to be incorporated into clinically useful predictive models of AMD. PMID:26959068

  13. Genetic Determinants of Risk, Severity, and Outcome in Intracerebral Hemorrhage.

    PubMed

    Falcone, Guido J; Rosand, Jonathan

    2016-06-01

    Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is the most severe manifestation of common forms of cerebral small vessel disease. Although ICH represents only 15% of all strokes, it accounts for a large proportion of stroke-related costs and mortality. Preventive and acute treatments remain limited. Because genetic variation contributes substantially to ICH, genomic analyses constitute a powerful tool to identify new biological mechanisms involved in its occurrence. Through translational research efforts, these newly identified mechanisms can become targets for innovative therapeutic interventions. Here, the authors summarize the most recent genetic discoveries for ICH. They also introduce the Platform for Accelerating Genetic Discovery for Cerebrovascular Disease, a newly created resource that aims to create a common workspace for genetic analyses that will bring together 100,000 stroke cases and suitable controls from numerous institutions in several countries. PMID:27214705

  14. Genetic risk signatures of opioid-induced respiratory depression following pediatric tonsillectomy

    PubMed Central

    Biesiada, Jacek; Chidambaran, Vidya; Wagner, Michael; Zhang, Xue; Martin, Lisa J; Meller, Jaroslaw; Sadhasivam, Senthilkumar

    2015-01-01

    Background Respiratory depression is a clinically and economically important but preventable complication of opioids. Genetic factors can help identify patients with high risk for respiratory depression. Methods In this prospective genotype blinded clinical study, we evaluated the effect of a panel of variants in candidate genes on opioid-related respiratory depression in 347 children following tonsillectomy. Results Using unsupervised hierarchical clustering and a combination of candidate genotypes and clinical variables, we identified several distinct clusters of patients at high risk (36–38%) and low risk (10–17%) of respiratory depression; the relative risk of respiratory depression for high versus low risk clusters was 2.1–3.8 (p = 0.003). Conclusion Genetic risk predictions (genetic signatures) along with clinical risk factors effectively identify children at higher and lower risks of opioid-induced respiratory depression. Genetic signatures of respiratory depression offer strategies for improved clinical decision support to guide clinicians to balance the risks of opioid adverse effects with analgesia. PMID:25493568

  15. Subjects At-Risk for Genetic Diseases in Portugal: Illness Representations.

    PubMed

    Leite, Ângela; Dinis, Maria Alzira P; Sequeiros, Jorge; Paúl, Constança

    2016-02-01

    This study investigates illness representations of subjects at-risk for 3 autosomal dominant late-onset disorders: Familial Amyloid Polyneuropathy (FAP) TTR V30M, Huntington's disease (HD) and Machado-Joseph disease (MJD), comparing them with the illness representations of subjects at-risk for Hemochromatosis (HH). The present study included a clinical group that consisted of 213 subjects at genetic risk (FAP, HD and MJD), comprising 174 subjects at-risk for FAP, 34 subjects at-risk for HD and only 5 subjects at-risk for MJD; and the control group consisting of 31 subjects at genetic risk for HH. All subjects at-risk were undergoing the process of genetic counseling to learn their genetic status (carrier or non-carrier). Subjects were assessed through a semi-structured single interview, in order to obtain sociodemographic data and the answer to an open-ended question relating to the illness representation issue: "What does this illness mean to you?/ What is this disease to you?" It was in the subjects' metaphors that subjects best expressed what they felt regarding the disease and the situation of being at-risk for this disease. Family is their mirror and their source of learning and, therefore, it is inevitable that family is related to the meaning of the disease itself. PMID:25986962

  16. The interaction between genetic risk and childhood sexual abuse in the prediction of adolescent violent behavior.

    PubMed

    Beaver, Kevin M

    2008-12-01

    A rich line of empirical research has indicated that antisocial behaviors are the result of genetic factors and environmental factors working interactively. The current study uses this knowledge base as a springboard to examine the effects of childhood sexual abuse and genetic risk in the prediction of adolescent violent delinquency. To address this issue, data from the National Longitudinal Study of Adolescent Health were analyzed. The results of the analyses reveal that childhood sexual abuse interacts with genetic risk to predict involvement in violent delinquency for males. The effects of childhood sexual abuse and genetic risk as well as the interaction between the two are unrelated to violent delinquency for females. Implications of the study are discussed. PMID:18840900

  17. Genetic Association Studies in Uterine Fibroids: Risk Alleles Presage the Path to Personalized Therapies.

    PubMed

    Gallagher, C Scott; Morton, Cynthia C

    2016-07-01

    Uterine leiomyoma (UL) is the most common tumor of the female reproductive system. Epidemiological analyses, including familial aggregation, twin studies, and racial discrepancies in disease prevalence and morbidity, indicated genetic factors influence risk for developing UL. Genome-wide association studies (GWASs) are a powerful method for identifying genetic variants that are associated with elevated risk for a common, complex disease. To date, three genome-wide scans for UL have been performed: a GWAS in Japanese women, a genome-wide linkage and association study in women of European decent, and an admixture-based analysis in African American women. Results from each of the three genome-wide scans performed have had varying success in identifying unique loci associated with predisposition to developing UL. Here, we address the evidence for a genetic basis for UL risk, discuss genetic association studies and their results, and identify challenges and future directions for UL GWAS analyses. PMID:27513025

  18. Plant Oils and Cardiometabolic Risk Factors: The Role of Genetics.

    PubMed

    Smith, Caren E

    2012-09-01

    More than 25 years have passed since Ancel Keys and others observed that high intake of monounsaturated fatty acids, especially as supplied by plants (eg, olive oil) was associated with lower cardiovascular and overall mortality. About 15 years later, advances in genotyping technologies began to facilitate widespread study of relationships between dietary fats and genetic variants, illuminating the role of genetic variation in modulating human responses to fatty acids. More recently, microarray technologies evaluate the ways in which minor, bioactive compounds in plant oils (including olive, thyme, lemongrass, clove, eucalyptus, and others) alter gene expression to mediate anti-inflammatory and antioxidant effects. Results from a range of diverse technologies and approaches are coalescing to improve understanding of the role of the genome in shaping our responses to plant oils, and to clarify the genetic mechanisms underlying the cardioprotective benefits we derive from a wide range of plant oil constituents. PMID:23001455

  19. Plant Oils and Cardiometabolic Risk Factors: The Role of Genetics

    PubMed Central

    Smith, Caren E.

    2012-01-01

    More than 25 years have passed since Ancel Keys and others observed that high intake of monounsaturated fatty acids, especially as supplied by plants (eg, olive oil) was associated with lower cardiovascular and overall mortality. About 15 years later, advances in genotyping technologies began to facilitate widespread study of relationships between dietary fats and genetic variants, illuminating the role of genetic variation in modulating human responses to fatty acids. More recently, microarray technologies evaluate the ways in which minor, bioactive compounds in plant oils (including olive, thyme, lemongrass, clove, eucalyptus, and others) alter gene expression to mediate anti-inflammatory and antioxidant effects. Results from a range of diverse technologies and approaches are coalescing to improve understanding of the role of the genome in shaping our responses to plant oils, and to clarify the genetic mechanisms underlying the cardioprotective benefits we derive from a wide range of plant oil constituents. PMID:23001455

  20. Genetic factors involved in risk for methamphetamine intake and sensitization

    PubMed Central

    Belknap, John K.; McWeeney, Shannon; Reed, Cheryl; Burkhart-Kasch, Sue; McKinnon, Carrie S.; Li, Na; Baba, Harue; Scibelli, Angela C.; Hitzemann, Robert; Phillips, Tamara J.

    2013-01-01

    Lines of mice were created by selective breeding for the purpose of identifying genetic mechanisms that influence magnitude of the selected trait and to explore genetic correlations for additional traits thought to be influenced by shared mechanisms. DNA samples from high and low methamphetamine drinking (MADR) and high and low methamphetamine sensitization lines were used for quantitative trait locus (QTL) mapping. Significant additive genetic correlations between the two traits indicated common genetic influence, and a QTL on chromosome X was detected for both traits, suggesting one source of this commonality. For MADR mice, a QTL on chromosome 10 accounted for more than 50% of the genetic variance in that trait. Microarray gene expression analyses were performed for 3 brain regions for methamphetamine-naïve MADR line mice: nucleus accumbens, prefrontal cortex and ventral midbrain. Many of the genes that were differentially expressed between the high and low MADR lines were shared in common across the 3 brain regions. A gene network highly enriched in transcription factor genes was identified as being relevant to genetically-determined differences in methamphetamine intake. When the mu opioid receptor gene (Oprm1), located on chromosome 10 in the QTL region, was added to this top ranked transcription factor network, it became a hub in the network. These data are consistent with previously published findings of opioid response and intake differences between the MADR lines and suggest that Oprm1 or a gene that impacts activity of the opioid system, plays a role in genetically–determined differences in methamphetamine intake. PMID:24217691

  1. ACRYLAMIDE: A REVIEW OF ITS GENOTOXICITY AND AN ASSESSMENT OF HERITABLE GENETIC RISK

    EPA Science Inventory

    This acrylamide assessment is the culmination of an effort emanating from an October 1993 joint European Commission/United tates EPA Workshop Risk Assessment examining "Human Genetic Risks from Exposure to Chemicals, Focusing on the Feasibility of a Parallelogram Approach". orkgr...

  2. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  3. The potential of large studies for building genetic risk prediction models

    Cancer.gov

    NCI scientists have developed a new paradigm to assess hereditary risk prediction in common diseases, such as prostate cancer. This genetic risk prediction concept is based on polygenic analysis—the study of a group of common DNA sequences, known as singl

  4. Genetic Profiling to Determine Risk of Relapse Free Survival in High-risk Localized Prostate Cancer

    PubMed Central

    Barnett, Christine M.; Heinrich, Michael C.; Lim, Jeong; Nelson, Dylan; Beadling, Carol; Warrick, Andrea; Neff, Tanaya; Higano, Celestia S.; Garzotto, Mark; Qian, David; Corless, Christopher L.; Thomas, George V.; Beer, Tomasz M.

    2014-01-01

    Purpose The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high risk clinically localized prostate cancer. Experimental Design 48 samples of formalin fixed paraffin embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy based sequencing. In addition, PTEN loss and ERG translocations were examined using immunohistochemistry in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations. Results Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse free survival, 19 vs. 106 months (p = .01). Conclusions This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. While point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery. PMID:24352642

  5. EDITORIAL INTRODUCTION [TO FEMALE GERM CELLS: BIOLOGY AND GENETIC RISK

    EPA Science Inventory

    This is an editorial introduction to the special issue of utation Research, titled, emale Germ Cells: Biology and Genetic isk, which is an attempt to present a collection of papers that emphasize the distinct properties of female germ cells and their characteristic response to mu...

  6. Genetic variation in CYP2J2 and risk of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CYP2J2 metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs) which regulate endothelial function and serve as a reserve system to endothelial nitric oxide synthase (NOS3). We sought to determine if genetic variation in CYP2J2 was associated with risk of coronary heart disease (CHD) events...

  7. Autism spectrum disorders: perceptions of genetic etiology and recurrence risk among Taiwanese parents of affected children.

    PubMed

    Chen, L S; Li, C; Wang, C H; Amuta, A; Li, M; Huang, T Y; Dhar, S U; Talwar, D; Jung, E

    2015-08-01

    In Taiwan, autism spectrum disorders (ASDs) are an emerging public health concern. The ongoing scientific progress for understanding the genetic etiology of ASD makes it increasingly important to examine how parents of children with ASD perceive the causes and recurrence risk of having another child with ASD. These perceptions may influence their family planning, attitudes toward genetic services, and willingness to take their children for ASD genetic testing. However, previous studies addressing this issue were conducted primarily in Western countries. As culture might shape an individual's views of genetic/genomic disorders, this first-of-its-kind study examined the perceptions of the genetic etiology for ASD and the recurrence risk among Taiwanese parents of children affected with ASD. In-depth, semi-structured interviews were conducted among 39 parents having at least one child with ASD. Although the majority of participants believed that ASD has a genetic link, less than half perceived genetic factors as the cause of their own child's ASD. Moreover, most participants articulated their recurrence risk incorrectly. Some parents were concerned about their doctors' limited genomic competencies. To provide parents with better education, counseling, and support for making reproductive decisions, ASD-related genomic education among Taiwanese physicians is needed. PMID:25267333

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

    PubMed Central

    Scarpa, Joseph R.; Jiang, Peng; Losic, Bojan; Readhead, Ben; Dudley, Joel T.; Vitaterna, Martha H.; Turek, Fred W.

    2016-01-01

    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

  9. Association between genetic risk scoring for schizophrenia and bipolar disorder with regional subcortical volumes.

    PubMed

    Caseras, X; Tansey, K E; Foley, S; Linden, D

    2015-01-01

    Previous research has shown coincident abnormal regional brain volume in patients with schizophrenia (SCZ) and bipolar disorder (BD) compared with controls. Whether these abnormalities are genetically driven or explained by secondary effects of the disorder or environmental factors is unknown. We aimed to investigate the association between genetic risk scoring (GRS) for SCZ and BD with volume of brain areas previously shown to be different between these clinical groups and healthy controls. We obtained subcortical brain volume measures and GRS for SCZ and BD from a sample of 274 healthy volunteers (71.4% females, mean age 24.7 (s.d. 6.9)). Volume of the globus pallidus was associated with the shared GRS between SCZ and BD, and also with the independent GRS for each of these disorders. Volume of the amygdala was associated with the non-shared GRS between SCZ and BD, and with the independent GRS for BD. Our results for volume of the globus pallidus support the idea of SCZ and BD sharing a common underlying neurobiological abnormality associated with a common genetic risk for both these disorders. Results for volume of the amygdala, though, would suggest the existence of a distinct mechanism only associated with genetic risk for BD. Finally, the lack of association between genetic risk and volume of most subcortical structures suggests that the volumetric differences reported in patient-control comparisons may not be genetically driven, but a consequence of the disorder or co-occurring environmental factors. PMID:26645627

  10. High genetic-risk individuals benefit less from resistance exercise intervention

    PubMed Central

    Klimentidis, Yann C.; Bea, Jennifer W.; Lohman, Timothy; Hsieh, Pei-Shan; Going, Scott; Chen, Zhao

    2015-01-01

    Background/Objectives Genetic factors play an important role in body mass index (BMI) variation, and also likely play a role in the weight-loss and body composition response to physical activity/exercise. With the recent identification of BMI–associated genetic variants, it is possible to investigate the interaction of these genetic factors with exercise on body composition outcomes. Subjects/Methods In a block-randomized clinical trial of resistance exercise among women (n=148), we examined whether the putative effect of exercise on weight and DXA-derived body composition measurements differs according to genetic risk for obesity. Approximately one-half of the sample was randomized to an intervention consisting of a supervised, intensive, resistance exercise program, lasting one year. Genetic risk for obesity was defined as a genetic risk score (GRS) comprised of 21 SNPs known to be associated with normal BMI variation. We examined the interaction of exercise intervention and the GRS on anthropometric and body composition measurements after one year of the exercise intervention. Results We found statistically significant interactions for body weight (p=0.01), body fat (p=0.01), body fat % (p=0.02), and abdominal fat (p=0.02), whereby the putative effect of exercise is greater among those with a lower level of genetic risk for obesity. No single SNP appears to be a major driver of these interactions. Conclusions The weight-loss response to resistance exercise, including changes in body composition, differs according to an individual’s genetic risk for obesity. PMID:25924711

  11. [Genetically modified foods. Advantages and human health risks].

    PubMed

    Filip, Lorena; Miere, Doina; Indrei, L L

    2004-01-01

    One of the most important issue with which the mankind is confronting now is related to the quantitatively as well as qualitatively assurance of the food supply necessary for human species existence. In this context, by means of genetic engineering, modified genetic organisms were obtained. In the first stage, plant crops with high productivity and resistant against diseases and pests were obtained. After that, food products having modified organoleptic properties and high nutrition values were produced. The main problem concerning the long-term consumption of these products is their toxicity, which until now was not confirmed or denied. For this reason, tests are necessary to be made in order to stipulate and prevent these effects. PMID:16004228

  12. Cost sharing and hereditary cancer risk: predictors of willingness-to-pay for genetic testing.

    PubMed

    Matro, Jennifer M; Ruth, Karen J; Wong, Yu-Ning; McCully, Katen C; Rybak, Christina M; Meropol, Neal J; Hall, Michael J

    2014-12-01

    Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals' willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25-$2,000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤$200 vs. ≥$500). All statistical tests are two-sided (α = 0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p < 0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p < 0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care. PMID:24794065

  13. Clinical and Genetic Determinants of Cardiomyopathy Risk among Hematopoietic Cell Transplantation Survivors.

    PubMed

    Leger, Kasey J; Cushing-Haugen, Kara; Hansen, John A; Fan, Wenhong; Leisenring, Wendy M; Martin, Paul J; Zhao, Lue Ping; Chow, Eric J

    2016-06-01

    Cardiomyopathy has been recognized as a complication after hematopoietic cell transplantation (HCT). Using a nested case-cohort design, we examined the relationships between demographic, therapeutic, and selected cardiovascular disease risk factors among ≥1-year HCT survivors who developed cardiomyopathy before (n = 43) or after (n = 89) 1 year from HCT as compared to a randomly selected subcohort of survivors without cardiomyopathy (n = 444). Genomic data were available for 79 cases and 267 noncases. Clinical and genetic covariates were examined for association with the risk of early or late cardiomyopathy. Clinical risk factors associated with both early- and late-onset cardiomyopathy included anthracycline exposure ≥250 mg/m(2) and pre-existing hypertension. Among late-onset cardiomyopathy cases, the development of diabetes and ischemic heart disease further increased risk. We replicated several previously reported genetic associations among early-onset cardiomyopathy cases, including rs1786814 in CELF4, rs2232228 in HAS3, and rs17863783 in UGT1A6. None of these markers were associated with risk of late-onset cardiomyopathy. A combination of demographic, treatment, and clinical covariates predicted early-onset cardiomyopathy with reasonable accuracy (area under the curve [AUC], .76; 95% confidence interval [CI], .68 to .83), but prediction of late cardiomyopathy was poor (AUC, .59; 95% CI .53 to .67). The addition of genetic polymorphisms with marginal associations (odds ratios ≥1.3) did not enhance prediction for either early- or late-onset cardiomyopathy. Conventional cardiovascular risk factors influence the risk of both early- and late-onset cardiomyopathy in HCT survivors. Although certain genetic markers may influence the risk of early-onset disease, further work is required to validate previously reported findings and to determine how genetic information should be incorporated into clinically useful risk prediction models. PMID:26968791

  14. Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease

    PubMed Central

    Smith, J. Carson; Nielson, Kristy A.; Woodard, John L.; Seidenberg, Michael; Durgerian, Sally; Hazlett, Kathleen E.; Figueroa, Christina M.; Kandah, Cassandra C.; Kay, Christina D.; Matthews, Monica A.; Rao, Stephen M.

    2014-01-01

    We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer's disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories. PMID:24795624

  15. Comparative genetic analyses of historical and contemporary collections highlight contrasting demographic histories for the bumble bees Bombus pensylvanicus and B. impatiens in Illinois.

    PubMed

    Lozier, Jeffrey D; Cameron, Sydney A

    2009-05-01

    Direct comparison of genetic patterns between museum specimens and contemporary collections can be a powerful approach for detecting recent demographic changes. Using microsatellite markers, we examined historical and contemporary genetic variation from an apparently declining bumble bee species, Bombus pensylvanicus, and from a stable species, Bombus impatiens, in central Illinois. For each species, we genotyped specimens from the Illinois Natural History Survey collected from three populations between 1969-1972 and from a resurvey of the same areas conducted in 2008. Population structure in B. pensylvanicus increased markedly over the last four decades (from theta(ST) = 0.001 to 0.027) while no structure was detected in B. impatiens for either time period (theta(ST) = -0.006 to -0.003). Changes in genetic diversity were not significant for either species, although small reductions were observed for B. pensylvanicus in all three populations. Coalescent simulations incorporating both contemporary and historical samples suggest that this small change is not surprising for recent population declines, as large reductions in genetic diversity were only apparent under the most severe bottleneck scenarios. These results demonstrate how comparisons of genetic patterns between temporal periods and species can help elucidate potential threats to population health and suggest several strategies that might be useful in the conservation of B. pensylvanicus in the Midwestern USA. PMID:19344350

  16. Genetic, nongenetic and epigenetic risk determinants in developmental programming of type 2 diabetes.

    PubMed

    Vaag, Allan; Brøns, Charlotte; Gillberg, Linn; Hansen, Ninna S; Hjort, Line; Arora, Geeti P; Thomas, Nihal; Broholm, Christa; Ribel-Madsen, Rasmus; Grunnet, Louise G

    2014-11-01

    Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms. PMID:25179736

  17. The Palau Early Psychosis Study: distribution of cases by level of genetic risk.

    PubMed

    Myles-Worsley, Marina; Blailes, Francisca; Ord, Lisa M; Weaver, Starla; Dever, Gregory; Faraone, Stephen V

    2007-01-01

    The Palau Early Psychosis Study (PEPS) was designed to examine the pathogenesis of early psychosis in a high-risk population isolate. This paper describes the characteristics of our community-based, non-help seeking sample of 404 Palauan adolescents and quantifies the presence of early psychosis by level of genetic risk. The sample included 53 offspring of a schizophrenic parent designated as "Genetically Highest Risk" (GHR+) and 68 nieces/nephews of sib-pairs/trios, designated as "Genetically High Risk" (GHR). The remaining subjects were recruited through a high school survey that identified 62 "Genetically Moderate Risk" (GMR) adolescents with an affected second or third degree relative and 221 "Genetically Low Risk" (GLR) subjects with no close affected relatives. The GLR adolescents included 117 symptomatic or "Clinically High Risk" (CHR) adolescents and 104 asymptomatic normal controls. Based on a modified K-SADS-PL assessment, we identified 221 adolescents with early psychosis, 62 or 28% of whom had already transitioned to a psychotic disorder. Together, the two highest risk groups contributed 31% of the adolescent-onset psychosis cases and 27% of the prodromals. More than half of the early psychosis cases (53%) were GLR adolescents. The mean age of onset for DSM-IV psychosis was 12.9 years, and males transitioned at an earlier age than females. Our results indicate that Palauan adolescents, even GLR adolescents with no close affected relatives, have elevated rates of early psychosis. These young subjects can contribute valuable information about the familial transmission of schizophrenia, the developmental course of the illness, and rates of transition to frank psychosis. PMID:17034019

  18. Comparison of the incidence of pathogenic and antibiotic-resistant Escherichia coli strains in adult cattle and veal calf slaughterhouse effluents highlighted different risks for public health.

    PubMed

    Um, Maryse Michèle; Barraud, Olivier; Kérourédan, Monique; Gaschet, Margaux; Stalder, Thibault; Oswald, Eric; Dagot, Christophe; Ploy, Marie-Cecile; Brugère, Hubert; Bibbal, Delphine

    2016-01-01

    The goal of this study was to investigate the involvement of bovine slaughterhouse effluents and biosolids in the risk of environmental dissemination of pathogenic and antibiotic-resistant Escherichia coli. Several samples were collected from one adult cattle and one veal calf slaughterhouse wastewater treatment plant (WWTP). The treatment process had no impact on the percentage of Shiga toxin-producing E. coli (STEC) and on the percentage of atypical enteropathogenic E. coli (aEPEC). A STEC O157:H7 was isolated from the thickened sludge of the adult cattle slaughterhouse. As thickened sludge is intended to be spread on agricultural lands, the detection of this pathogenic strain is a public health issue. The percentage of antibiotic-resistant E. coli was 5.0% and 87.5% in wastewater from the adult cattle and the veal calf slaughterhouse, respectively. These percentages were not significantly different after treatment. Integron-bearing E. coli isolates were only detected in the veal calf slaughterhouse WWTP with percentages above 50.0% for all sampling points whatever the step of the treatment process. Taken together, these findings highlighted the fact that different public health risks might be associated with adult cattle or veal calf slaughterhouses regarding the dissemination of pathogenic and antibiotic-resistant E. coli isolates into the environment. PMID:26460853

  19. Property rights and genetic engineering: developing nations at risk.

    PubMed

    Shrader-Frechette, Kristin

    2005-01-01

    Eighty percent of (commercial) genetically engineered seeds (GES) are designed only to resist herbicides. Letting farmers use more chemicals, they cut labor costs. But developing nations say GES cause food shortages, unemployment, resistant weeds, and extinction of native cultivars when "volunteers" drift nearby. While GES patents are reasonable, this paper argues many patent policies are not. The paper surveys GE technology, outlines John Locke's classic account of property rights, and argues that current patent policies must be revised to take account of Lockean ethical constraints. After answering a key objection, it provides concrete suggestions for implementing its ethical conclusions. PMID:15727008

  20. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population.

    PubMed

    Robinson, Elise B; St Pourcain, Beate; Anttila, Verneri; Kosmicki, Jack A; Bulik-Sullivan, Brendan; Grove, Jakob; Maller, Julian; Samocha, Kaitlin E; Sanders, Stephan J; Ripke, Stephan; Martin, Joanna; Hollegaard, Mads V; Werge, Thomas; Hougaard, David M; Neale, Benjamin M; Evans, David M; Skuse, David; Mortensen, Preben Bo; Børglum, Anders D; Ronald, Angelica; Smith, George Davey; Daly, Mark J

    2016-05-01

    Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology. PMID:26998691

  1. Neuroimaging and Genetic Risk for Alzheimer’s Disease and Addiction-Related Degenerative Brain Disorders

    PubMed Central

    Jahanshad, Neda; Leonardo, Cassandra D.; Thompson, Paul M.

    2014-01-01

    Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer’s disease (AD). Here we describe how multimodal imaging can be used to study the changing brain during the different stages of AD. We integrate findings from a range of studies using magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI) and diffusion weighted imaging (DWI). Neuroimaging reveals how risk genes for degenerative disorders affect the brain, including several recently discovered genetic variants that may disrupt brain connectivity. We review some recent neuroimaging studies of genetic polymorphisms associated with increased risk for late-onset Alzheimer’s disease (LOAD). Some genetic variants that increase risk for drug addiction may overlap with those associated with degenerative brain disorders. These common associations offer new insight into mechanisms underlying neurodegeneration and addictive behaviors, and may offer new leads for treating them before severe and irreversible neurological symptoms appear. PMID:24142306

  2. Factors Motivating Individuals to Consider Genetic Testing for Type 2 Diabetes Risk Prediction.

    PubMed

    Wessel, Jennifer; Gupta, Jyoti; de Groot, Mary

    2016-01-01

    The purpose of this study was to identify attitudes and perceptions of willingness to participate in genetic testing for type 2 diabetes (T2D) risk prediction in the general population. Adults (n = 598) were surveyed on attitudes about utilizing genetic testing to predict future risk of T2D. Participants were recruited from public libraries (53%), online registry (37%) and a safety net hospital emergency department (10%). Respondents were 37 ± 11 years old, primarily White (54%), female (69%), college educated (46%), with an annual income ≥$25,000 (56%). Half of participants were interested in genetic testing for T2D (52%) and 81% agreed/strongly agreed genetic testing should be available to the public. Only 57% of individuals knew T2D is preventable. A multivariate model to predict interest in genetic testing was adjusted for age, gender, recruitment location and BMI; significant predictors were motivation (high perceived personal risk of T2D [OR = 4.38 (1.76, 10.9)]; family history [OR = 2.56 (1.46, 4.48)]; desire to know risk prior to disease onset [OR = 3.25 (1.94, 5.42)]; and knowing T2D is preventable [OR = 2.11 (1.24, 3.60)], intention (if the cost is free [OR = 10.2 (4.27, 24.6)]; and learning T2D is preventable [OR = 5.18 (1.95, 13.7)]) and trust of genetic testing results [OR = 0.03 (0.003, 0.30)]. Individuals are interested in genetic testing for T2D risk which offers unique information that is personalized. Financial accessibility, validity of the test and availability of diabetes prevention programs were identified as predictors of interest in T2D testing. PMID:26789839

  3. Factors Motivating Individuals to Consider Genetic Testing for Type 2 Diabetes Risk Prediction

    PubMed Central

    Wessel, Jennifer; Gupta, Jyoti; de Groot, Mary

    2016-01-01

    The purpose of this study was to identify attitudes and perceptions of willingness to participate in genetic testing for type 2 diabetes (T2D) risk prediction in the general population. Adults (n = 598) were surveyed on attitudes about utilizing genetic testing to predict future risk of T2D. Participants were recruited from public libraries (53%), online registry (37%) and a safety net hospital emergency department (10%). Respondents were 37±11 years old, primarily White (54%), female (69%), college educated (46%), with an annual income ≥$25,000 (56%). Half of participants were interested in genetic testing for T2D (52%) and 81% agreed/strongly agreed genetic testing should be available to the public. Only 57% of individuals knew T2D is preventable. A multivariate model to predict interest in genetic testing was adjusted for age, gender, recruitment location and BMI; significant predictors were motivation (high perceived personal risk of T2D [OR = 4.38 (1.76, 10.9)]; family history [OR = 2.56 (1.46, 4.48)]; desire to know risk prior to disease onset [OR = 3.25 (1.94, 5.42)]; and knowing T2D is preventable [OR = 2.11 (1.24, 3.60)], intention (if the cost is free [OR = 10.2 (4.27, 24.6)]; and learning T2D is preventable [OR = 5.18 (1.95, 13.7)]) and trust of genetic testing results [OR = 0.03 (0.003, 0.30)]. Individuals are interested in genetic testing for T2D risk which offers unique information that is personalized. Financial accessibility, validity of the test and availability of diabetes prevention programs were identified as predictors of interest in T2D testing. PMID:26789839

  4. The Next Challenge for Psychiatric Genetics: Characterizing the Risk Associated with Identified Genes

    PubMed Central

    Dick, Danielle M.; Rose, Richard J.; Kaprio, Jaakko

    2006-01-01

    Background As advances in genetics further our ability to identify genes influencing psychiatric disorders, the next challenge facing psychiatric genetics is to characterize the risk associated with specific genetic variants in order to better understand how these susceptibility genes are involved in the pathways leading to illness. Methods To further this goal, findings from behavior genetic analyses about how genetic influences act can be used to guide hypothesis testing about the effects associated with specific genes. Results Using the phenotype of alcohol dependence as an example, this paper provides an overview of how the integration of behavioral and statistical genetics can advance our knowledge about the genetics of psychiatric disorders. Areas currently being investigated in behavior genetics include careful delineation of phenotypes, to examine the heritability of various aspects of normal and abnormal behavior; developmental changes in the nature and magnitude of genetic and environmental effects; the extent to which different behaviors are influenced by common genes; and different forms of gene-environment correlation and interaction. Conclusions Understanding how specific genes are involved in these processes has the potential to significantly enhance our understanding of the development of psychiatric disorders. PMID:17162621

  5. Multivariate Methods for Genetic Variants Selection and Risk Prediction in Cardiovascular Diseases.

    PubMed

    Malovini, Alberto; Bellazzi, Riccardo; Napolitano, Carlo; Guffanti, Guia

    2016-01-01

    Over the last decade, high-throughput genotyping and sequencing technologies have contributed to major advancements in genetics research, as these technologies now facilitate affordable mapping of the entire genome for large sets of individuals. Given this, genome-wide association studies are proving to be powerful tools in identifying genetic variants that have the capacity to modify the probability of developing a disease or trait of interest. However, when the study's goal is to evaluate the effect of the presence of genetic variants mapping to specific chromosomes regions on a specific phenotype, the candidate loci approach is still preferred. Regardless of which approach is taken, such a large data set calls for the establishment and development of appropriate analytical methods in order to translate such knowledge into biological or clinical findings. Standard univariate tests often fail to identify informative genetic variants, especially when dealing with complex traits, which are more likely to result from a combination of rare and common variants and non-genetic determinants. These limitations can partially be overcome by multivariate methods, which allow for the identification of informative combinations of genetic variants and non-genetic features. Furthermore, such methods can help to generate additive genetic scores and risk stratification algorithms that, once extensively validated in independent cohorts, could serve as useful tools to assist clinicians in decision-making. This review aims to provide readers with an overview of the main multivariate methods for genetic data analysis that could be applied to the analysis of cardiovascular traits. PMID:27376073

  6. Genetic Influences on Blood Lipids and Cardiovascular Risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Changes in diet are likely to modulate cardiovascular disease risk, but after decades of active research and heated discussion the question still remains: what is the optimal diet to achieve this elusive goal? A well-known phenomenon in nutrition research and practice is the dramatic variability in ...

  7. Impact of genetic risk assessment on nutrition-related lifestyle behaviours

    PubMed Central

    Vernarelli, Jacqueline A.

    2013-01-01

    Genetic susceptibility testing for common complex disease is a practice that is currently in clinical use. There are two types of gene mutations, and therefore, two varieties of genotype testing: deterministic and susceptibility. As the term suggests, deterministic genes determine whether or not a person will develop a given trait in Mendelian fashion, such as Huntington’s disease. Genotype screening for such deterministic mutations has existed for decades, and is commonly used in routine medical practice. In recent years, the sequencing of the human genome has identified several ‘susceptibility genes’ or genes with incomplete penetrance. Mutations in these genes may increase disease susceptibility, but are not causative for disease. Genetic susceptibility testing allows unaffected individuals to obtain risk information for a variety of common complex diseases and health conditions including Alzheimer’s disease (AD), CVD, cancer and diabetes. The availability of genetic susceptibility testing has increased over the past decade, and several studies are now focusing on the impact that genetic testing has on health and other lifestyle behaviours related to nutrition. The aim of this paper is to review the literature and evaluate what, if any, impact genetic risk assessment has on behaviours related to nutrition and physical activity. This paper summarises seven clinical studies that evaluated the impact of disclosing genetic risk information for disease on nutrition-related health behaviour changes. Of these seven studies, only three studies reported that health behaviour change was influenced by genotype disclosure. PMID:23095764

  8. The Genetics Revolution: Programs and Issues for the Community College. A Monograph Highlighting the Winners of the Exxon Education Foundation Innovation Awards.

    ERIC Educational Resources Information Center

    Mays, Marilyn Elaine, Ed.

    Presented at a 1996 conference on the implications of the Human Genome Project for community and technical colleges, the 30 papers included in this monograph describe methods for incorporating genetics studies into the two-year college curriculum. Among the papers provided are: (1) "Facing the Unknown: The Ethical Challenges of Biotechnology" (J.…

  9. Association of Obesity-related Genetic Variants With Endometrial Cancer Risk: A Report From the Shanghai Endometrial Cancer Genetics Study

    PubMed Central

    Delahanty, Ryan J.; Beeghly-Fadiel, Alicia; Xiang, Yong-Bing; Long, Jirong; Cai, Qiuyin; Wen, Wanqing; Xu, Wang-Hong; Cai, Hui; He, Jing; Gao, Yu-Tang; Zheng, Wei; Shu, Xiao Ou

    2011-01-01

    Obesity is a well-established risk factor for endometrial cancer, the most common gynecologic malignancy. Recent genome-wide association studies (GWAS) have identified multiple genetic markers for obesity. The authors evaluated the association of obesity-related single nucleotide polymorphisms (SNPs) with endometrial cancer using GWAS data from their recently completed study, the Shanghai Endometrial Cancer Genetics Study, which comprised 832 endometrial cancer cases and 2,049 controls (1996–2005). Thirty-five SNPs previously associated with obesity or body mass index (BMI; weight (kg)/height (m)2) at a minimum significance level of ≤5 × 10−7 in the US National Human Genome Research Institute's GWAS catalog (http://genome.gov/gwastudies) and representing 26 unique loci were evaluated by either direct genotyping or imputation. The authors found that for 22 of the 26 unique loci tested (84.6%), the BMI-associated risk variants were present at a higher frequency in cases than in population controls (P = 0.0003). Multiple regression analysis showed that 9 of 35 BMI-associated variants, representing 7 loci, were significantly associated (P ≤ 0.05) with the risk of endometrial cancer; for all but 1 SNP, the direction of association was consistent with that found for BMI. For consistent SNPs, the allelic odds ratios ranged from 1.15 to 1.29. These 7 loci are in the SEC16B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes. The associations persisted after adjustment for BMI, suggesting that genetic markers of obesity provide value in addition to BMI in predicting endometrial cancer risk. PMID:21976109

  10. Genetic Variants Associated with Breast Cancer Risk: Comprehensive Field Synopsis, Meta-Analysis, and Epidemiologic Evidence

    PubMed Central

    Zhang, Ben; Beeghly-Fadiel, Alicia; Long, Jirong; Zheng, Wei

    2011-01-01

    SUMMARY Background Over 1,000 reports have been published during the past two decades on associations between genetic variants in candidate genes and breast cancer risk. Results have been generally inconsistent. We conducted literature searches and meta-analyses to provide a field synopsis of the current understanding of the genetic architecture of breast cancer risk. Methods Systematic literature searches for candidate gene association studies of breast cancer risk were conducted in two stages using PubMed on or before February 28, 2010. A total of 24,500 publications were identified, of which, 1,059 were deemed eligible for inclusion. Meta-analyses were conducted for 279 genetic variants in 128 candidate genes or chromosomal loci that had a minimum of three data sources available. Variants with significant associations by meta-analysis were assessed using the Venice criteria and scored as having strong, moderate, or weak cumulative evidence for an association with breast cancer risk. Findings Fifty-one variants in 40 genes showed statistically significant associations with breast cancer risk. Cumulative epidemiologic evidence for an association with breast cancer risk was graded as strong for 10 variants in six genes (ATM, CASP8, CHEK2, CTLA4, NBN, and TP53), moderate for four variants in four genes (ATM, CYP19A1, TERT, and XRCC3), and weak for 37 additional variants. Additionally, in meta-analyses that included a minimum of 10,000 cases and 10,000 controls, convincing evidence of no association with breast cancer risk was identified for 45 variants in 37 genes. Interpretation While most genetic variants evaluated in previous candidate gene studies showed no association with breast cancer risk in meta-analyses, 14 variants in 9 genes were found to have moderate to strong evidence for an association with breast cancer risk. Further evaluation of these variants is warranted. PMID:21514219

  11. Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review

    PubMed Central

    Jing, Lijun; Su, Li; Ring, Brian Z.

    2014-01-01

    The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in 68 studies across six different cancer types, comparing association results between ethnic groups and examining linkage disequilibrium between risk alleles and nearby genetic loci. We find that the relevance of ethnic background depends on the question. If asked whether the association of variants with disease risk is conserved across ethnic boundaries, we find that the answer is yes, the majority of markers show insignificant variability in association with cancer risk across ethnic groups. However if the question is whether a significant association between a variant and cancer risk is likely to reproduce, the answer is no, most markers do not validate in an ethnic group other than the discovery cohort’s ancestry. This lack of reproducibility is not attributable to studies being inadequately populated due to low allele frequency in other ethnic groups. Instead, differences in local genomic structure between ethnic groups are associated with the strength of association with cancer risk and therefore confound interpretation of the implied physiologic association tracked by the disease allele. This suggest that a biological association for cancer risk alleles may be broadly consistent across ethnic boundaries, but reproduction of a clinical study in another ethnic group is uncommon, in part due to confounding genomic architecture. As clinical studies are increasingly performed globally this has important implications for how cancer risk stratifiers should be studied and

  12. Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

    PubMed Central

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara; Aspesi, Anna; Casadio, Caterina; Ardissone, Francesco; Ruffini, Enrico; Betta, Pier Giacomo; Libener, Roberta; Guaschino, Roberto; Piccolini, Ezio; Neri, Monica; Musk, Arthur W. B.; de Klerk, Nicholas H.; Hui, Jennie; Beilby, John; James, Alan L.; Creaney, Jenette; Robinson, Bruce W.; Mukherjee, Sutapa; Palmer, Lyle J.; Mirabelli, Dario; Ugolini, Donatella; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5–17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2–3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52–95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos. PMID:23626673

  13. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    PubMed

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara; Aspesi, Anna; Casadio, Caterina; Ardissone, Francesco; Ruffini, Enrico; Betta, Pier Giacomo; Libener, Roberta; Guaschino, Roberto; Piccolini, Ezio; Neri, Monica; Musk, Arthur W B; de Klerk, Nicholas H; Hui, Jennie; Beilby, John; James, Alan L; Creaney, Jenette; Robinson, Bruce W; Mukherjee, Sutapa; Palmer, Lyle J; Mirabelli, Dario; Ugolini, Donatella; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos. PMID:23626673

  14. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women

    MedlinePlus

    ... Task Force learned about the potential benefits and harms of this multi- step process: (1) Women who ... remove her breasts or ovaries. Potential Benefits and Harms of Using Medications to Reduce Breast Cancer Risk ...

  15. Prenatal smoking and genetic risk: examining the childhood origins of externalizing behavioral problems.

    PubMed

    Petkovsek, Melissa A; Boutwell, Brian B; Beaver, Kevin M; Barnes, J C

    2014-06-01

    An ever-growing body of research has begun to focus closely on the role of prenatal smoke exposure in the development of conduct problems in children. To this point, there appears to be a correlation between prenatal nicotine exposure and behavioral problems. We build on this prior research by examining the coalescence of prenatal smoke exposure and genetic risk factors in the prediction of behavior problems. Specifically, the current study analyzed data from a nationally representative sample of twin pairs collected during early childhood. Our findings suggested that an interaction existed between prenatal smoke exposure and genetic risk factors which corresponded to increased risk of behavior problems. These findings provide evidence of a gene-environment interaction, in that prenatal smoke exposure conditioned the influence of genetic risk factors in the prediction of aggressive behavior. Interestingly, the association between genetic risk and prenatal smoking was sex-specific, and only reached statistical significance in females. Given the nature of our findings, it may shed light on why heterogeneity exists concerning the relationship between prenatal smoke exposure and externalizing behavioral problems in children. PMID:24739935

  16. Genetics of Type 2 Diabetes: It Matters From Which Parent We Inherit the Risk.

    PubMed

    Lyssenko, Valeriya; Groop, Leif; Prasad, Rashmi B

    2015-01-01

    Type 2 diabetes (T2D) results from a co-occurrence of genes and environmental factors. There are more than 120 genetic loci suggested to be associated with T2D, or with glucose and insulin levels in European and multi-ethnic populations. Risk of T2D is higher in the offspring if the mother rather than the father has T2D. Genetically, this can be associated with a unique parent-of-origin (PoO) transmission of risk alleles, and it relates to genetic programming during the intrauterine period, resulting in the inability to increase insulin secretion in response to increased demands imposed by insulin resistance later in life. Such PoO transmission is seen for variants in the KLF14, KCNQ1, GRB10, TCF7L2, THADA, and PEG3 genes. Here we describe T2D susceptibility genes associated with defects in insulin secretion, and thereby risk of overt T2D. This review emphasizes the need to consider distorted parental transmission of risk alleles by exploring the genetic risk of T2D. PMID:27111116

  17. Managing patients at genetic risk of breast cancer.

    PubMed

    Pederson, Holly J; Padia, Shilpa A; May, Maureen; Grobmyer, Stephen

    2016-03-01

    Hereditary syndromes that increase the risk of breast cancer are not common, but it is critical to recognize and manage them appropriately. This paper reviews the management of patients with the most common hereditary breast cancer syndromes, ie, hereditary breast and ovarian cancer syndrome, hereditary diffuse gastric cancer, Cowden syndrome (PTEN hamartoma tumor syndrome), Peutz-Jeghers syndrome, and Li-Fraumeni syndrome. PMID:26974991

  18. Meat, vegetables and genetic polymorphisms and the risk of colorectal carcinomas and adenomas

    PubMed Central

    Skjelbred, Camilla F; Sæbø, Mona; Hjartåker, Anette; Grotmol, Tom; Hansteen, Inger-Lise; Tveit, Kjell M; Hoff, Geir; Kure, Elin H

    2007-01-01

    Background The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population. Methods We used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1, GSTT1, GSTP1 Ile105Val, EPHX1 Tyr113His and EPHX1 His139Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression. Results A higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2nd quartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of the EPHX1 codon 113 polymorphism. An association was also observed for the EPHX1 codon 113 polymorphism in the low-risk adenomas, although not as obvious. Conclusion Although, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma. PMID:18093316

  19. Low frequency genetic variants in the mu-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine

    PubMed Central

    Clarke, Toni-Kim; Crist, Richard C.; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; O’Brien, Charles P.; Oslin, David W.; Ferraro, Thomas N.; Lohoff, Falk W.; Berrettini, Wade H.

    2013-01-01

    The μ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute –Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24–0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. PMID:23454283

  20. Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine.

    PubMed

    Clarke, Toni-Kim; Crist, Richard C; Kampman, Kyle M; Dackis, Charles A; Pettinati, Helen M; O'Brien, Charles P; Oslin, David W; Ferraro, Thomas N; Lohoff, Falk W; Berrettini, Wade H

    2013-05-10

    The μ-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute - Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24-0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. PMID:23454283

  1. Genetic toxicology at the crossroads-from qualitative hazard evaluation to quantitative risk assessment.

    PubMed

    White, Paul A; Johnson, George E

    2016-05-01

    Applied genetic toxicology is undergoing a transition from qualitative hazard identification to quantitative dose-response analysis and risk assessment. To facilitate this change, the Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC) sponsored a workshop held in Lancaster, UK on July 10-11, 2014. The event included invited speakers from several institutions and the contents was divided into three themes-1: Point-of-departure Metrics for Quantitative Dose-Response Analysis in Genetic Toxicology; 2: Measurement and Estimation of Exposures for Better Extrapolation to Humans and 3: The Use of Quantitative Approaches in Genetic Toxicology for human health risk assessment (HHRA). A host of pertinent issues were discussed relating to the use of in vitro and in vivo dose-response data, the development of methods for in vitro to in vivo extrapolation and approaches to use in vivo dose-response data to determine human exposure limits for regulatory evaluations and decision-making. This Special Issue, which was inspired by the workshop, contains a series of papers that collectively address topics related to the aforementioned themes. The Issue includes contributions that collectively evaluate, describe and discuss in silico, in vitro, in vivo and statistical approaches that are facilitating the shift from qualitative hazard evaluation to quantitative risk assessment. The use and application of the benchmark dose approach was a central theme in many of the workshop presentations and discussions, and the Special Issue includes several contributions that outline novel applications for the analysis and interpretation of genetic toxicity data. Although the contents of the Special Issue constitutes an important step towards the adoption of quantitative methods for regulatory assessment of genetic toxicity, formal acceptance of quantitative methods for HHRA and regulatory decision-making will require consensus regarding the

  2. Genetic Testing for Sports Performance, Responses to Training and Injury Risk: Practical and Ethical Considerations.

    PubMed

    Williams, Alun G; Wackerhage, Henning; Day, Stephen H

    2016-01-01

    This paper addresses practical and ethical considerations regarding genetic tests to predict performance and/or risk of exercise-related injury or illness. Various people might wish to conduct sport-related genetic tests for a variety of reasons. For example, an individual might seek personal genetic information to help guide their own sport participation. A sports coach might wish to test young athletes to aid team selection or individualize training. A physician might want to predict the risk of injury or illness in athletes and advise regarding selection or preventative measures. An insurance company might seek to estimate the risk of career-threatening injury for athletes based partly on genetic information. Whilst this information is, in part, encoded in our DNA sequence, the available tests allow generally only a poor prediction of the aforementioned variables. In other words, the current genetic tests and analysis methods are not powerful enough to inform important decisions in sport to a substantial degree. It is particularly disappointing that more than half of the commercially available genetic tests related to exercise and sport do not appear to identify publicly the genetic variants they assess, making scrutiny by academic scholars and consumers (or their representatives) impossible. There are also challenging ethical issues to consider. For example, the imposition of genetic tests on individuals (especially young people) by third parties is potentially susceptible to abuse. Scientists and practitioners should understand the limitations of the tests currently available, the ethical concerns and the importance of counselling before and after testing so that they are only used in a responsible manner. PMID:27287080

  3. Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether t...

  4. Genetic variants related to height and risk of atrial fibrillation: the cardiovascular health study.

    PubMed

    Rosenberg, Michael A; Kaplan, Robert C; Siscovick, David S; Psaty, Bruce M; Heckbert, Susan R; Newton-Cheh, Christopher; Mukamal, Kenneth J

    2014-07-15

    Increased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥ 65 years) enrolled in 1989-1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10(-8)). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets. PMID:24944287

  5. 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

    PubMed Central

    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

  6. 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.

    PubMed

    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

  7. Regional differences in awareness and attitudes regarding genetic testing for disease risk and ancestry.

    PubMed

    Jonassaint, Charles R; Santos, Eunice R; Glover, Crystal M; Payne, Perry W; Fasaye, Grace-Ann; Oji-Njideka, Nefertiti; Hooker, Stanley; Hernandez, Wenndy; Foster, Morris W; Kittles, Rick A; Royal, Charmaine D

    2010-09-01

    Little is known about the lay public's awareness and attitudes concerning genetic testing and what factors influence their perspectives. The existing literature focuses mainly on ethnic and socioeconomic differences; however, here we focus on how awareness and attitudes regarding genetic testing differ by geographical regions in the US. We compared awareness and attitudes concerning genetic testing for disease risk and ancestry among 452 adults (41% Black and 67% female) in four major US cities, Norman, OK; Cincinnati, OH; Harlem, NY; and Washington, DC; prior to their participation in genetic ancestry testing. The OK participants reported more detail about their personal ancestries (p = 0.02) and valued ancestry testing over disease testing more than all other sites (p < 0.01). The NY participants were more likely than other sites to seek genetic testing for disease (p = 0.01) and to see benefit in finding out more about one's ancestry (p = 0.02), while the DC participants reported reading and hearing more about genetic testing for African ancestry than all other sites (p < 0.01). These site differences were not better accounted for by sex, age, education, self-reported ethnicity, religion, or previous experience with genetic testing/counseling. Regional differences in awareness and attitudes transcend traditional demographic predictors, such as ethnicity, age and education. Local sociocultural factors, more than ethnicity and socioeconomic status, may influence the public's awareness and belief systems, particularly with respect to genetics. PMID:20549517

  8. Breast cancer risk in MEN1 - a cancer genetics perspective.

    PubMed

    Brennan, Paul

    2015-03-01

    The tumour spectrum associated with multiple endocrine neoplasia type 1 (MEN1) has been known for many years. New data suggest that females with MEN1 may face an additional, hitherto unrecognized, risk of early-onset breast cancer. The menin protein is certainly known to have a role in regulating oestrogen receptor activity; but how robust are the data linking MEN1 to breast cancer? This article examines the published data from the viewpoint of a cancer geneticist and considers whether there really is a justifiable indication for enhanced breast surveillance in women with MEN1. PMID:25279812

  9. Genetic Association Between Angiotensinogen Polymorphisms and Lung Cancer Risk

    PubMed Central

    Wang, Hong; Zhang, Kun; Qin, Haifeng; Yang, Lin; Zhang, Liyu; Cao, Yanyan

    2015-01-01

    Abstract Earlier published studies investigating the association between polymorphisms in the angiotensinogen gene and lung cancer risk showed no consistent results. In this study, we have summarized all currently available data to examine the correlation by meta-analysis. Case–control studies addressing the association being examined were identified through Embase, the Cochrane Library, ISI Web of Science (Web of Knowledge), Google Scholar, PubMed, and CNKI databases. Risk of lung cancer (odds ratio [OR] and 95% confidence interval [CI]) was estimated with the fixed or the random effects model assuming homozygous, allele, heterozygous, dominant, and recessive models for all angiotensinogen polymorphisms. We identified a total of 10 articles in this meta-analysis, including 7 for Leu84Phe, 4 for Ile143Val, and 3 for Leu53Leu. In the meta-analysis of Leu84Phe polymorphism, the homozygous model provided an OR of 1.44 (Phe/Phe vs Ile/Ile: OR = 1.44, 95% CI = 1.04–1.99, P values for heterogeneity test (Q-test) [PHet] = 0.382). The significantly increased risk was similarly indicated in the recessive model (Phe/Phe vs Phe/Ile + Ile/Ile: OR = 1.41, 95% CI = 1.02–1.95, PHet = 0.381). We also observed a positive association in the Caucasian subgroup. The heterozygous model and the dominant model tested for the Ile143Val polymorphism showed a marginally increased risk (Ile/Val vs Ile/Ile: OR = 1.16, 95% CI = 1.00–1.36, PHet = 0.323; Val/Val + Ile/Val vs Ile/Ile: OR = 1.15, 95% CI = 0.99–1.34, PHet = 0.253). These data suggest that Leu84Phe and Ile143Val polymorphisms in the angiotensinogen gene may be useful biomarkers for lung cancer in some specific populations. PMID:26376373

  10. Genetic Association Between Angiotensinogen Polymorphisms and Lung Cancer Risk.

    PubMed

    Wang, Hong; Zhang, Kun; Qin, Haifeng; Yang, Lin; Zhang, Liyu; Cao, Yanyan

    2015-09-01

    Earlier published studies investigating the association between polymorphisms in the angiotensinogen gene and lung cancer risk showed no consistent results. In this study, we have summarized all currently available data to examine the correlation by meta-analysis. Case-control studies addressing the association being examined were identified through Embase, the Cochrane Library, ISI Web of Science (Web of Knowledge), Google Scholar, PubMed, and CNKI databases. Risk of lung cancer (odds ratio [OR] and 95% confidence interval [CI]) was estimated with the fixed or the random effects model assuming homozygous, allele, heterozygous, dominant, and recessive models for all angiotensinogen polymorphisms. We identified a total of 10 articles in this meta-analysis, including 7 for Leu84Phe, 4 for Ile143Val, and 3 for Leu53Leu. In the meta-analysis of Leu84Phe polymorphism, the homozygous model provided an OR of 1.44 (Phe/Phe vs Ile/Ile: OR = 1.44, 95% CI = 1.04-1.99, P values for heterogeneity test (Q-test) [P(Het)] = 0.382). The significantly increased risk was similarly indicated in the recessive model (Phe/Phe vs Phe/Ile + Ile/Ile: OR = 1.41, 95% CI = 1.02-1.95, P(Het) = 0.381). We also observed a positive association in the Caucasian subgroup. The heterozygous model and the dominant model tested for the Ile143Val polymorphism showed a marginally increased risk (Ile/Val vs Ile/Ile: OR = 1.16, 95% CI = 1.00-1.36, P(Het) = 0.323; Val/Val + Ile/Val vs Ile/Ile: OR = 1.15, 95% CI = 0.99-1.34, P(Het) = 0.253). These data suggest that Leu84Phe and Ile143Val polymorphisms in the angiotensinogen gene may be useful biomarkers for lung cancer in some specific populations. PMID:26376373

  11. Predicting the Risk of Rheumatoid Arthritis and Its Age of Onset through Modelling Genetic Risk Variants with Smoking

    PubMed Central

    Scott, Ian C.; Seegobin, Seth D.; Steer, Sophia; Tan, Rachael; Forabosco, Paola; Hinks, Anne; Eyre, Stephen; Morgan, Ann W.; Wilson, Anthony G.; Hocking, Lynne J.; Wordsworth, Paul; Barton, Anne; Worthington, Jane; Cope, Andrew P.; Lewis, Cathryn M.

    2013-01-01

    The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factor's impact on prediction. Each model's ability to discriminate anti-citrullinated protein antibody (ACPA)-positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P<0.0001); ever-smoking associated with older onset disease. This latter finding suggests smoking's impact on RA risk manifests later in life. Our modelling demonstrates that combining risk factors provides clinically informative RA prediction; additionally HLA and smoking status can be used to predict the risk of younger and older onset RA, respectively. PMID:24068971

  12. Genetic markers of pigmentation are novel risk loci for uveal melanoma.

    PubMed

    Ferguson, Robert; Vogelsang, Matjaz; Ucisik-Akkaya, Esma; Rai, Karan; Pilarski, Robert; Martinez, Carlos N; Rendleman, Justin; Kazlow, Esther; Nagdimov, Khagay; Osman, Iman; Klein, Robert J; Davidorf, Frederick H; Cebulla, Colleen M; Abdel-Rahman, Mohamed H; Kirchhoff, Tomas

    2016-01-01

    While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r(2) > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility. PMID:27499155

  13. Genetic markers of pigmentation are novel risk loci for uveal melanoma

    PubMed Central

    Ferguson, Robert; Vogelsang, Matjaz; Ucisik-Akkaya, Esma; Rai, Karan; Pilarski, Robert; Martinez, Carlos N.; Rendleman, Justin; Kazlow, Esther; Nagdimov, Khagay; Osman, Iman; Klein, Robert J.; Davidorf , Frederick H.; Cebulla, Colleen M.; Abdel-Rahman, Mohamed H.; Kirchhoff , Tomas

    2016-01-01

    While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415–0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419–0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339–0.637; p = 3.04E-07) are correlated (r2 > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility. PMID:27499155

  14. Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

    PubMed

    Schrauwen, Isabelle; Barber, Renee M; Schatzberg, Scott J; Siniard, Ashley L; Corneveaux, Jason J; Porter, Brian F; Vernau, Karen M; Keesler, Rebekah I; Matiasek, Kaspar; Flegel, Thomas; Miller, Andrew D; Southard, Teresa; Mariani, Christopher L; Johnson, Gayle C; Huentelman, Matthew J

    2014-01-01

    Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated. PMID:25393235

  15. Identification of Novel Genetic Risk Loci in Maltese Dogs with Necrotizing Meningoencephalitis and Evidence of a Shared Genetic Risk across Toy Dog Breeds

    PubMed Central

    Schatzberg, Scott J.; Siniard, Ashley L.; Corneveaux, Jason J.; Porter, Brian F.; Vernau, Karen M.; Keesler, Rebekah I.; Matiasek, Kaspar; Flegel, Thomas; Miller, Andrew D.; Southard, Teresa; Mariani, Christopher L.; Johnson, Gayle C.; Huentelman, Matthew J.

    2014-01-01

    Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10−7) and 15 (chr15:53338796A>G, p = 1.5×10−7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10–11 and p = 2.5×10−7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated. PMID:25393235

  16. A Twelve-SNP Genetic Risk Score Identifies Individuals at Increased Risk for Future Atrial Fibrillation and Stroke

    PubMed Central

    Smith, J. Gustav; Sjögren, Marketa; Lubitz, Steven A.; Ellinor, Patrick T.; Louie, Judy Z.; Catanese, Joseph J.; Engström, Gunnar; Devlin, James J.

    2015-01-01

    Background and Purpose Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF. Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need. Here, we investigate whether multiple single nucleotide polymorphisms (SNPs) together as an AF genetic risk score (AF-GRS) can improve prediction of one's risk for AF. Methods In 27,471 participants of the Malmö Diet and Cancer Study, a prospective, community-based cohort, we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke. Median follow-up was 14.4 years for incident AF and 14.5 years for ischemic stroke. The AF-GRS comprised 12 SNPs that had been previously shown to be associated with AF at genome-wide significance. Results During follow-up, 2,160 participants experienced a first AF event and 1,495 had a first ischemic stroke event. Participants in the top AF-GRS quintile were at increased risk for incident AF (HR = 2.00; 95%CI = 1.73 to 2.31; P=2.7×10−21) and ischemic stroke (HR = 1.23; 95%CI = 1.04 to 1.46; P=0.02) when compared with the bottom quintile. Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification (P<0.0001 for both). Conclusions An AF-GRS can identify 20% of individuals who are at approximately two-fold increased risk for incident AF and at 23% increased risk for ischemic stroke. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful. PMID:25123217

  17. Genetic Testing and Neuroimaging: Trading off Benefit and Risk for Youth with Mental Illness

    PubMed Central

    Lee, Grace; Mizgalewicz, Ania; Borgelt, Emily; Illes, Judy

    2015-01-01

    According to the World Health Organization, mental illness is one of the leading causes of disability worldwide. The first onset of mental illness usually occurs during childhood or adolescence. Neuroimaging and genetic testing have been invaluable in research on behavioral and intentional disorders, particularly with their potential to lead to improved diagnostic and predictive capabilities and to decrease the associated burdens of disease. The present study focused specifically the perspectives of mental health providers on the role of neuroimaging and genetic testing in clinical practice with children and adolescents. We interviewed 38 psychiatrists, psychologists, and allied mental health professionals who work primarily with youth about their receptivity towards either the use of neuroimaging or genetic testing. Interviews probed the role they foresee for these modalities for prediction, diagnosis, and treatment planning, and the benefits and risks they anticipate. Practitioners anticipated three major benefits associated with clinical introduction of imaging and genetic testing in the mental health care for youth: (1) improved understanding of illness, (2) more accurate diagnosis than available through conventional clinical examination, and (3) validation of treatment plans. They also perceived three major risks: (1) potential adverse impacts on employment and insurance as adolescents reach adulthood, (2) misuse or misinterpretation of the imaging or genetic data, and (3) infringements on self-esteem or self-motivation. Movement of brain imaging and genetic testing into clinical care will require a delicate balance of biology and respect for autonomy in the still-evolving cognitive and affective world of young individuals. PMID:26949737

  18. Assessing genetic risks: Implications for health and social policy. Executive summary

    SciTech Connect

    Andrews, L.B.; Fullarton, J.E.; Holtzman, N.A.; Motulsky, A.G.

    1994-12-31

    The last decade has seen remarkable growth in the understanding of genetics as applied to medicine. In addition, the technology for the detection of genetic diseases has developed rapidly, and testing for genetic diseases with DNA techniques has become increasingly possible. The last few years have also seen the initiation of the Human Genome Project, the aim of which is mapping and ultimately sequencing all human genes--giving special attention to genes that cause or may predispose to disease. As part of this ambitious project, and for the first time in the history of science, a special effort is being made as part of a large research project to explore its broader social implications. Three to five percent of the funding available for the Human Genome Project has been set aside to study the many social, ethical, and legal implications that will result from better understanding of human heredity and its impact on disease. Since assessment of genetic risks by genetic testing is expanding rapidly, the Institute of medicine (IOM) of the National Academy of Sciences undertook this study to assess the current status and future implications of such testing. This study deals with some of the scientific aspects of genetic risk assessment as well as the many societal problems that have already arisen and are likely to be posed by future developments.

  19. Population-standardized genetic risk score: the SNP-based method of choice for inherited risk assessment of prostate cancer.

    PubMed

    Conran, Carly A; Na, Rong; Chen, Haitao; Jiang, Deke; Lin, Xiaoling; Zheng, S Lilly; Brendler, Charles B; Xu, Jianfeng

    2016-01-01

    Several different approaches are available to clinicians for determining prostate cancer (PCa) risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms (SNPs) has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men (n = 1654) enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores (GRSs) were used for the evaluation of individual disease risk such as risk allele count (GRS-RAC), weighted risk allele count (GRS-wRAC), and population-standardized genetic risk score (GRS-PS). Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV). All SNP-based methods were found to be independently associated with PCa (all P < 0.05; hence their clinical validity). The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively (all P < 0.05 for differences between patients with or without PCa). All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV (all P > 0.05 for comparisons between the three methods), and all three SNP-based methods had a significantly higher AUC than family history (all P < 0.05). Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value (where 1.0 represents average population risk) can be easily interpreted regardless

  20. Population-standardized genetic risk score: the SNP-based method of choice for inherited risk assessment of prostate cancer

    PubMed Central

    Conran, Carly A; Na, Rong; Chen, Haitao; Jiang, Deke; Lin, Xiaoling; Zheng, S Lilly; Brendler, Charles B; Xu, Jianfeng

    2016-01-01

    Several different approaches are available to clinicians for determining prostate cancer (PCa) risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms (SNPs) has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men (n = 1654) enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores (GRSs) were used for the evaluation of individual disease risk such as risk allele count (GRS-RAC), weighted risk allele count (GRS-wRAC), and population-standardized genetic risk score (GRS-PS). Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV). All SNP-based methods were found to be independently associated with PCa (all P < 0.05; hence their clinical validity). The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively (all P < 0.05 for differences between patients with or without PCa). All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV (all P > 0.05 for comparisons between the three methods), and all three SNP-based methods had a significantly higher AUC than family history (all P < 0.05). Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value (where 1.0 represents average population risk) can be easily interpreted regardless

  1. Genetic influences on blood lipids and cardiovascular disease risk: tools for primary prevention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic polymorphism in the human population is part of the evolutionary process that results from the interaction between the environment and the human genome. Recent changes in diet have upset this equilibrium, potentially influencing the risk of most common morbidities such as cardiovascular dise...

  2. Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke

    PubMed Central

    Rutten-Jacobs, Loes C.A.; Thijs, Vincent; Holliday, Elizabeth G.; Levi, Chris; Bevan, Steve; Malik, Rainer; Boncoraglio, Giorgio; Sudlow, Cathie; Rothwell, Peter M.; Dichgans, Martin; Markus, Hugh S.

    2016-01-01

    Background and Purpose— White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. Methods— We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging–confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. Results— The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI

  3. Psychological Risks of Genetically Testing Children for a Hereditary Cancer Syndrome.

    ERIC Educational Resources Information Center

    Grosfeld, F. J. M.; Lips, C. J. M.; Beemer, F. A.; van Spijker, H. G.; Brouwers-Smalbraak, G. J.; ten Kroode, H. F. J.

    1997-01-01

    Medical considerations about testing and possible psychological consequences for the child and family of genetically testing children are discussed. Risks include distress from ambivalent feelings toward testing, preoccupation with disease-related signs, changes in family interactions, the burdening prospect of a future disease, and medicalization…

  4. Estimating interaction between genetic and environmental risk factors efficiency of sampling designs within a cohort

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Large prospective cohorts originally assembled to study environmental risk factors are increasingly exploited to study gene-environment interactions. Given the cost of genetic studies in large numbers of subjects, being able to select a sub-sample for genotyping that contains most of the information...

  5. DEVELOPING MECHANISTIC DATA FOR INCORPORATION INTO CANCER AND GENETIC RISK ASSESSMENTS: OLD PROBLEMS AND NEW APPROACHES

    EPA Science Inventory

    26th Lauriston S. Taylor Lecture
    DEVELOPING MECHANISTIC DATA FOR INCORPORATION INTO CANCER AND
    GENETIC RISK ASSESSMENTS: OLD PROBLEMS AND NEW APPROACHES
    R. Julian Preston, Environmental Carcinogenesis Division, U.S. Environmental Protection
    Agency, NHEERL, Research Tr...

  6. Genetic variants in IRS2 may contribute to obesity and diabetes familial risk in Hispanic children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    IRS2 is a key regulator of glucose homeostasis and an obesity candidate gene, however, its role in children’s susceptibility to obesity and diabetes risk is unknown. Our specific aim was to identify genetic variants explaining a statistically significant quantitative trait locus on chromosome 13q fo...

  7. Pathways to Childhood Depressive Symptoms: The Role of Social, Cognitive, and Genetic Risk Factors

    ERIC Educational Resources Information Center

    Lau, Jennifer Y. F.; Rijsdijk, Fruhling; Gregory, Alice M.; McGuffin, Peter; Eley, Thalia C.

    2007-01-01

    Childhood depressive conditions have been explored from multiple theoretical approaches but with few empirical attempts to address the interrelationships among these different domains and their combined effects. In the present study, the authors examined different pathways through which social, cognitive, and genetic risk factors may be expressed…

  8. Epigenomic strategies at the interface of genetic and environmental risk factors for autism

    PubMed Central

    LaSalle, Janine M.

    2014-01-01

    Autism spectrum disorders have been increasing in prevalence over the past two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of autism spectrum disorders. PMID:23677056

  9. Cost-effectiveness of a genetic test for breast cancer risk.

    PubMed

    Folse, Henry J; Green, Linda E; Kress, Andrea; Allman, Richard; Dinh, Tuan A

    2013-12-01

    Genetic testing of seven single-nucleotide polymorphisms (7SNP) can improve estimates of risk of breast cancer relative to the Gail risk test alone, for the purpose of recommending MRI screening for women at high risk. A simulation of breast cancer and health care processes was used to conduct a virtual trial comparing the use of the 7SNP test with the Gail risk test to categorize patients by risk. Average-risk patients received annual mammogram, whereas high-risk patients received annual MRI. Cancer incidence was based on Surveillance, Epidemiology, and End Results data and validated to Cancer Prevention Study II Nutrition Cohort data. Risk factor values were drawn from National Health and Nutrition Examination Survey (NHANES-4) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial data. Mammogram characteristics were derived from Breast Cancer Surveillance Consortium data. The test was most cost-effective when given to patients at an intermediate lifetime risk of breast cancer. For patients with a risk of 16% to 28%, it resulted in a 1.91% reduction in cancer deaths, saving 0.005 quality-adjusted life years per person at a cost of $163,264 per QALY. These results were sensitive to the age at which the test is given, the discount rate, and the costs of the genetic test and MRI. The cost effectiveness of using the 7SNP test for patients with intermediate Gail risk is similar to that of other recommended strategies, including annual MRI for patients with a lifetime risk greater than 20% or BRCA1/2 mutations. PMID:24309564

  10. MTHFR genetic polymorphism increases the risk of preterm delivery

    PubMed Central

    Nan, Yanrong; Li, Hongmei

    2015-01-01

    Aims: This study aimed to investigate the association between the methylene tetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and premature delivery susceptibility. Methods: With matched age and gender, 108 premature delivery pregnant women as cases and 108 healthy pregnant women as controls were recruited in this case-control study. The cases and controls had same gestational weeks. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyze C677T and A1298C polymorphisms of the participants. Linkage disequilibrium (LD) and haplotype analysis were conducted by Haploview software. The differences for frequencies of gene type, allele and haplotypes in cases and controls were tested by chi-square test. The relevant risk of premature delivery was represented by odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: TT gene type frequency of C677T polymorphsim was higher in cases than the controls (P=0.004, OR=3.077, 95% CI=1.469-6.447), so was allele T (P=0.002, OR=1.853, 95% CI=1.265-2.716). Whereas, CC gene type of A1298C polymorphism had a lower distribution in cases than the controls (P=0.008, OR=0.095, 95% CI=0.012-0.775), so was allele C (P=0.047, OR=0.610, 95% CI=0.384-0.970). Haplotype analysis and linkage disequilibrium test conducted on the alleles of two polymorphisms in MTHFR gene, we discovered that haplotype T-A had a higher distribution in cases, which indicated that susceptible haplotype T-A was the candidate factor for premature delivery. Conclusions: Gene type TT of MTHFR C677T polymorphism might make premature delivery risk rise while gene type CC of A1298C polymorphism might have protective influence on premature delivery. PMID:26261642

  11. A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk.

    PubMed

    Ratner, Elena; Lu, Lingeng; Boeke, Marta; Barnett, Rachel; Nallur, Sunitha; Chin, Lena J; Pelletier, Cory; Blitzblau, Rachel; Tassi, Renata; Paranjape, Trupti; Hui, Pei; Godwin, Andrew K; Yu, Herbert; Risch, Harvey; Rutherford, Thomas; Schwartz, Peter; Santin, Alessandro; Matloff, Ellen; Zelterman, Daniel; Slack, Frank J; Weidhaas, Joanne B

    2010-08-15

    Ovarian cancer (OC) is the single most deadly form of women's cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA (miRNA) let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of OC and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, which disrupts a let-7 miRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from nonselected OC patients in three independent cohorts, two independent ovarian case-control studies, and OC patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as their family members. Our results indicate that the KRAS-variant is associated with more than 25% of nonselected OC cases. Further, we found that it is a marker for a significant increased risk of developing OC, as confirmed by two independent case-control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing OC, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities. PMID:20647319

  12. Placental genetic variations in circadian clock-related genes increase the risk of placental abruption

    PubMed Central

    Qiu, Chunfang; Gelaye, Bizu; Denis, Marie; Tadesse, Mahlet G; Enquobahrie, Daniel A; Ananth, Cande V; Pacora, Percy N; Salazar, Manuel; Sanchez, Sixto E; Williams, Michelle A

    2016-01-01

    The genetic architecture of placental abruption (PA) remains poorly understood. We examined variations in SNPs of circadian clock-related genes in placenta with PA risk. We also explored placental and maternal genomic contributions to PA risk. Placental genomic DNA samples were isolated from 280 PA cases and 244 controls. Genotyping was performed using the Illumina Cardio-MetaboChip. We examined 116 SNPs in 13 genes known to moderate circadian rhythms. Logistic regression models were fit to estimate odds ratios (ORs). The combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score. We examined independent and joint associations of wGRS derived from placental and maternal genomes with PA. Seven SNPs in five genes (ARNTL2, CRY2, DEC1, PER3 and RORA), in the placental genome, were associated with PA risk. Each copy of the minor allele (G) of a SNP in the RORA gene (rs2899663) was associated with a 30% reduced odds of PA (95% CI 0.52-0.95). The odds of PA increased with increasing placental-wGRS (Ptrend<0.001). The ORs were 1.00, 2.16, 3.24 and 4.48 across quartiles. Associations persisted after the maternal-wGRS was included in the model. There was evidence of an additive contribution of placental and maternal genetic contributions to PA risk. Participants with placental- and maternal-wGRS in the highest quartile, compared with those in the lowest quartile, had a 15.57-fold (95% CI 3.34-72.60) increased odds of PA. Placental variants in circadian clock-related genes are associated with PA risk; and the association persists after control of genetic variants in the maternal genome. PMID:27186326

  13. Dopamine Genetic Risk Score Predicts Depressive Symptoms in Healthy Adults and Adults with Depression

    PubMed Central

    Mortero, Sarah; Devan, William J.; Falcone, Guido J.; Lee, Phil; Holmes, Avram J.; Hollinshead, Marisa O.; Roffman, Joshua L.; Smoller, Jordan W.; Rosand, Jonathan; Cramer, Steven C.

    2014-01-01

    Background Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression. Methods Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3). Results In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15). Conclusions Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression. PMID:24834916

  14. Social Engagement with Parents in 11-Month-Old Siblings at High and Low Genetic Risk for Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Campbell, Susan B.; Leezenbaum, Nina B.; Mahoney, Amanda S.; Day, Taylor N.; Schmidt, Emily N.

    2015-01-01

    Infant siblings of children with an autism spectrum disorder are at heightened genetic risk to develop autism spectrum disorder. We observed high risk (n?=?35) and low risk (n?=?27) infants at 11?months during free play with a parent. Children were assessed for autism spectrum disorder in toddlerhood. High-risk infants with a later diagnosis…

  15. Assessing the benefits and risks of translocations in changing environments: a genetic perspective

    PubMed Central

    Weeks, Andrew R; Sgro, Carla M; Young, Andrew G; Frankham, Richard; Mitchell, Nicki J; Miller, Kim A; Byrne, Margaret; Coates, David J; Eldridge, Mark D B; Sunnucks, Paul; Breed, Martin F; James, Elizabeth A; Hoffmann, Ary A

    2011-01-01

    Translocations are being increasingly proposed as a way of conserving biodiversity, particularly in the management of threatened and keystone species, with the aims of maintaining biodiversity and ecosystem function under the combined pressures of habitat fragmentation and climate change. Evolutionary genetic considerations should be an important part of translocation strategies, but there is often confusion about concepts and goals. Here, we provide a classification of translocations based on specific genetic goals for both threatened species and ecological restoration, separating targets based on ‘genetic rescue’ of current population fitness from those focused on maintaining adaptive potential. We then provide a framework for assessing the genetic benefits and risks associated with translocations and provide guidelines for managers focused on conserving biodiversity and evolutionary processes. Case studies are developed to illustrate the framework. PMID:22287981

  16. The Association between Infants' Attention Control and Social Inhibition Is Moderated by Genetic and Environmental Risk for Anxiety

    ERIC Educational Resources Information Center

    Brooker, Rebecca J.; Neiderhiser, Jenae M.; Kiel, Elizabeth J.; Leve, Leslie D.; Shaw, Daniel S.; Reiss, David

    2011-01-01

    Infant social inhibition is associated with increased risk for anxiety later in life. Although both genetic and environmental factors are associated with anxiety, little empirical work has addressed how developing regulatory abilities work with genetic and environmental risk to exacerbate or mitigate problem behaviors. The current study was aimed…

  17. Developmental course of subclinical positive and negative psychotic symptoms and their associations with genetic risk status and impairment.

    PubMed

    Janssens, Mayke; Boyette, Lindy-Lou; Heering, Henriëtte D; Bartels-Velthuis, Agna A; Lataster, Tineke

    2016-07-01

    The proneness-persistence-impairment (PPI) model states that psychotic experiences are more likely to lead to impairment if their expression becomes persistent. Higher genetic risk for psychosis is known to affect proneness and persistence of subclinical positive symptoms. Less is known about potential effects of genetic risk on the course of subclinical negative symptoms, impairment, and their subsequent associations. The current study examined these issues in a large sample (n=1131), consisting of individuals with higher genetic risk (siblings of patients with psychotic disorders, n=703) and lower genetic risk (controls without a family member with lifetime psychosis, n=428). Psychotic experiences were assessed with the CAPE questionnaire, at two time points three years apart. Participants were allocated to one of four groups representing developmental course: stable low, decreasing, increasing or persisting subclinical positive/negative symptoms. Lifetime clinical psychosis was an exclusion criterion at baseline. Higher genetic risk status was found to be associated with a persisting course of both subclinical positive and negative symptoms, symptom-related distress and functional impairment. There is no evidence for an effect of genetic risk status on the association between developmental course and impairment. The results of the current study underline the importance of assessing psychotic experiences in the context of genetic risk, multidimensional and over time. Additionally, the current findings both underscore and contribute to the PPI model: psychotic experiences are more likely to lead to impairment if their expression becomes persistent, both in individuals with higher and lower genetic risk for psychosis. PMID:27157801

  18. Utility of genetic determinants of lipids and cardiovascular events in assessing risk.

    PubMed

    Holmes, Michael V; Harrison, Seamus; Talmud, Philippa J; Hingorani, Aroon D; Humphries, Steve E

    2011-04-01

    The prevention of coronary heart disease (CHD) is a major public-health goal, but disease architecture is such that a larger proportion of clinical events occur among the average majority than among the high-risk minority--the prevention paradox. Genetic findings over the past few years have resulted in the reopening of the old debate on whether an individualized or a population-based approach to prevention is preferable. Genetic testing is an attractive tool for CHD risk prediction because it is a low-cost, high-fidelity technology with multiplex capability. Moreover, by contrast with nongenetic markers, genotype is invariant and determined from conception, which eliminates biological variability and makes prediction from early life possible. Mindful of the prevention paradox, this Review examines the potential applications and challenges of using genetic information for predicting CHD, focusing on lipid risk factors and drawing on experience in the evaluation of nongenetic risk factors as screening tests for CHD. Many of the issues we discuss hold true for any late-onset common disease with modifiable risk factors and proven preventative strategies. PMID:21321562

  19. The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume.

    PubMed

    Lupton, Michelle K; Strike, Lachlan; Hansell, Narelle K; Wen, Wei; Mather, Karen A; Armstrong, Nicola J; Thalamuthu, Anbupalam; McMahon, Katie L; de Zubicaray, Greig I; Assareh, Amelia A; Simmons, Andrew; Proitsi, Petroula; Powell, John F; Montgomery, Grant W; Hibar, Derrek P; Westman, Eric; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Velas, Bruno; Lovestone, Simon; Brodaty, Henry; Ames, David; Trollor, Julian N; Martin, Nicholas G; Thompson, Paul M; Sachdev, Perminder S; Wright, Margaret J

    2016-04-01

    Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer's disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16-30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ε4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults. PMID:26973105

  20. Genetically Determined Amerindian Ancestry Correlates with Increased Frequency of Risk Alleles for Systemic Lupus Erythematosus

    PubMed Central

    Sanchez, E; Webb, R; Rasmussen, A.; Kelly, J.A; Riba, L.; Kaufman, K.M.; Garcia-de la Torre, I.; Moctezuma, J.F.; Maradiaga-Ceceña, M.A.; Cardiel, M.; Acevedo, E.; Cucho-Venegas, M.; Garcia, M.A.; Gamron, S.; Pons-Estel, B.A.; Vasconcelos, C.; Martin, J.; Tusié-Luna, T.; Harley, J.B.; Richardson, B.; Sawalha, A.H.; Alarcón-Riquelme, M.E.

    2011-01-01

    Objectives To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus. Methods Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression. Results A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele. Conclusion Amerindian ancestry increased the number of risk alleles for lupus. PMID:20848568

  1. The genetic landscape of high-risk neuroblastoma

    PubMed Central

    Pugh, Trevor J.; Morozova, Olena; Attiyeh, Edward F.; Asgharzadeh, Shahab; Wei, Jun S.; Auclair, Daniel; Carter, Scott L.; Cibulskis, Kristian; Hanna, Megan; Kiezun, Adam; Kim, Jaegil; Lawrence, Michael S.; Lichenstein, Lee; McKenna, Aaron; Pedamallu, Chandra Sekhar; Ramos, Alex H.; Shefler, Erica; Sivachenko, Andrey; Sougnez, Carrie; Stewart, Chip; Ally, Adrian; Birol, Inanc; Chiu, Readman; Corbett, Richard D.; Hirst, Martin; Jackman, Shaun D.; Kamoh, Baljit; Khodabakshi, Alireza Hadj; Krzywinski, Martin; Lo, Allan; Moore, Richard A.; Mungall, Karen L.; Qian, Jenny; Tam, Angela; Thiessen, Nina; Zhao, Yongjun; Cole, Kristina A.; Diamond, Maura; Diskin, Sharon J.; Mosse, Yael P.; Wood, Andrew C.; Ji, Lingyun; Sposto, Richard; Badgett, Thomas; London, Wendy B.; Moyer, Yvonne; Gastier-Foster, Julie M.; Smith, Malcolm A.; Auvil, Jaime M. Guidry; Gerhard, Daniela S.; Hogarty, Michael D.; Jones, Steven J. M.; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Seeger, Robert C.; Khan, Javed; Marra, Marco A.; Meyerson, Matthew; Maris, John M.

    2013-01-01

    Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers. PMID:23334666

  2. Differential Genetic Susceptibility to Child Risk at Birth in Predicting Observed Maternal Behavior

    PubMed Central

    Fortuna, Keren; van IJzendoorn, Marinus H.; Mankuta, David; Kaitz, Marsha; Avinun, Reut; Ebstein, Richard P.; Knafo, Ariel

    2011-01-01

    This study examined parenting as a function of child medical risks at birth and parental genotype (dopamine D4 receptor; DRD4). Our hypothesis was that the relation between child risks and later maternal sensitivity would depend on the presence/absence of a genetic variant in the mothers, thus revealing a gene by environment interaction (GXE). Risk at birth was defined by combining risk indices of children's gestational age at birth, birth weight, and admission to the neonatal intensive care unit. The DRD4-III 7-repeat allele was chosen as a relevant genotype as it was recently shown to moderate the effect of environmental stress on parental sensitivity. Mothers of 104 twin pairs provided DNA samples and were observed with their children in a laboratory play session when the children were 3.5 years old. Results indicate that higher levels of risk at birth were associated with less sensitive parenting only among mothers carrying the 7-repeat allele, but not among mothers carrying shorter alleles. Moreover, mothers who are carriers of the 7-repeat allele and whose children scored low on the risk index were observed to have the highest levels of sensitivity. These findings provide evidence for the interactive effects of genes and environment (in this study, children born at higher risk) on parenting, and are consistent with a genetic differential susceptibility model of parenting by demonstrating that some parents are inherently more susceptible to environmental influences, both good and bad, than are others. PMID:21603618

  3. A signal detection analysis of gist-based discrimination of genetic breast cancer risk

    PubMed Central

    Fisher, Christopher R.; Reyna, Valerie F.; Widmer, Colin L.; Cedillos, Elizabeth M.; Brust-Renck, Priscilla G.

    2013-01-01

    Pervasive biases in probability judgment render the probability scale a poor response mode for assessing risk judgments. By applying fuzzy trace theory, we used ordinal gist categories as a response mode, coupled with a signal detection model to assess risk judgments. The signal detection model is an extension of the familiar model used in binary choice paradigms. It provides three measures of discriminability—low versus medium risk, medium versus high risk, and low versus high risk—and two measures of response bias. We used the model to assess the effectiveness of BRCA Gist, an intelligent tutoring system designed to improve women’s judgments and understanding of genetic risk for breast cancer. Participants were randomly assigned to the BRCA Gist intelligent tutoring system, the National Cancer Institute (NCI) Web pages, or a control group, and then they rated cases that had been developed using the Pedigree Assessment Tool and also vetted by medical experts. BRCA Gist participants demonstrated increased discriminability for all three risk categories, relative to the control group; the NCI group showed increased discriminability for two of the three levels. This result suggests that BRCA Gist best improved discriminability among genetic risk categories, and both BRCA Gist and the NCI website improved participants’ ability to discriminate, rather than simply shifting their decision criterion. A spreadsheet that fits the model and compares parameters across the conditions can be downloaded from the Behavior Research Methods website and used in any research involving categorical responses. PMID:23784010

  4. Genetics

    MedlinePlus

    Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  5. Genetics

    MedlinePlus

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  6. A Statistical Model for Assessing Genetic Susceptibility as a Risk Factor in Multifactorial Diseases: Lessons from Occupational Asthma

    PubMed Central

    Demchuk, Eugene; Yucesoy, Berran; Johnson, Victor J.; Andrew, Michael; Weston, Ainsley; Germolec, Dori R.; De Rosa, Christopher T.; Luster, Michael I.

    2007-01-01

    Background Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. Objective The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. Methods We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. Results Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. Conclusion The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment. PMID:17384770

  7. A multi-case report of the pathways to and through genetic testing and cancer risk management for BRCA mutation-positive women aged 18-25.

    PubMed

    Hoskins, Lindsey M; Werner-Lin, Allison

    2013-02-01

    Much of the extant literature addressing the psychosocial aspects of BRCA1/2 mutation testing and risk management aggregates mutation carriers of all ages in study recruitment, data analysis, and interpretation. This analytic strategy does not adequately address the needs of the youngest genetic testing consumers, i.e., women aged 18-25. Despite low absolute cancer risk estimates before age 30, BRCA1/2 mutation-positive women aged 18-25 feel vulnerable to a cancer diagnosis but find themselves in a management quandary because the clinical utility of screening and prevention options are not yet well defined for such young carriers. We present three cases, selected from a larger study of 32 BRCA1/2 mutation-positive women who completed or considered genetic testing before age 25, to demonstrate the unique developmental, relational and temporal influences, as well as the challenges, experienced by very young BRCA mutation-positive women as they complete genetic testing and initiate cancer risk management. The first case describes the maturation of a young woman whose family participated in a national cancer registry. The second addresses the experiences and expectations of a young woman who completed genetic testing after learning that her unaffected father was a mutation carrier. The third case highlights the experiences of a young woman parentally bereaved in childhood, who presented for genetic counseling and testing due to intense family pressure. Together, these cases suggest that BRCA1/2-positive women aged 18-25 are challenged to reconcile their burgeoning independence from their families with risk-related support needs. Loved ones acting in ways meant to care for these young women may inadvertently apply pressure, convoluting family support dynamics and autonomous decision-making. Ongoing support from competent healthcare professionals will enable these young women to remain informed and receive objective counsel about their risk-management decisions. PMID

  8. At risk of population decline? An ecological and genetic approach to the threatened palm species Butia eriospatha (Arecaceae) of Southern Brazil.

    PubMed

    Nazareno, Alison G; dos Reis, Maurício S

    2014-01-01

    To estimate the risk of population decline for the threatened palm species Butia eriospatha, we investigated the patterns of demography, natural regeneration, herbivory, and the levels of genetic diversity using 9 microsatellite loci from both adults and seedlings sampled from 4 populations in Southern Brazil (n = 330). Our results indicate that cattle grazing in B. eriospatha population areas severely affect their demographic structure. Three B. eriospatha populations showed a bimodal age structure made up of adult plants and seedlings and high rates (>77%) of livestock herbivory. For 1 population, we describe and quantify for the first time the occurrence of 6 ontogenetic stages for this threatened palm species. Populations of B. eriospatha showed high levels of genetic differentiation (F ST adult plants = 0.287, F ST seedlings = 0.175). The amount of observed heterozygosity differed significantly between small (H O = 0.329) and large populations (H O = 0.461), indicating that small populations can be more susceptible to genetic drift. With no recruitment and a mortality rate of 2.0%, we show that the populations investigated in this study would be at an extremely high risk of local extinction, with a greater than 50% reduction in the effective population size, in the next 40 years. Although this study highlights the importance of analyzing both population ecology parameters and genetic data to better understand the level of risk facing threatened species, we emphasize that policy actions are urgently needed for effective conservation of this vulnerable biological resource. PMID:24078681

  9. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.

    PubMed

    Machiela, Mitchell J; Lan, Qing; Slager, Susan L; Vermeulen, Roel C H; Teras, Lauren R; Camp, Nicola J; Cerhan, James R; Spinelli, John J; Wang, Sophia S; Nieters, Alexandra; Vijai, Joseph; Yeager, Meredith; Wang, Zhaoming; Ghesquières, Hervé; McKay, James; Conde, Lucia; de Bakker, Paul I W; Cox, David G; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R; De Roos, Anneclaire J; Brooks-Wilson, Angela R; Giles, Graham G; Melbye, Mads; Gu, Jian; Jackson, Rebecca D; Kane, Eleanor; Purdue, Mark P; Vajdic, Claire M; Albanes, Demetrius; Kelly, Rachel S; Zucca, Mariagrazia; Bertrand, Kimberly A; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M; Link, Brian K; Novak, Anne J; Dogan, Ahmet; Asmann, Yan W; Liebow, Mark; Thompson, Carrie A; Ansell, Stephen M; Witzig, Thomas E; Tilly, Hervé; Haioun, Corinne; Molina, Thierry J; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans-Olov; Roos, Göran; Bracci, Paige M; Riby, Jacques; Smith, Martyn T; Holly, Elizabeth A; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M; Severson, Richard K; Tinker, Lesley F; North, Kari E; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J; Villano, Danylo J; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R; Turner, Jenny; Southey, Melissa C; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Boeing, Heiner; Tjønneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; De Vivo, Immaculata; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Liang, Liming; Park, Ju-Hyun; Chung, Charles C; Weisenburger, Dennis D; Fraumeni, Joseph F; Salles, Gilles; Glenn, Martha; Cannon-Albright, Lisa; Curtin, Karen; Wu, Xifeng; Smedby, Karin E; de Sanjose, Silvia; Skibola, Christine F; Berndt, Sonja I; Birmann, Brenda M; Chanock, Stephen J; Rothman, Nathaniel

    2016-04-15

    Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk. PMID:27008888

  10. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study

    PubMed Central

    Zhang, Chenan; Doherty, Jennifer A.; Burgess, Stephen; Hung, Rayjean J.; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I.; Sellers, Thomas A.; Monteiro, Alvaro N.A.; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D.; Houlston, Richard S.; Landi, Maria Teresa; Timofeeva, Maria N.; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A.; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I.; Chanock, Stephen J.; Schumacher, Fredrick; Haiman, Christopher A.; Henderson, Brian E.; Amin Al Olama, Ali; Andrulis, Irene L.; Hopper, John L.; Chang-Claude, Jenny; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Ursin, Giske; Whittemore, Alice S.; Hunter, David J.; Gruber, Stephen B.; Knight, Julia A.; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A.; Hudson, Thomas J.; Chan, Andrew T.; Li, Li; Woods, Michael O.; Ahsan, Habibul; Pierce, Brandon L.

    2015-01-01

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10−15), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10−6). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. PMID:26138067

  11. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

    PubMed

    Zhang, Chenan; Doherty, Jennifer A; Burgess, Stephen; Hung, Rayjean J; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I; Sellers, Thomas A; Monteiro, Alvaro N A; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D; Houlston, Richard S; Landi, Maria Teresa; Timofeeva, Maria N; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I; Chanock, Stephen J; Schumacher, Fredrick; Haiman, Christopher A; Henderson, Brian E; Amin Al Olama, Ali; Andrulis, Irene L; Hopper, John L; Chang-Claude, Jenny; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Ursin, Giske; Whittemore, Alice S; Hunter, David J; Gruber, Stephen B; Knight, Julia A; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A; Hudson, Thomas J; Chan, Andrew T; Li, Li; Woods, Michael O; Ahsan, Habibul; Pierce, Brandon L

    2015-09-15

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. PMID:26138067

  12. Target cell frequency is a genetically determined risk factor in radiation leukaemogenesis.

    PubMed

    Jawad, M; Giotopoulos, G; Cole, C; Plumb, M

    2007-09-01

    Whole body exposure to ionizing radiation increases the risk of radiation-induced acute myeloid leukaemia (r-AML). r-AML is the result of the accumulation of mutations in a single haemopoietic stem cell, so risk is therefore a function of the number of mutations required to transform the stem cell and the mutation rate. There is a genetic component to the risk of AML within the general population, and low penetrance variant alleles encoding DNA repair enzymes have been genetically implicated in therapy-related AML susceptibility. However, what is largely ignored is that target cell number, which defines the number of genomes at risk from DNA damaging agents, is also part of the equation that defines risk. We will review the evidence from genetic studies of inbred mouse models that target cell frequency is a risk factor in radiation leukaemogenesis. Inbred mouse strains that differ in their susceptibility to radiation-induced r-AML and thymic lymphoma (r-TL), spontaneous TL and pristane-induced plasmacytoma (PCT) have been exploited to identify susceptibility loci. The target cell in AML is the haemopoietic stem cell, whereas TLs and PCT arise from more mature lymphoid progenitor cells. Inbred mice also differ significantly in all aspects of haemopoiesis, and these differences have been used to identify quantitative trait loci (QTL) that determine the frequency of specific haemopoietic stem, progenitor or mature blood cells. The co-localization of QTL that determine risk and target cell frequency in all three haemopoietic malignancies is strong evidence that target cell frequency is a risk factor in radiation leukaemogenesis. PMID:17704327

  13. Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk.

    PubMed

    Ziakas, Panayiotis D; Poulou, Loukia S; Pavlou, Matthaios; Zintzaras, Elias

    2015-08-01

    Three common polymorphic variants, namely Factor V Leiden (FVL), Prothrombin G20210A (PT G20210A) and Methylenetetrahydrofolate Reductase (MTHFR) C677T are candidate genes for venous thromboembolism (VTE) in pregnancy. We performed a literature review and meta-analysis of pertinent genetic association studies (GAS) in pregnancy, to quantify the genetic risk of VTE in pregnancy. We used the model-free approach of generalized odds ratio (ORG) to estimate gene-to-disease association and explored the mode of inheritance using the degree of dominance h index. Twelve case-control GAS studies provided the full genotype distributions for at least one candidate gene to assess the genetic risk. FVL was associated with a significant risk of VTE in pregnancy (ORG 7.28; 95% confidence interval 5.53-9.58) and a dominant mode of inheritance (h=0.76), that is the effect of heterozygous carriers will lie close to the homozygous mutant genotype. PT G20210A mutation was also associated with a significant VTE risk (ORG 5.43; 95% CI 3.66-8.03) and had an over-dominant mode of inheritance (h=1.5), suggesting that the effect of heterozygous carriers may exceed that of homozygous mutant. MTHFR C677T had no association with VTE risk in pregnancy (ORG 1.24; 95% CI 0.88-1.73). Our analysis provided robust data on VTE in pregnancy, relative to FVL and PT G20210A status and suggested that the genetic effects of heterozygous over homozygous carriers do not justify stratification of heterozygous as "lower risk" over homozygous mutants. On clinical grounds this may impact decisions to preferentially exclude heterozygous from anticoagulation prophylaxis. PMID:26115054

  14. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study.

    PubMed

    Du, Yeting; Ter-Minassian, Monica; Brais, Lauren; Brooks, Nichole; Waldron, Amanda; Chan, Jennifer A; Lin, Xihong; Kraft, Peter; Christiani, David C; Kulke, Matthew H

    2016-08-01

    The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted. PMID:27492634

  15. Regulators of genetic risk of breast cancer identified by integrative network analysis

    PubMed Central

    Castro, Mauro AA; de Santiago, Ines; Campbell, Thomas M; Vaughn, Courtney; Hickey, Theresa E; Ross, Edith; Tilley, Wayne D; Markowetz, Florian; Ponder, Bruce AJ; Meyer, Kerstin B

    2015-01-01

    Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network between transcription factors (TFs) and putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via eQTLs. We identified 36 overlapping regulons that were enriched and formed a distinct cluster within the network, suggesting shared biology. The risk-TFs driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to ER+ luminal A/B and to ER− basal-like cancers and to different, luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation to reveal the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings. PMID:26618344

  16. DTREEv2, a computer-based support system for the risk assessment of genetically modified plants.

    PubMed

    Pertry, Ine; Nothegger, Clemens; Sweet, Jeremy; Kuiper, Harry; Davies, Howard; Iserentant, Dirk; Hull, Roger; Mezzetti, Bruno; Messens, Kathy; De Loose, Marc; de Oliveira, Dulce; Burssens, Sylvia; Gheysen, Godelieve; Tzotzos, George

    2014-03-25

    Risk assessment of genetically modified organisms (GMOs) remains a contentious area and a major factor influencing the adoption of agricultural biotech. Methodologically, in many countries, risk assessment is conducted by expert committees with little or no recourse to databases and expert systems that can facilitate the risk assessment process. In this paper we describe DTREEv2, a computer-based decision support system for the identification of hazards related to the introduction of GM-crops into the environment. DTREEv2 structures hazard identification and evaluation by means of an Event-Tree type of analysis. The system produces an output flagging identified hazards and potential risks. It is intended to be used for the preparation and evaluation of biosafety dossiers and, as such, its usefulness extends to researchers, risk assessors and regulators in government and industry. PMID:24308933

  17. The RAG Model: A New Paradigm for Genetic Risk Stratification in Multiple Myeloma

    PubMed Central

    Prideaux, Steven M.; Conway O'Brien, Emma; Chevassut, Timothy J.

    2014-01-01

    Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based “traffic-light” risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient. PMID:25295194

  18. The RAG Model: A New Paradigm for Genetic Risk Stratification in Multiple Myeloma.

    PubMed

    Prideaux, Steven M; Conway O'Brien, Emma; Chevassut, Timothy J

    2014-01-01

    Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based "traffic-light" risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient. PMID:25295194

  19. Multivariate Methods for Genetic Variants Selection and Risk Prediction in Cardiovascular Diseases

    PubMed Central

    Malovini, Alberto; Bellazzi, Riccardo; Napolitano, Carlo; Guffanti, Guia

    2016-01-01

    Over the last decade, high-throughput genotyping and sequencing technologies have contributed to major advancements in genetics research, as these technologies now facilitate affordable mapping of the entire genome for large sets of individuals. Given this, genome-wide association studies are proving to be powerful tools in identifying genetic variants that have the capacity to modify the probability of developing a disease or trait of interest. However, when the study’s goal is to evaluate the effect of the presence of genetic variants mapping to specific chromosomes regions on a specific phenotype, the candidate loci approach is still preferred. Regardless of which approach is taken, such a large data set calls for the establishment and development of appropriate analytical methods in order to translate such knowledge into biological or clinical findings. Standard univariate tests often fail to identify informative genetic variants, especially when dealing with complex traits, which are more likely to result from a combination of rare and common variants and non-genetic determinants. These limitations can partially be overcome by multivariate methods, which allow for the identification of informative combinations of genetic variants and non-genetic features. Furthermore, such methods can help to generate additive genetic scores and risk stratification algorithms that, once extensively validated in independent cohorts, could serve as useful tools to assist clinicians in decision-making. This review aims to provide readers with an overview of the main multivariate methods for genetic data analysis that could be applied to the analysis of cardiovascular traits. PMID:27376073

  20. Genes and/or jeans?: Genetic and socio-cultural contributions to risk for eating disorders.

    PubMed

    Becker, Anne E; Keel, Pamela; Anderson-Fye, Eileen P; Thomas, Jennifer J

    2004-01-01

    Eating disorders are prevalent among young adult females and pose serious psychological and medical risks. Notwithstanding important advances, efforts to develop effective means of preventing and treating eating disorders have been limited by an incomplete understanding of their multifactorial etiology. Whereas epidemiologic data strongly suggest the influence of socio-cultural context in moderating risk, many hypotheses about how these effects are exerted have remained empirically unevaluated. Specifically, experimental and observational data suggest that social transition (e.g., transnational migration, urbanization, modernization), Western media exposure, and certain peer environments (involving social comparison and teasing) may all contribute to risk. With respect to genetic influences on etiology, family and twin studies have supported a genetic diathesis to eating disorders. Whereas, molecular genetic studies have generated interesting leads- with the most promising findings emerging for genes related to the function of serotonin-they have yet to identify well-replicated susceptibility loci. This paper reviews the data supporting both socio-cultural and genetic contributions for eating disorders and suggests productive future strategies for continuing to unravel their likely multiple and complex interactions. PMID:15256346

  1. The role of community review in evaluating the risks of human genetic variation research.

    PubMed

    Foster, M W; Sharp, R R; Freeman, W L; Chino, M; Bernsten, D; Carter, T H

    1999-06-01

    The practicality and moral value of community review of human genetic research has become a focus of debate. Examples from two Native American communities are used to address four aspects of that debate: (1) the value of community review in larger, geographically dispersed populations; (2) the identification of culturally specific risks; (3) the potential conflict between individual and group assessments of research-related risks; and (4) the confusion of social categories with biological categories. Our experiences working with these two communities suggest that: (1) successful community review may require the involvement of private social units (e.g., families); (2) culturally specific implications of genetic research may be identifiable only by community members and are of valid concern in their moral universes; (3) community concerns can be incorporated into existing review mechanisms without necessarily giving communities the power to veto research proposals; and (4) the conflation of social and biological categories presents recruitment problems for genetic studies. These conclusions argue for the use of community review to identify and minimize research-related risks posed by genetic studies. Community review also can assist in facilitating participant recruitment and retention, as well as in developing partnerships between researchers and communities. PMID:10330360

  2. Common Genetic Polymorphisms within NFκB-Related Genes and the Risk of Developing Invasive Aspergillosis

    PubMed Central

    Lupiañez, Carmen B.; Villaescusa, María T.; Carvalho, Agostinho; Springer, Jan; Lackner, Michaela; Sánchez-Maldonado, José M.; Canet, Luz M.; Cunha, Cristina; Segura-Catena, Juana; Alcazar-Fuoli, Laura; Solano, Carlos; Fianchi, Luana; Pagano, Livio; Potenza, Leonardo; Aguado, José M.; Luppi, Mario; Cuenca-Estrella, Manuel; Lass-Flörl, Cornelia; Einsele, Hermann; Vázquez, Lourdes; Ríos-Tamayo, Rafael; Loeffler, Jurgen; Jurado, Manuel; Sainz, Juan

    2016-01-01

    Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25–31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA. PMID:27570521

  3. Additive genetic risk from five serotonin system polymorphisms interacts with interpersonal stress to predict depression.

    PubMed

    Vrshek-Schallhorn, Suzanne; Stroud, Catherine B; Mineka, Susan; Zinbarg, Richard E; Adam, Emma K; Redei, Eva E; Hammen, Constance; Craske, Michelle G

    2015-11-01

    Behavioral genetic research supports polygenic models of depression in which many genetic variations each contribute a small amount of risk, and prevailing diathesis-stress models suggest gene-environment interactions (G×E). Multilocus profile scores of additive risk offer an approach that is consistent with polygenic models of depression risk. In a first demonstration of this approach in a G×E predicting depression, we created an additive multilocus profile score from 5 serotonin system polymorphisms (1 each in the genes HTR1A, HTR2A, HTR2C, and 2 in TPH2). Analyses focused on 2 forms of interpersonal stress as environmental risk factors. Using 5 years of longitudinal diagnostic and life stress interviews from 387 emerging young adults in the Youth Emotion Project, survival analyses show that this multilocus profile score interacts with major interpersonal stressful life events to predict major depressive episode onsets (hazard ratio [HR] = 1.815, p = .007). Simultaneously, there was a significant protective effect of the profile score without a recent event (HR = 0.83, p = .030). The G×E effect with interpersonal chronic stress was not significant (HR = 1.15, p = .165). Finally, effect sizes for genetic factors examined ignoring stress suggested such an approach could lead to overlooking or misinterpreting genetic effects. Both the G×E effect and the protective simple main effect were replicated in a sample of early adolescent girls (N = 105). We discuss potential benefits of the multilocus genetic profile score approach and caveats for future research. PMID:26595467

  4. Identifying Multimodal Intermediate Phenotypes Between Genetic Risk Factors and Disease Status in Alzheimer's Disease.

    PubMed

    Hao, Xiaoke; Yao, Xiaohui; Yan, Jingwen; Risacher, Shannon L; Saykin, Andrew J; Zhang, Daoqiang; Shen, Li

    2016-10-01

    Neuroimaging genetics has attracted growing attention and interest, which is thought to be a powerful strategy to examine the influence of genetic variants (i.e., single nucleotide polymorphisms (SNPs)) on structures or functions of human brain. In recent studies, univariate or multivariate regression analysis methods are typically used to capture the effective associations between genetic variants and quantitative traits (QTs) such as brain imaging phenotypes. The identified imaging QTs, although associated with certain genetic markers, may not be all disease specific. A useful, but underexplored, scenario could be to discover only those QTs associated with both genetic markers and disease status for revealing the chain from genotype to phenotype to symptom. In addition, multimodal brain imaging phenotypes are extracted from different perspectives and imaging markers consistently showing up in multimodalities may provide more insights for mechanistic understanding of diseases (i.e., Alzheimer's disease (AD)). In this work, we propose a general framework to exploit multi-modal brain imaging phenotypes as intermediate traits that bridge genetic risk factors and multi-class disease status. We applied our proposed method to explore the relation between the well-known AD risk SNP APOE rs429358 and three baseline brain imaging modalities (i.e., structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and F-18 florbetapir PET scans amyloid imaging (AV45)) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The empirical results demonstrate that our proposed method not only helps improve the performances of imaging genetic associations, but also discovers robust and consistent regions of interests (ROIs) across multi-modalities to guide the disease-induced interpretation. PMID:27277494

  5. Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival

    PubMed Central

    Kong, Jinyu; Xu, Fangxiu; Qu, Jinli; Wang, Yu; Gao, Ming; Yu, Herbert; Qian, Biyun

    2015-01-01

    Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival. PMID:25544771

  6. Linking Genetic Counseling Content to Short-Term Outcomes in Individuals at Elevated Breast Cancer Risk

    PubMed Central

    Ellington, Lee; Schoenberg, Nancy; Agarwal, Parul; Jackson, Thomas; Dickinson, Stephanie; Abraham, Jame; Paskett, Electra D.; Leventhal, Howard; Andrykowski, Michael

    2014-01-01

    Few studies have linked actual genetic counseling content to short-term outcomes. Using the Self-regulation Model, the impact of cognitive and affective content in genetic counseling on short-term outcomes was studied in individuals at elevated risk of familial breast-ovarian cancer. Surveys assessed dependent variables: distress, perceived risk, and 6 knowledge measures (Meaning of Positive Test; Meaning of Negative Test; Personal Behavior; Practitioner Knowledge; Mechanisms of Cancer Inheritance; Frequency of Inherited Cancer) measured at pre- and post-counseling. Proportion of participant cognitive and affective and counselor cognitive and affective content during sessions (using LIWC software) were predictors in regressions. Knowledge increased for 5 measures and decreased for Personal Behavior, Distress and Perceived Risk. Controlling for age and education, results were significant/marginally significant for three measures. More counselor content was associated with decreases in knowledge of Personal Behavior. More participant and less counselor affective content was associated with gains in Practitioner Knowledge. More counselor cognitive, and interaction of counselor cognitive and affective content, were associated with higher perceived risk. Genetic counselors dominate the content of counseling sessions. Therefore, their content is tied more closely to short term outcomes than participant content. A lack of patient communication in sessions may pose problems for understanding of complex concepts. PMID:24671341

  7. Genetically engineered Oenococcus oeni strains to highlight the impact of estA2 and estA7 esterase genes on wine ester profile.

    PubMed

    Darsonval, M; Alexandre, H; Grandvalet, C

    2016-12-01

    Besides deacidifying wine, Oenococcus oeni bring significant changes in the chemical composition of wine by releasing esters by the action of their own esterases. The impact of O. oeni esterases remains relatively unexplored. Four esterase genes were identified from O. oeni genome (estA2, estA7, estC, and estB). The dual objective of this study was, first to use a genetic tool enabling the expression of esterase genes in enological conditions and, second, to investigate the impact of O. oeni esterase gene expression during winemaking on wine aromatic profile. Both estA2 and estA7 genes were successfully cloned and expressed in O. oeni and recombinant strains were inoculated in Aligoté wine to initiate malolactic fermentation (MLF). Ester profile of experimental wine was established by SPME-GC-MS. EstA2 caused significant decreases in the concentrations of isoamyl acetate, ethyl hexanoate, isobutyl acetate, and hexyl acetate, by 42.7%, 23.4%, 51.5%, and 28.9%, respectively. EstA2 has preferential hydrolytic activity toward acetate esters from higher alcohols. EstA7 has synthetic activity toward hexyl acetate with a significant 22.7% increase. This study reports the first efficient expression system enabling the production of a functional protein in O. oeni in enological conditions. PMID:27554142

  8. Low levels of hybridization between sympatric Arctic char (Salvelinus alpinus) and Dolly Varden char (Salvelinus malma) highlights their genetic distinctiveness and ecological segregation

    PubMed Central

    May-McNally, Shannan L; Quinn, Thomas P; Taylor, Eric B

    2015-01-01

    Understanding the extent of interspecific hybridization and how ecological segregation may influence hybridization requires comprehensively sampling different habitats over a range of life history stages. Arctic char (Salvelinus alpinus) and Dolly Varden (S. malma) are recently diverged salmonid fishes that come into contact in several areas of the North Pacific where they occasionally hybridize. To better quantify the degree of hybridization and ecological segregation between these taxa, we sampled over 700 fish from multiple lake (littoral and profundal) and stream sites in two large, interconnected southwestern Alaskan lakes. Individuals were genotyped at 12 microsatellite markers, and genetic admixture (Q) values generated through Bayesian-based clustering revealed hybridization levels generally lower than reported in a previous study (<0.6% to 5% of samples classified as late-generation hybrids). Dolly Varden and Arctic char tended to make different use of stream habitats with the latter apparently abandoning streams for lake habitats after 2–3 years of age. Our results support the distinct biological species status of Dolly Varden and Arctic char and suggest that ecological segregation may be an important factor limiting opportunities for hybridization and/or the ecological performance of hybrid char. PMID:26356310

  9. Novel Genetic Markers Associate with Atrial Fibrillation Risk in Europeans and Japanese

    PubMed Central

    Agarwal, Sunil K.; Bis, Joshua C.; Brody, Jennifer A.; Chen, Lin Y.; Everett, Brendan M.; Ford, Ian; Franco, Oscar H.; Harris, Tamara B.; Hofman, Albert; Kääb, Stefan; Mahida, Saagar; Kathiresan, Sekar; Kubo, Michiaki; Launer, Lenore J.; MacFarlane, Peter W.; Magnani, Jared W.; McKnight, Barbara; McManus, David D.; Peters, Annette; Psaty, Bruce M.; Rose, Lynda M.; Rotter, Jerome I.; Silbernagel, Guenther; Smith, Jonathan D.; Sotoodehnia, Nona; Stott, David J.; Taylor, Kent D.; Tomaschitz, Andreas; Tsunoda, Tatsuhiko; Uitterlinden, Andre G.; Van Wagoner, David R.; Völker, Uwe; Völzke, Henry

    2014-01-01

    Objectives To identify non-redundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. Methods We performed association testing conditioned on the most significant, independently associated genetic markers at nine established AF loci using two complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). Results We observed at least four distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining eight AF loci. A multilocus score comprised of 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least four AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity. PMID:24486271

  10. Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA

    PubMed Central

    Ognjanovic, Simona; Yuan, Jian-Min; Chaptman, Ann K.; Fan, Yunhua; Yu, Mimi C.

    2009-01-01

    Polymorphisms in cytokine genes responsible for inflammatory and immune responses are associated with risk of hepatocellular carcinoma (HCC) in high-risk Chinese population. Similar data in low-risk populations are lacking. A population-based case–control study of HCC was conducted including 120 HCC patients and 230 matched control subjects of non-Asian residents in Los Angeles County, California. Genetic variants in the interferon γ (IFNγ), tumor necrosis factor-α (TNFα), interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12 and IL-18 genes were determined by Taqman assays. The logistic regression method was used to analyze the data. For T helper (Th) 1 genes (IFNγ, IL-6 and IL-12), relative to the putative high-activity genotypes, individual low-activity genotypes were associated with statistically non-significant increases in HCC risk. The odds ratio (OR) was 1.53 [95% confidence interval (CI) = 0.53–4.39] for three versus zero low-activity genotypes. For Th2 cytokines (IL-4 and IL-10), low- versus high-activity genotypes were associated with statistically non-significant decreases in HCC risk. The OR was 0.64 (95% CI = 0.27–1.55) for two versus zero low-activity genotypes. When the Th1 and Th2 genotypes were examined simultaneously, the highest level of risk was observed in individuals jointly possessing the highest number of low-activity Th1 genotypes and the lowest number of low-activity Th2 genotypes. There was a roughly doubling of risk between these two extreme genetic profiles, which did not reach statistical significance (OR = 1.98, 95% CI = 0.50–7.84, P = 0.08). In contrast to high-risk Chinese, Th1 and Th2 genotypes did not impact in a major way on risk of HCC in USA non-Asians. PMID:19126646

  11. Do personality traits moderate the manifestation of type 2 diabetes genetic risk?☆

    PubMed Central

    Čukić, Iva; Mõttus, René; Luciano, Michelle; Starr, John M; Weiss, Alexander; Deary, Ian J

    2015-01-01

    Objective. To test whether personality traits moderate type 2 diabetes (T2D) genetic risk. Methods. Using a large community-dwelling sample (n = 837, Mage = 69.59 ± 0.85 years, 49% males) we fitted a series of linear regression models predicting glycated haemoglobin (HbA1c) from T2D polygenic risk — aggregation of small individual effects of a large number of single nucleotide polymorphisms (SNPs) — and five personality traits. We tested the main effects of personality traits and their interactions with T2D polygenic risk score, controlling for age and sex. The models in the final set were adjusted for cognitive ability, highest educational qualification, and occupational class. Results. Lower levels of openness were associated with heightened levels of HbA1c (β = − 0.014, p = .032). There was a significant interaction between T2D polygenic risk score and agreeableness: lower agreeableness was related to a stronger association between T2D polygenic risk and HbA1c (β = − 0.08, p = .021). In the model adjusted for cognitive ability, the main effect of openness was not significant (β = − 0.08, p = .057). The interaction between agreeableness and T2D polygenic risk was still present after controlling for cognitive ability and socioeconomic status indicators, and the interaction between conscientiousness and polygenic risk score was also significant: lower conscientiousness was associated with a stronger association between T2D polygenic risk and HbA1c levels (β = 0.09, p = .04). Conclusions. Personality may be associated with markers of diabetes, and may moderate the expression of its genetic risk. PMID:26213352

  12. Genetic dissection of fruit quality traits in the octoploid cultivated strawberry highlights the role of homoeo-QTL in their control.

    PubMed

    Lerceteau-Köhler, E; Moing, A; Guérin, G; Renaud, C; Petit, A; Rothan, C; Denoyes, Béatrice

    2012-04-01

    Fruit quality traits are major breeding targets in the Rosaceae. Several of the major Rosaceae species are current or ancient polyploids. To dissect the inheritance of fruit quality traits in polyploid fleshy fruit species, we used a cultivated strawberry segregating population comprising a 213 full-sibling F1 progeny from a cross between the variety 'Capitola' and the genotype 'CF1116'. We previously developed the most comprehensive strawberry linkage map, which displays seven homoeology groups (HG), including each four homoeology linkage groups (Genetics 179:2045-2060, 2008). The map was used to identify quantitative trait loci (QTL) for 19 fruit traits related to fruit development, texture, colour, anthocyanin, sugar and organic acid contents. Analyses were carried out over two or three successive years on field-grown plants. QTL were detected for all the analysed traits. Because strawberry is an octopolyploid species, QTL controlling a given trait and located at orthologous positions on different homoeologous linkage groups within one HG are considered as homoeo-QTL. We found that, for various traits, about one-fourth of QTL were putative homoeo-QTL and were localised on two linkage groups. Several homoeo-QTL could be detected the same year, suggesting that several copies of the gene underlying the QTL are functional. The detection of some other homoeo-QTL was year-dependent. Therefore, changes in allelic expression could take place in response to environmental changes. We believe that, in strawberry as in other polyploid fruit species, the mechanisms unravelled in the present study may play a crucial role in the variations of fruit quality. PMID:22215248

  13. Regional differences in awareness and attitudes regarding genetic testing for disease risk and ancestry

    PubMed Central

    Jonassaint, Charles R.; Santos, Eunice R.; Glover, Crystal M.; Payne, Perry W.; Fasaye, Grace-Ann; Oji-Njideka, Nefertiti; Hooker, Stanley; Hernandez, Wenndy; Foster, Morris W.; Kittles, Rick A.

    2010-01-01

    Little is known about the lay public’s awareness and attitudes concerning genetic testing and what factors influence their perspectives. The existing literature focuses mainly on ethnic and socioeconomic differences; however, here we focus on how awareness and attitudes regarding genetic testing differ by geographical regions in the US. We compared awareness and attitudes concerning genetic testing for disease risk and ancestry among 452 adults (41% Black and 67% female) in four major US cities, Norman, OK; Cincinnati, OH; Harlem, NY; and Washington, DC; prior to their participation in genetic ancestry testing. The OK participants reported more detail about their personal ancestries (p = 0.02) and valued ancestry testing over disease testing more than all other sites (p < 0.01). The NY participants were more likely than other sites to seek genetic testing for disease (p = 0.01) and to see benefit in finding out more about one’s ancestry (p = 0.02), while the DC participants reported reading and hearing more about genetic testing for African ancestry than all other sites (p < 0.01). These site differences were not better accounted for by sex, age, education, self-reported ethnicity, religion, or previous experience with genetic testing/counseling. Regional differences in awareness and attitudes transcend traditional demographic predictors, such as ethnicity, age and education. Local sociocultural factors, more than ethnicity and socioeconomic status, may influence the public’s awareness and belief systems, particularly with respect to genetics. PMID:20549517

  14. Contralateral Risk-Reducing Mastectomy in Young Breast Cancer Patients with and without Genetic Cancer Risk Assessment

    PubMed Central

    Mai, Phuong L.; Lagos, Veronica I.; Palomares, Melanie R.; Weitzel, Jeffrey N.

    2010-01-01

    Background Decisions regarding contralateral risk-reducing mastectomy (CRRM) among women diagnosed with unilateral breast cancer can potentially be influenced by age at diagnosis and other factors. In this study, we examined the use of CRRM before versus after genetic cancer risk assessment (GCRA) in women diagnosed with breast cancer before age 50. Methods We conducted a retrospective analysis of women with invasive breast cancer diagnosed before age 50 who were seen for GCRA between October 1996 and March 2005. Associations between the presence of generally accepted indications for risk-reducing surgery among women who had CRRM and the timing of GCRA were examined. Results The cohort included 378 women, of whom 57 had CRRM pre-GCRA and 45 had CRRM post-GCRA after a median follow-up of 26 months. Women who had CRRM pre-GCRA were more likely to not have a generally accepted indication for the procedure than those who did after GCRA (odds ratio [OR] 5.3, 95% confidence interval [95% CI] 1.6–17.8, P = .007). Women diagnosed with breast cancer before BRCA genetic testing became clinically available (1997) were more likely to have had CRRM pre-GCRA than those who were diagnosed more recently (OR 2.9, 95% CI 1.6–5.2, P = .0003). Conclusion When personal and family history was carefully examined, a substantial proportion of women seen in our clinic did not have a clear indication for CRRM. Decreased use of empiric CRRM among women diagnosed after 1997 may indicate increased awareness and use of GCRA. Thus, judicious application of GCRA may help focus use of surgical risk reduction measures to the most risk-appropriate patients. PMID:18836779

  15. Limited Clinical Utility of a Genetic Risk Score for the Prediction of Fracture Risk in Elderly Subjects

    PubMed Central

    Eriksson, Joel; Evans, Daniel S.; Nielson, Carrie M.; Shen, Jian; Srikanth, Priya; Hochberg, Marc; McWeeney, Shannon; Cawthon, Peggy M.; Wilmot, Beth; Zmuda, Joseph; Tranah, Greg; Mirel, Daniel B; Challa, Sashi; Mooney, Michael; Crenshaw, Andrew; Karlsson, Magnus; Mellström, Dan; Vandenput, Liesbeth; Orwoll, Eric; Ohlsson, Claes

    2014-01-01

    Context It is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal SNPs associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings two genetic risk scores (GRS63 and GRS16) were developed. Objective To determine the clinical usefulness of these GRS for the prediction of BMD, BMD change and fracture risk in elderly subjects. Design, Settings and Participants Two male (MrOS US, MrOS Sweden) and one female (SOF) large prospective cohorts of older subjects. Main Outcome Measures BMD, BMD change and radiographically and/or medically confirmed incident fractures (8,067 subjects, 2,185 incident non-vertebral or vertebral fractures). Results GRS63 was associated with BMD (≅3% of the variation explained), but not with BMD change. Both GRS63 and GRS16 were associated with fractures. After BMD-adjustment, the effect sizes for these associations were substantially reduced. Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared to those found using the corresponding weighted risk scores. Only minor improvements in C-statistics (AUC) for fractures were seen when the GRSs were added to a base model (age, weight and height) and no significant improvements in C-statistics were seen when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models. Conclusions and Relevance GRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects. PMID:25043339

  16. Spatially Explicit Modeling of Schistosomiasis Risk in Eastern China Based on a Synthesis of Epidemiological, Environmental and Intermediate Host Genetic Data

    PubMed Central

    Schrader, Matthias; Hauffe, Torsten; Zhang, Zhijie; Davis, George M.; Jopp, Fred; Remais, Justin V.; Wilke, Thomas

    2013-01-01

    also highlight how genetic information on taxa that constitute bottlenecks to disease transmission can be of value for risk modeling. PMID:23936563

  17. The Palau Early Psychosis Study: Distribution of Cases by Level of Genetic Risk

    PubMed Central

    Myles-Worsley, Marina; Blailes, Francisca; Ord, Lisa M.; Weaver, Starla; Dever, Gregory; Faraone, Stephen V.

    2008-01-01

    The Palau Early Psychosis Study (PEPS) was designed to examine the pathogenesis of early psychosis in a high risk population isolate. This paper describes the characteristics of our community-based, non-help seeking sample of 404 Palauan adolescents and quantifies the presence of early psychosis by level of genetic risk. The sample included 53 offspring of a schizophrenic parent designated as “Genetically Highest Risk” (GHR+) and 68 nieces/nephews of sib-pairs/trios, designated as “Genetically High Risk” (GHR). The remaining subjects were recruited through a high school survey that identified 62 “Genetically Moderate Risk” (GMR) adolescents with an affected 2nd or 3rd degree relative and 221 “Genetically Low Risk” (GLR) subjects with no close affected relatives. The GLR adolescents included 117 symptomatic or “Clinically High Risk” (CHR) adolescents and 104 asymptomatic normal controls. Based on a modified K-SADS-PL assessment, we identified 221 adolescents with early psychosis, 62 or 28% of whom had already transitioned to a psychotic disorder. Together, the two highest risk groups contributed 31% of the adolescent-onset psychosis cases and 27% of the prodromals. More than half of the early psychosis cases (53%) were GLR adolescents. The mean age of onset for DSM-IV psychosis was 12.9 years, and males transitioned at an earlier age than females. Our results indicate that Palauan adolescents, even GLR adolescents with no close affected relatives, have elevated rates of early psychosis. These young subjects can contribute valuable information about the familial transmission of schizophrenia, the developmental course of the illness, and rates of transition to frank psychosis. PMID:17034019

  18. Genetically modified foods: safety, risks and public concerns-a review.

    PubMed

    Bawa, A S; Anilakumar, K R

    2013-12-01

    Genetic modification is a special set of gene technology that alters the genetic machinery of such living organisms as animals, plants or microorganisms. Combining genes from different organisms is known as recombinant DNA technology and the resulting organism is said to be 'Genetically modified (GM)', 'Genetically engineered' or 'Transgenic'. The principal transgenic crops grown commercially in field are herbicide and insecticide resistant soybeans, corn, cotton and canola. Other crops grown commercially and/or field-tested are sweet potato resistant to a virus that could destroy most of the African harvest, rice with increased iron and vitamins that may alleviate chronic malnutrition in Asian countries and a variety of plants that are able to survive weather extremes. There are bananas that produce human vaccines against infectious diseases such as hepatitis B, fish that mature more quickly, fruit and nut trees that yield years earlier and plants that produce new plastics with unique properties. Technologies for genetically modifying foods offer dramatic promise for meeting some areas of greatest challenge for the 21st century. Like all new technologies, they also pose some risks, both known and unknown. Controversies and public concern surrounding GM foods and crops commonly focus on human and environmental safety, labelling and consumer choice, intellectual property rights, ethics, food security, poverty reduction and environmental conservation. With this new technology on gene manipulation what are the risks of "tampering with Mother Nature"?, what effects will this have on the environment?, what are the health concerns that consumers should be aware of? and is recombinant technology really beneficial? This review will also address some major concerns about the safety, environmental and ecological risks and health hazards involved with GM foods and recombinant technology. PMID:24426015

  19. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges

    PubMed Central

    Wilke, Russell A.; Lin, Debbie W.; Roden, Dan M.; Watkins, Paul B.; Flockhart, David; Zineh, Issam; Giacomini, Kathleen M.; Krauss, Ronald M.

    2009-01-01

    Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drug's pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic. Genetic factors may underlie susceptibility to SADRs and the identification of predisposing genotypes may improve patient management through the prospective selection of appropriate candidates. Here we discuss three specific SADRs with an emphasis on genetic risk factors. These SADRs, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes. Key challenges for the discovery of predictive risk alleles for these SADRs are also considered. PMID:17971785

  20. Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism

    PubMed Central

    Corominas, Roser; Yang, Xinping; Lin, Guan Ning; Kang, Shuli; Shen, Yun; Ghamsari, Lila; Broly, Martin; Rodriguez, Maria; Tam, Stanley; Trigg, Shelly A.; Fan, Changyu; Yi, Song; Tasan, Murat; Lemmens, Irma; Kuang, Xingyan; Zhao, Nan; Malhotra, Dheeraj; Michaelson, Jacob J.; Vacic, Vladimir; Calderwood, Michael A.; Roth, Frederick P.; Tavernier, Jan; Horvath, Steve; Salehi-Ashtiani, Kourosh; Korkin, Dmitry; Sebat, Jonathan; Hill, David E.; Hao, Tong; Vidal, Marc; Iakoucheva, Lilia M.

    2014-01-01

    Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases. PMID:24722188

  1. Relevance of Crop Biology for Environmental Risk Assessment of Genetically Modified Crops in Africa.

    PubMed

    Akinbo, Olalekan; Hancock, James F; Makinde, Diran

    2015-01-01

    Knowledge about the crop biology of economic crops in Africa is needed for regulators to accurately review dossiers and conduct comprehensive environmental risk assessments (ERAs). This information allows regulators to decide whether biotech crops present a risk to biodiversity, since crossing between domesticated crops and their wild relatives could affect the adaptations of the wild species. The criteria that should be used in the evaluation of African crops for ERA include growth habit, center of origin, center of genetic diversity, proximity of wild relatives, inter-fertility, mode of pollen dispersal, length of pollen viability, mating system, invasiveness, weediness, mode of propagation, mode of seed dispersal, and length of seed dormancy. In this paper, we discuss the crops being genetic engineered in Africa and describe the crop biology of those with native relatives. PMID:26501055

  2. Relevance of Crop Biology for Environmental Risk Assessment of Genetically Modified Crops in Africa

    PubMed Central

    Akinbo, Olalekan; Hancock, James F.; Makinde, Diran

    2015-01-01

    Knowledge about the crop biology of economic crops in Africa is needed for regulators to accurately review dossiers and conduct comprehensive environmental risk assessments (ERAs). This information allows regulators to decide whether biotech crops present a risk to biodiversity, since crossing between domesticated crops and their wild relatives could affect the adaptations of the wild species. The criteria that should be used in the evaluation of African crops for ERA include growth habit, center of origin, center of genetic diversity, proximity of wild relatives, inter-fertility, mode of pollen dispersal, length of pollen viability, mating system, invasiveness, weediness, mode of propagation, mode of seed dispersal, and length of seed dormancy. In this paper, we discuss the crops being genetic engineered in Africa and describe the crop biology of those with native relatives. PMID:26501055

  3. Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia.

    PubMed

    Martin, Andrew K; Robinson, G; Reutens, D; Mowry, B

    2015-09-30

    Schizophrenia is a clinically heterogeneous disorder associated with broad deficits across cognitive domains. As large genomewide association studies uncover the genetic architecture of schizophrenia, the relationship between common genetic variants and clinical and cognitive characteristics will form part of an integrative approach to understanding genetic effects on the clinical phenotype. In the current study, association between common genetic risk variants and clinical and cognitive variables was investigated. Common risk variants were associated with positive symptoms and decision-making ability from the Cambridge Gambling Task with trends in other domains. PMID:26070766

  4. Ecological risk assessment of genetically modified crops based on cellular automata modeling.

    PubMed

    Yang, Jun; Wang, Zhi-Rui; Yang, De-Li; Yang, Qing; Yan, Jun; He, Ming-Feng

    2009-01-01

    The assessment of ecological risk in genetically modified (GM) biological systems is critically important for decision-making and public acceptance. Cellular automata (CA) provide a potential modeling and simulation framework for representing relationships and interspecies interactions both temporally and spatially. In this paper, a simple subsystem contains only four species: crop, target pest, non-target pest and enemy insect, and a three layer arrangement of LxL stochastic cellular automata with a periodic boundary were established. The simulation of this simplified system showed abundant and sufficient complexity in population assembly and densities, suggesting a prospective application in ecological risk assessment of GM crops. PMID:19477260

  5. Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia.

    PubMed

    Irving, Julie A E; Enshaei, Amir; Parker, Catriona A; Sutton, Rosemary; Kuiper, Roland P; Erhorn, Amy; Minto, Lynne; Venn, Nicola C; Law, Tamara; Yu, Jiangyan; Schwab, Claire; Davies, Rosanna; Matheson, Elizabeth; Davies, Alysia; Sonneveld, Edwin; den Boer, Monique L; Love, Sharon B; Harrison, Christine J; Hoogerbrugge, Peter M; Revesz, Tamas; Saha, Vaskar; Moorman, Anthony V

    2016-08-18

    Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312. PMID:27229005

  6. Explaining public resistance to genetically modified corn: an analysis of the distribution of benefits and risks.

    PubMed

    Wu, Felicia

    2004-06-01

    Genetically modified (GM) crops have met with widespread approval among scientists and policy makers in the United States, but public approval of GM crops, both domestically and abroad, is progressing much more slowly. An underlying cause of public wariness may be that both nations and individual consumers do not perceive significant benefits to themselves from GM crops, while fearing the risks they may incur. In this study, an economic analysis is conducted to determine whether the benefits of one type of GM corn, Bt corn (genetically modified to resist damage from the ECB and Southwestern corn borer), outweigh the potential risks; and who the "winners" and "losers" are among stakeholder groups that may be affected by Bt corn. It is found that Bt corn growers, consumers, and industry all benefit from Bt corn adoption, though the purported health and environmental benefits of reducing chemical pesticide usage through Bt corn are negligible. Though the aggregated public benefit is large, the welfare gain to individual consumers is small and may not make up for perceived risks. While environmental and health risks of Bt corn are unlikely, the potential market risks-impacting both the organic corn market and total U.S. corn exports-are found to be significant. Currently, distributional analysis is not a part of regulatory decision making of Bt corn in the United States; yet it may help to explain why decision makers at both the government and individual-consumer levels have failed to embrace Bt corn and other GM crops. PMID:15209940

  7. Hodgkin Lymphoma Risk: Role of Genetic Polymorphisms and Gene-Gene Interactions in DNA repair pathways

    PubMed Central

    Monroy, Claudia M.; Cortes, Andrea C.; Lopez, Mirtha; Rourke, Elizabeth; Etzel, Carol J.; Younes, Anas; Strom, Sara S.; El-Zein, Randa

    2011-01-01

    DNA repair variants may play a potentially important role in an individual’s susceptibility to developing cancer. Numerous studies have reported the association between genetic single nucleotide polymorphisms (SNPs) in DNA repair genes and different types of hematologic cancers. However, to date, the effects of such SNPs on modulating Hodgkin Lymphoma (HL) risk have not yet been investigated. We hypothesized that gene-gene interaction between candidate genes in Direct Reversal, Nucleotide excision repair (NER), Base excision repair (BER) and Double strand break (DSB) pathways may contribute to susceptibility to HL. To test this hypothesis, we conducted a study on 200 HL cases and 220 controls to assess associations between HL risk and 21 functional SNPs in DNA repair genes. We evaluated potential gene-gene interactions and the association of multiple polymorphisms in a chromosome region using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction and classification and regression tree approaches. We observed that, in combination, allelic variants in the XPC Ala499Val, NBN Glu185Gln, XRCC3 Thr241Me, XRCC1 Arg194Trp and XRCC1 399Gln polymorphisms modify the risk for developing HL. Moreover, the cumulative genetic risk score revealed a significant trend where the risk for developing HL increases as the number of adverse alleles in BER and DSB genes increase. These findings suggest that DNA repair variants in BER and DSB pathways may play an important role in the development of HL. PMID:21374732

  8. Reproductive aging-associated common genetic variants and the risk of breast cancer

    PubMed Central

    2012-01-01

    Introduction A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown. Methods In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait. Results After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile. Conclusions Our study suggests that three genetic variants, independent of their

  9. Genetic Underpinnings of White Matter ‘Connectivity’: Heritability, Risk, and Heterogeneity in Schizophrenia

    PubMed Central

    Voineskos, Aristotle N.

    2014-01-01

    Schizophrenia is a highly heritable disorder. Thus, the combination of genetics and brain imaging may be a useful strategy to investigate the effects of risk genes on anatomical connectivity, and for gene discovery, i.e. discovering the genetic correlates of white matter phenotypes. Following a database search, I review evidence for heritability of white matter phenotypes. I also review candidate gene investigations, examining association of putative risk variants with white matter phenotypes, as well as the recent flurry of research exploring relationships of genome-wide significant risk loci with white matter phenotypes. Finally, I review multivariate and polygene approaches, which constitute a new wave of imaging-genetics research, including large collaborative initiatives aiming to discover new genes that may predict aspects of white matter microstructure. The literature supports the heritability of white matter phenotypes. Loci in genes intimately implicated in oligodendrocyte and myelin development, growth and maintenance, and neurotrophic systems are associated with white matter microstructure. GWAS variants have not yet sufficiently been explored using DTI-based evaluation of white matter to draw conclusions, although micro-RNA 137 is promising due to its potential regulation of other GWAS schizophrenia genes. Many imaging-genetic studies only include healthy participants, which, while helping control for certain confounds, cannot address questions related to disease heterogeneity or symptom expression, and thus more studies should include participants with schizophrenia. With sufficiently large sample sizes, the future of this field lies in polygene strategies aimed at risk prediction and heterogeneity dissection of schizophrenia that can translate to personalized interventions. PMID:24893906

  10. Genetic Risk for Attention-Deficit/Hyperactivity Disorder Contributes to Neurodevelopmental Traits in the General Population

    PubMed Central

    Martin, Joanna; Hamshere, Marian L.; Stergiakouli, Evangelia; O’Donovan, Michael C.; Thapar, Anita

    2014-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population. Methods Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥1) ADHD item (n = 3623). Results Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥1 for ADHD traits, girls had a higher polygenic score than boys (p = .003). Conclusions These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD. PMID:24673882

  11. The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis

    PubMed Central

    Hollands, Gareth J; French, David P; Griffin, Simon J; Prevost, A Toby; Sutton, Stephen; King, Sarah

    2016-01-01

    . These results do not support use of genetic testing or the search for risk-conferring gene variants for common complex diseases on the basis that they motivate risk-reducing behaviour. Systematic review registration This is a revised and updated version of a Cochrane review from 2010, adding 11 studies to the seven previously identified. PMID:26979548

  12. Genetic dyslexia risk variant is related to neural connectivity patterns underlying phonological awareness in children.

    PubMed

    Skeide, Michael A; Kirsten, Holger; Kraft, Indra; Schaadt, Gesa; Müller, Bent; Neef, Nicole; Brauer, Jens; Wilcke, Arndt; Emmrich, Frank; Boltze, Johannes; Friederici, Angela D

    2015-09-01

    Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia. PMID:26080313

  13. EFSA's scientific activities and achievements on the risk assessment of genetically modified organisms (GMOs) during its first decade of existence: looking back and ahead.

    PubMed

    Devos, Yann; Aguilera, Jaime; Diveki, Zoltán; Gomes, Ana; Liu, Yi; Paoletti, Claudia; du Jardin, Patrick; Herman, Lieve; Perry, Joe N; Waigmann, Elisabeth

    2014-02-01

    Genetically modified organisms (GMOs) and derived food and feed products are subject to a risk analysis and regulatory approval before they can enter the market in the European Union (EU). In this risk analysis process, the role of the European Food Safety Authority (EFSA), which was created in 2002 in response to multiple food crises, is to independently assess and provide scientific advice to risk managers on any possible risks that the use of GMOs may pose to human and animal health and the environment. EFSA's scientific advice is elaborated by its GMO Panel with the scientific support of several working groups and EFSA's GMO Unit. This review presents EFSA's scientific activities and highlights its achievements on the risk assessment of GMOs for the first 10 years of its existence. Since 2002, EFSA has issued 69 scientific opinions on genetically modified (GM) plant market registration applications, of which 62 for import and processing for food and feed uses, six for cultivation and one for the use of pollen (as or in food), and 19 scientific opinions on applications for marketing products made with GM microorganisms. Several guidelines for the risk assessment of GM plants, GM microorganisms and GM animals, as well as on specific issues such as post-market environmental monitoring (PMEM) were elaborated. EFSA also provided scientific advice upon request of the European Commission on safeguard clause and emergency measures invoked by EU Member States, annual PMEM reports, the potential risks of new biotechnology-based plant breeding techniques, evaluations of previously assessed GMOs in the light of new scientific publications, and the use of antibiotic resistance marker genes in GM plants. Future challenges relevant to the risk assessment of GMOs are discussed. EFSA's risk assessments of GMO applications ensure that data are analysed and presented in a way that facilitates scientifically sound decisions that protect human and animal health and the environment

  14. Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci

    PubMed Central

    Thompson, Wesley K.; McEvoy, Linda K.; Schork, Andrew J.; Zuber, Verena; LeBlanc, Marissa; Bettella, Francesco; Mills, Ian G.; Desikan, Rahul S.; Djurovic, Srdjan; Gautvik, Kaare M.; Dale, Anders M.; Andreassen, Ole A.

    2015-01-01

    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. PMID:26695485

  15. Risk factors for venous thromboembolism in women under combined oral contraceptive. The PILl Genetic RIsk Monitoring (PILGRIM) Study.

    PubMed

    Suchon, Pierre; Al Frouh, Fadi; Henneuse, Agathe; Ibrahim, Manal; Brunet, Dominique; Barthet, Marie-Christine; Aillaud, Marie-Françoise; Venton, Geoffroy; Alessi, Marie-Christine; Trégouët, David-Alexandre; Morange, Pierre-Emmanuel

    2016-01-01

    Identifying women at risk of venous thromboembolism (VTE) is a major public health issue. The objective of this study was to identify environmental and genetic determinants of VTE risk in a large sample of women under combined oral contraceptives (COC). A total of 968 women who had had one event of VTE during COC use were compared to 874 women under COC but with no personal history of VTE. Clinical data were collected and a systematic thrombophilia screening was performed together with ABO blood group assessment. After adjusting for age, family history, and type and duration of COC use, main environmental determinants of VTE were smoking (odds ratio [OR] =1.65, 95% confidence interval [1.30-2.10]) and a body mass index higher than 35 kg.m⁻² (OR=3.46 [1.81-7.03]). In addition, severe inherited thrombophilia (OR=2.13 [1.32-3.51]) and non-O blood groups (OR=1.98 [1.57-2.49]) were strong genetic risk factors for VTE. Family history poorly predicted thrombophilia as its prevalence was similar in patients with or without first degree family history of VTE (29.3% vs 23.9%, p=0.09). In conclusion, this study confirms the influence of smoking and obesity and shows for the first time the impact of ABO blood group on the risk of VTE in women under COC. It also confirms the inaccuracy of the family history of VTE to detect inherited thrombophilia. PMID:26290123

  16. Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk?

    PubMed Central

    2013-01-01

    Background Autism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families. Methods We extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven’s Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS). Results The prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4). Conclusions Epilepsy in multiplex autism may define a different subgroup in terms of clinical

  17. GENETIC VARIATION AND DECREASED RISK FOR OBESITY IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our objective was to investigate the effects of variation in the leptin [LEP (19A>G)] and melanocortin-4 receptor [MC4R (V103I)] genes on obesity-related traits in 13 405 African-American (AA) and white participants from the Atherosclerosis Risk in Communities (ARIC) Study. We tested the association...

  18. Toenail iron, genetic determinants of iron status and the risk of glioma

    PubMed Central

    Anic, Gabriella M.; Madden, Melissa H.; Thompson, Reid C.; Nabors, L. Burton; Olson, Jeffrey J.; LaRocca, Renato V.; Browning, James E.; Brockman, John D.; Forsyth, Peter A.; Egan, Kathleen M.

    2013-01-01

    Purpose Iron is essential for oxygen transport and oxidative metabolism; however, elevated iron stores can trigger overproduction of reactive oxygen species and induce DNA damage. Little is known about the association between body iron stores and glioma risk. This study examined associations of iron levels measured in toenails and genetic variants linked to body iron stores with risk of glioma in a clinic-based case-control study. Methods Samples were collected a median of 24 days following glioma diagnosis in the cases (10th-90th percentile range: 10-44 days). Nail iron levels were measured in 300 cases and 300 controls using neutron-activation analysis. A total of 24 genetic variants associated with iron status were genotyped in 622 cases and 628 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to toenail iron and the examined genotypes. Results No association was observed between toenail iron and glioma risk when restricting to cases with nails collected within ~3 weeks of diagnosis (OR=0.93; 95% CI: 0.46, 1.87 comparing those with high (≥ 14 μg/g) versus low (<6 μg/g) iron levels). In contrast, an inverse association with increasing iron was observed after restricting to cases with a delay of 3 weeks or greater (OR=0.42; 95% CI: 0.19, 0.95) reflecting potentially insidious effects of advancing disease on iron levels among the cases. No associations were observed for any of the examined genetic variants. Conclusion The results do not support a role for body iron stores as a determinant of glioma risk. PMID:23996192

  19. Genetic variants and the risk of gestational diabetes mellitus: a systematic review

    PubMed Central

    Zhang, Cuilin; Bao, Wei; Rong, Ying; Yang, Huixia; Bowers, Katherine; Yeung, Edwina; Kiely, Michele

    2013-01-01

    BACKGROUND Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies. METHODS Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNP–GDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity. RESULTS Overall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (−30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95% CIs) of 1.44 (1.29–1.60, P < 0.001) per T allele of rs7903146 and 1.46 (1.15–1.84, P = 0.002) per T allele of rs12255372. CONCLUSIONS In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion. PMID:23690305

  20. Combining social and genetic networks to study HIV transmission in mixing risk groups

    NASA Astrophysics Data System (ADS)

    Zarrabi, Narges; Prosperi, Mattia C. F.; Belleman, Robbert G.; Di Giambenedetto, Simona; Fabbiani, Massimiliano; De Luca, Andrea; Sloot, Peter M. A.

    2013-09-01

    Reconstruction of HIV transmission networks is important for understanding and preventing the spread of the virus and drug resistant variants. Mixing risk groups is important in network analysis of HIV in order to assess the role of transmission between risk groups in the HIV epidemic. Most of the research focuses on the transmission within HIV risk groups, while transmission between different risk groups has been less studied. We use a proposed filter-reduction method to infer hypothetical transmission networks of HIV by combining data from social and genetic scales. We modified the filtering process in order to include mixing risk groups in the model. For this, we use the information on phylogenetic clusters obtained through phylogenetic analysis. A probability matrix is also defined to specify contact rates between individuals form the same and different risk groups. The method converts the data form each scale into network forms and combines them by overlaying and computing their intersection. We apply this method to reconstruct networks of HIV infected patients in central Italy, including mixing between risk groups. Our results suggests that bisexual behavior among Italian MSM and IDU partnership are relatively important in heterosexual transmission of HIV in central Italy.

  1. Primer Part 1-The building blocks of epilepsy genetics.

    PubMed

    Helbig, Ingo; Heinzen, Erin L; Mefford, Heather C

    2016-06-01

    This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies. PMID:27226047

  2. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

    PubMed Central

    Pharoah, Paul D. P.; Michailidou, Kyriaki; Tyrer, Jonathan; Brook, Mark N.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Brown, Judith; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Peto, Julian; dos-Santos-Silva, Isabel; Dudbridge, Frank; Johnson, Nichola; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Rutgers, Emiel J.; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Figueroa, Jonine; Chanock, Stephen J.; Brinton, Louise; Lissowska, Jolanta; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Pankratz, Vernon S.; Lambrechts, Diether; Wildiers, Hans; Van Ongeval, Chantal; van Limbergen, Erik; Kristensen, Vessela; Grenaker Alnæs, Grethe; Nord, Silje; Borresen-Dale, Anne-Lise; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Trentham-Dietz, Amy; Newcomb, Polly; Titus, Linda; Egan, Kathleen M.; Hunter, David J.; Lindstrom, Sara; Tamimi, Rulla M.; Kraft, Peter; Rahman, Nazneen; Turnbull, Clare; Renwick, Anthony; Seal, Sheila; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Benitez, Javier; Pilar Zamora, M.; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Dörk, Thilo; Anton-Culver, Hoda; Neuhausen, Susan L.; Ziogas, Argyrios; Bernstein, Leslie; Devilee, Peter; Tollenaar, Robert A. E. M.; Seynaeve, Caroline; van Asperen, Christi J.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Khusnutdinova, Elza; Bermisheva, Marina; Prokofyeva, Darya; Takhirova, Zalina; Meindl, Alfons; Schmutzler, Rita K.; Sutter, Christian; Yang, Rongxi; Schürmann, Peter; Bremer, Michael; Christiansen, Hans; Park-Simon, Tjoung-Won; Hillemanns, Peter; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Pensotti, Valeria; Hopper, John L.; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C.; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Sigurdson, Alice J.; Doody, Michele M.; Hamann, Ute; Torres, Diana; Ulmer, Hans-Ulrich; Försti, Asta; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Marie Mulligan, Anna; Chenevix-Trench, Georgia; Balleine, Rosemary; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Lindblom, Annika; Margolin, Sara; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Eilber, Ursula; Wang-Gohrke, Shan; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Koppert, Linetta B.; Carpenter, Jane; Clarke, Christine; Scott, Rodney; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Brenner, Hermann; Arndt, Volker; Stegmaier, Christa; Karina Dieffenbach, Aida; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Offit, Kenneth; Vijai, Joseph; Robson, Mark; Rau-Murthy, Rohini; Dwek, Miriam; Swann, Ruth; Annie Perkins, Katherine; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Eccles, Diana M.; Tapper, William J.; Rafiq, Sajjad; John, Esther M.; Whittemore, Alice S.; Slager, Susan; Yannoukakos, Drakoulis; Toland, Amanda E.; Yao, Song; Zheng, Wei; Halverson, Sandra L.; González-Neira, Anna; Pita, Guillermo; Rosario Alonso, M.; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; Simard, Jacques; Hall, Per; Easton, Douglas F.; Garcia-Closas, Montserrat

    2015-01-01

    Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. PMID:25855707

  3. Race-specific genetic risk score is more accurate than nonrace-specific genetic risk score for predicting prostate cancer and high-grade diseases

    PubMed Central

    Na, Rong; Ye, Dingwei; Qi, Jun; Liu, Fang; Lin, Xiaoling; Helfand, Brian T; Brendler, Charles B; Conran, Carly; Gong, Jian; Wu, Yishuo; Gao, Xu; Chen, Yaqing; Zheng, S Lilly; Mo, Zengnan; Ding, Qiang; Sun, Yinghao; Xu, Jianfeng

    2016-01-01

    Genetic risk score (GRS) based on disease risk-associated single nucleotide polymorphisms (SNPs) is an informative tool that can be used to provide inherited information for specific diseases in addition to family history. However, it is still unknown whether only SNPs that are implicated in a specific racial group should be used when calculating GRSs. The objective of this study is to compare the performance of race-specific GRS and nonrace-specific GRS for predicting prostate cancer (PCa) among 1338 patients underwent prostate biopsy in Shanghai, China. A race-specific GRS was calculated with seven PCa risk-associated SNPs implicated in East Asians (GRS7), and a nonrace-specific GRS was calculated based on 76 PCa risk-associated SNPs implicated in at least one racial group (GRS76). The means of GRS7 and GRS76 were 1.19 and 1.85, respectively, in the study population. Higher GRS7 and GRS76 were independent predictors for PCa and high-grade PCa in univariate and multivariate analyses. GRS7 had a better area under the receiver-operating curve (AUC) than GRS76 for discriminating PCa (0.602 vs 0.573) and high-grade PCa (0.603 vs 0.575) but did not reach statistical significance. GRS7 had a better (up to 13% at different cutoffs) positive predictive value (PPV) than GRS76. In conclusion, a race-specific GRS is more robust and has a better performance when predicting PCa in East Asian men than a GRS calculated using SNPs that are not shown to be associated with East Asians. PMID:27140652

  4. Race-specific genetic risk score is more accurate than nonrace-specific genetic risk score for predicting prostate cancer and high-grade diseases.

    PubMed

    Na, Rong; Ye, Dingwei; Qi, Jun; Liu, Fang; Lin, Xiaoling; Helfand, Brian T; Brendler, Charles B; Conran, Carly; Gong, Jian; Wu, Yishuo; Gao, Xu; Chen, Yaqing; Zheng, S Lilly; Mo, Zengnan; Ding, Qiang; Sun, Yinghao; Xu, Jianfeng

    2016-01-01

    Genetic risk score (GRS) based on disease risk-associated single nucleotide polymorphisms (SNPs) is an informative tool that can be used to provide inherited information for specific diseases in addition to family history. However, it is still unknown whether only SNPs that are implicated in a specific racial group should be used when calculating GRSs. The objective of this study is to compare the performance of race-specific GRS and nonrace-specific GRS for predicting prostate cancer (PCa) among 1338 patients underwent prostate biopsy in Shanghai, China. A race-specific GRS was calculated with seven PCa risk-associated SNPs implicated in East Asians (GRS7), and a nonrace-specific GRS was calculated based on 76 PCa risk-associated SNPs implicated in at least one racial group (GRS76). The means of GRS7 and GRS76 were 1.19 and 1.85, respectively, in the study population. Higher GRS7 and GRS76 were independent predictors for PCa and high-grade PCa in univariate and multivariate analyses. GRS7 had a better area under the receiver-operating curve (AUC) than GRS76 for discriminating PCa (0.602 vs 0.573) and high-grade PCa (0.603 vs 0.575) but did not reach statistical significance. GRS7 had a better (up to 13% at different cutoffs) positive predictive value (PPV) than GRS76. In conclusion, a race-specific GRS is more robust and has a better performance when predicting PCa in East Asian men than a GRS calculated using SNPs that are not shown to be associated with East Asians. PMID:27140652

  5. Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

    PubMed Central

    Jansen, Henning; Loley, Christina; Lieb, Wolfgang; Pencina, Michael J; Nelson, Christopher P; Kathiresan, Sekar; Peloso, Gina M; Voight, Benjamin F; Reilly, Muredach P; Assimes, Themistocles L; Boerwinkle, Eric; Hengstenberg, Christian; Laaksonen, Reijo; McPherson, Ruth; Roberts, Robert; Thorsteinsdottir, Unnur; Peters, Annette; Gieger, Christian; Rawal, Rajesh; Thompson, John R; König, Inke R; Vasan, Ramachandran S; Erdmann, Jeanette; Samani, Nilesh J; Schunkert, Heribert

    2015-01-01

    Background The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. Methods and Results We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p<5*10−8) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p<0.05), more than expected by chance (p=5.0*10−5). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973–1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p=7.2*10−10 vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. Conclusions Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting. PMID:26074316

  6. Ecogenetics of mercury: from genetic polymorphisms and epigenetics to risk assessment and decision-making.

    PubMed

    Basu, Niladri; Goodrich, Jaclyn M; Head, Jessica

    2014-06-01

    The risk assessment of mercury (Hg), in both humans and wildlife, is made challenging by great variability in exposure and health effects. Although disease risk arises following complex interactions between genetic ("nature") and environmental ("nurture") factors, most Hg studies thus far have focused solely on environmental factors. In recent years, ecogenetic-based studies have emerged and have started to document genetic and epigenetic factors that may indeed influence the toxicokinetics or toxicodynamics of Hg. The present study reviews these studies and discusses their utility in terms of Hg risk assessment, management, and policy and offers perspectives on fruitful areas for future research. In brief, epidemiological studies on populations exposed to inorganic Hg (e.g., dentists and miners) or methylmercury (e.g., fish consumers) are showing that polymorphisms in a number of environmentally responsive genes can explain variations in Hg biomarker values and health outcomes. Studies on mammals (wildlife, humans, rodents) are showing Hg exposures to be related to epigenetic marks such as DNA methylation. Such findings are beginning to increase understanding of the mechanisms of action of Hg, and in doing so they may help identify candidate biomarkers and pinpoint susceptible groups or life stages. Furthermore, they may help refine uncertainty factors and thus lead to more accurate risk assessments and improved decision-making. PMID:24038486

  7. Organ doses, detriment and genetic risk from interventional vascular procedures in Málaga (Spain).

    PubMed

    Ruiz-Cruces, R; Perez-Martinez, M; Tort Ausina, I; Muñoz, V; Martinez-Morillo, M; Diez de los Ríos, A

    2000-01-01

    Nowadays, the radiological risk from simple X-ray procedures is well known. The purpose of this work has been to estimate the population risk from digital angiographic and interventional procedures and to compare it with the one from simple procedures in the same population. The population risk has been estimated according to the following quantities: genetically significant dose, somatic significant dose, collective effective dose, annual per caput effective dose and detriment. These have been estimated from dose area product and organ dose. Organ dose values were estimated with the Eff-Dose software. A population of 605410 people were included in the study. In 1996, 1312 patients were to digital interventional vascular procedures in Malaga, and 159 of them were selected in this research project to obtain the dose area product and organ dose. The results obtained for the quantities evaluated are: genetically significant dose, 4.1 microGy; somatic significant dose, 0.9 mSv; collective effective dose, 11.65 person-Sv: annual per caput effective dose, 0.02 mSv and detriment, 0.65 radiogenic cancers per year. These procedures supply a high radiation dose, so they should have a greater contribution to population dose and risk than simple examinations. However, our results indicate just the opposite. PMID:10674785

  8. Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome

    PubMed Central

    Dai, Yufei; Chen, Ying; Huang, Hanlin; Zhou, Wei; Niu, Yong; Zhang, Mingrong; Bin, Ping; Dong, Haiyan; Jia, Qiang; Huang, Jianxun; Yi, Juan; Liao, Qijun; Li, Haishan; Teng, Yanxia; Zang, Dan; Zhai, Qingfeng; Duan, Huawei; Shen, Juan; He, Jiaxi; Meng, Tao; Sha, Yan; Shen, Meili; Ye, Meng; Jia, Xiaowei; Xiang, Yingping; Huang, Huiping; Wu, Qifeng; Shi, Mingming; Huang, Xianqing; Yang, Huanming; Luo, Longhai; Li, Sai; Li, Lin; Zhao, Jinyang; Li, Laiyu; Wang, Jun; Zheng, Yuxin

    2015-01-01

    Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P < 5 × 10−8) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; Pmeta = 1.33 × 10−37) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; Pmeta = 8.79 × 10−35). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease, and could be considered for translational application for screening employees before exposure. PMID:26190474

  9. Genetic variants in lncRNA SRA and risk of breast cancer.

    PubMed

    Yan, Rui; Wang, Kaijuan; Peng, Rui; Wang, Shuaibing; Cao, Jingjing; Wang, Peng; Song, Chunhua

    2016-04-19

    Long non-coding RNA (lncRNA) steroid receptor RNA activator (SRA) has been identified to activate steroid receptor transcriptional activity and participate in tumor pathogenesis. This case-control study evaluated the association between two haplotype tagging SNPs (htSNPs) (rs10463297, rs801460) of the whole SRA sequence and breast cancer risk. We found that rs10463297 TC genotype significantly increased BC risk compared with CC genotype in both the codominant (TC vs. TT: OR=1.43, 95 % CI=1.02-2.00) and recessive (TC+CC vs. TT: OR=1.39, 95 % CI=1.01-1.92) genetic models. Both TC, TC + CC genotypes of rs10463297 and GA, AA, GA+AA genotypes of rs801460 were significantly associated with estrogen receptor (ER) positivity status. rs10463297 TC (2.09 ± 0.41), CC (2.42 ± 0.51) and TC + CC (2.20 ± 0.47) genotypes were associated with higher blood plasma SRA mRNA levels compared with the TT genotype (1.45 ± 0.34). Gene-reproductive interaction analysis presented a best model consisted of four factors (rs10463297, age, post-menopausal, No. of pregnancy), which could increase the BC risk with 1.58-fold (OR=1.58, 95 % CI=1.23-2.03). These findings suggest that SRA genetic variants may contribute to BC risk and have apparent interaction with reproductive factors in BC progression. PMID:26967566

  10. Decoding the non-coding genome: elucidating genetic risk outside the coding genome.

    PubMed

    Barr, C L; Misener, V L

    2016-01-01

    Current evidence emerging from genome-wide association studies indicates that the genetic underpinnings of complex traits are likely attributable to genetic variation that changes gene expression, rather than (or in combination with) variation that changes protein-coding sequences. This is particularly compelling with respect to psychiatric disorders, as genetic changes in regulatory regions may result in differential transcriptional responses to developmental cues and environmental/psychosocial stressors. Until recently, however, the link between transcriptional regulation and psychiatric genetic risk has been understudied. Multiple obstacles have contributed to the paucity of research in this area, including challenges in identifying the positions of remote (distal from the promoter) regulatory elements (e.g. enhancers) and their target genes and the underrepresentation of neural cell types and brain tissues in epigenome projects - the availability of high-quality brain tissues for epigenetic and transcriptome profiling, particularly for the adolescent and developing brain, has been limited. Further challenges have arisen in the prediction and testing of the functional impact of DNA variation with respect to multiple aspects of transcriptional control, including regulatory-element interaction (e.g. between enhancers and promoters), transcription factor binding and DNA methylation. Further, the brain has uncommon DNA-methylation marks with unique genomic distributions not found in other tissues - current evidence suggests the involvement of non-CG methylation and 5-hydroxymethylation in neurodevelopmental processes but much remains unknown. We review here knowledge gaps as well as both technological and resource obstacles that will need to be overcome in order to elucidate the involvement of brain-relevant gene-regulatory variants in genetic risk for psychiatric disorders. PMID:26515765

  11. Decoding the non-coding genome: elucidating genetic risk outside the coding genome

    PubMed Central

    Barr, C. L.; Misener, V. L.

    2016-01-01

    Current evidence emerging from genome-wide association studies indicates that the genetic underpinnings of complex traits are likely attributable to genetic variation that changes gene expression, rather than (or in combination with) variation that changes protein-coding sequences. This is particularly compelling with respect to psychiatric disorders, as genetic changes in regulatory regions may result in differential transcriptional responses to developmental cues and environmental/psychosocial stressors. Until recently, however, the link between transcriptional regulation and psychiatric genetic risk has been understudied. Multiple obstacles have contributed to the paucity of research in this area, including challenges in identifying the positions of remote (distal from the promoter) regulatory elements (e.g. enhancers) and their target genes and the under-representation of neural cell types and brain tissues in epigenome projects – the availability of high-quality brain tissues for epigenetic and transcriptome profiling, particularly for the adolescent and developing brain, has been limited. Further challenges have arisen in the prediction and testing of the functional impact of DNA variation with respect to multiple aspects of transcriptional control, including regulatory-element interaction (e.g. between enhancers and promoters), transcription factor binding and DNA methylation. Further, the brain has uncommon DNA-methylation marks with unique genomic distributions not found in other tissues – current evidence suggests the involvement of non-CG methylation and 5-hydroxymethylation in neurodevelopmental processes but much remains unknown. We review here knowledge gaps as well as both technological and resource obstacles that will need to be overcome in order to elucidate the involvement of brain-relevant gene-regulatory variants in genetic risk for psychiatric disorders. PMID:26515765

  12. Genetic and BMI Risks for Predicting Blood Pressure in Three Generations of West African Dogon Women

    PubMed Central

    Taylor, Jacquelyn Y.; Sampson, Deborah; Taylor, Andre D.; Caldwell, Dennis; Sun, Yan V.

    2011-01-01

    The study of genetic polymorphisms and body mass index (BMI) among African women in Africa and in the United States contributes to our understanding of the genetic and environmental risk factors for hypertension. African American women have the highest prevalence of hypertension and obesity compared to other ethnic groups in the United States. Using a crosssectional research design, we examined the effects of genetic and environmental risks of single nucleotide polymorphisms (SNPs) and BMI on blood pressure (BP) among three generations of West African Dogon women (N = 199). We genotyped six SNPs located in the candidate genes known to be related to hypertension. We tested the associations between these SNPs and systolic BP (SBP) and diastolic BP (DBP) with Fisher’s exact tests, chi-square tests for independence, and multivariable linear mixed models. The SNP rs8179526 (SLC4A5) was significantly associated with SBP adjusted for age, age2, and BMI (p = .02). The “C” allele variant of rs8179526 (allele frequency of 0.445) was associated with higher SBP. This SNP did not deviate from the Hardy-Weinberg equilibrium (HWE) with p value of .772. The SNP × BMI interaction effects associated with SBP and DBP were not significant. rs8179526 is located on the SLC4A5 gene on chromosome 2. SLC4A5 encodes a protein that transports sodium and bicarbonate across cell membranes while regulating cellular pH and contains several SNPs linked to elevated BP. Knowledge of the SNP’s effect on hypertension among West African women can help health practitioners educate their patients about genetic risks of developing hypertension. PMID:21859746

  13. Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease - risk discounting in preventive genetics.

    PubMed

    Schulman, J D; Stern, H J

    2015-09-01

    Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J. D. S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group. PMID:25307798

  14. Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history

    PubMed Central

    Tada, Hayato; Melander, Olle; Louie, Judy Z.; Catanese, Joseph J.; Rowland, Charles M.; Devlin, James J.; Kathiresan, Sekar; Shiffman, Dov

    2016-01-01

    Aims Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD. Methods and results The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmö Diet and Cancer study—a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48–1.94; Ptrend = 1.6 × 10−15 and HR = 1.92 for GRS50; 95% CI: 1.67–2.20; Ptrend = 6.2 × 10−22]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P = 3 × 10−6). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45–1.89) or GRS50 (HR = 1.87; 95% CI: 1.63–2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P < 0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P < 0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85–3.12) than those with low GRS50. Conclusion The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals. PMID:26392438

  15. COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

    PubMed Central

    Tomlinson, I P M; Dunlop, M; Campbell, H; Zanke, B; Gallinger, S; Hudson, T; Koessler, T; Pharoah, P D; Niittymäkix, I; Tuupanenx, S; Aaltonen, L A; Hemminki, K; Lindblom, A; Försti, A; Sieber, O; Lipton, L; van Wezel, T; Morreau, H; Wijnen, J T; Devilee, P; Matsuda, K; Nakamura, Y; Castellví-Bel, S; Ruiz-Ponte, C; Castells, A; Carracedo, A; Ho, J W C; Sham, P; Hofstra, R M W; Vodicka, P; Brenner, H; Hampe, J; Schafmayer, C; Tepel, J; Schreiber, S; Völzke, H; Lerch, M M; Schmidt, C A; Buch, S; Moreno, V; Villanueva, C M; Peterlongo, P; Radice, P; Echeverry, M M; Velez, A; Carvajal-Carmona, L; Scott, R; Penegar, S; Broderick, P; Tenesa, A; Houlston, R S

    2009-01-01

    It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT. PMID:19920828

  16. Career and Technical Education Reforms and Comprehensive School Reforms in High Schools: Their Impact on Education Outcomes for At-Risk Youth. The Highlight Zone: Research @ Work.

    ERIC Educational Resources Information Center

    Castellano, Marisa; Stringfield, Samuel; Stone, James R., III

    The impact of career and technical education (CTE) reforms and comprehensive school reforms in high schools on education outcomes for at-risk youth was examined in a review of research on current reforms. The review identified a series of individual, family and home, school, and community factors that can place students at risk of failing to…

  17. Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer.

    PubMed

    Nimptsch, Katharina; Aleksandrova, Krasimira; Boeing, Heiner; Janke, Jürgen; Lee, Young-Ae; Jenab, Mazda; Kong, So Yeon; Tsilidis, Konstantinos K; Weiderpass, Elisabete; Bueno-De-Mesquita, H B As; Siersema, Peter D; Jansen, Eugène H J M; Trichopoulou, Antonia; Tjønneland, Anne; Olsen, Anja; Wu, Chunsen; Overvad, Kim; Boutron-Ruault, Marie-Christine; Racine, Antoine; Freisling, Heinz; Katzke, Verena; Kaaks, Rudolf; Lagiou, Pagona; Trichopoulos, Dimitrios; Severi, Gianluca; Naccarati, Alessio; Mattiello, Amalia; Palli, Domenico; Grioni, Sara; Tumino, Rosario; Peeters, Petra H; Ljuslinder, Ingrid; Nyström, Hanna; Brändstedt, Jenny; Sánchez, María-José; Gurrea, Aurelio Barricarte; Bonet, Catalina Bonet; Chirlaque, María-Dolores; Dorronsoro, Miren; Quirós, José Ramón; Travis, Ruth C; Khaw, Kay-Tee; Wareham, Nick; Riboli, Elio; Gunter, Marc J; Pischon, Tobias

    2015-08-15

    Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 µg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 µg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development. PMID:25611809

  18. Meta-analysis of interaction between dietary magnesium intake and genetic risk variants on diabetes phenotypes in the charge consortium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about whether genetic variation modifies the effect of magnesium (Mg) intake on two important diabetes risk factors: fasting glucose (FG) and insulin (FI). We examined interactions between dietary Mg and genetic variants associated with glucose (16 SNPs), insulin (2 SNPs), or Mg home...

  19. BIVARIATE LINKAGE CONFIRMS GENETIC CONTRIBUTION TO FETAL ORIGINS OF CHILDHOOD GROWTH AND CARDIOVASCULAR DISEASE RISK IN HISPANIC CHILDREN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Birth weight has been shown to be associated with obesity and metabolic diseases in adulthood; however, the genetic contribution is still controversial. The objective of this analysis is to explore the genetic contribution to the relationship between birth weight and later risk for obesity and metab...

  20. What does "a gene for heart disease" mean? A focus group study of public understandings of genetic risk factors.

    PubMed

    Bates, Benjamin R; Templeton, Alan; Achter, Paul J; Harris, Tina M; Condit, Celeste M

    2003-06-01

    There is growing concern in the medical community about potential genetic determinism in the patient population. Limited information about the public understanding of genetic factors in disease formation is available. To access public perceptions of potentially deterministic phrasing of genetic risk factors, we sought to establish interpretations of the phrase, "a gene for heart disease." Focus groups in urban, suburban, and rural communities were conducted from July through October, 2001 in Georgia. A total of 108 participants were recruited. Participants were recruited to balance sex and racial representation. We used three outcome measures for participants understandings of the phrase: (1) participants' statements of the meaning of the phrase; (2) the level of determinism assigned to genetic factors by participants; and (3) participant reports of the health consequences of having "a gene for heart disease." Participants did not report a single interpretation of the phrase. There were dominant participant interpretations under each outcome measure: (1) "a gene for heart disease" was interpreted as meaning genetic and environmental factors both played roles in disease formation; (2) genetic predisposition was perceived as heightened, not absolute, risk; (3) the perceived health impact was a greater risk of becoming sick. Minority interpretations were found under each measure. Overall, naming "a gene for heart disease" does not appear to have a deterministic impact on a plurality of participants' perceptions of risks associated with genetic factors. Genetic fatalism in patient populations may be confined to a sizable minority. Important considerations for provider intervention and patient education are indicated. PMID:12749055

  1. [Assessment of the genetic risk of radiation by irradiation data from laboratory mammals].

    PubMed

    Benova, D K; Baĭrakova, A K; Vŭglenov, A K; Kusheva, R P; Rupova, I M

    1985-04-01

    An attempt has been made to assess quantitatively genetic risk of radiation for man based on mammalian (mostly mouse) data and using the direct method proposed by UNSCEAR. The parameter employed was induction of reciprocal translocations. Two assumptions were made: human radiosensitivity equals that of the mouse; and dose-response is linear. From observations with acute gamma irradiation the estimate of risk per 10(-2) Gy was as follows: 39 translocation heterozygotes are expected among one million F1 conceptions, 5 cases of multiple congenital anomalies, 25 abortions recorded and 49 unrecorded. Chronic gamma irradiation at dose rates of 1.3 X 10(-5), 1.7 X 10(-4) and 1.0 X 10(-4) Gy/min was 3 to 10 times less effective. Exposure to 4.2 GeV deuterons proved inferior in effectiveness to gamma irradiation. Chronic exposure to 4.1 MeV neutrons delivered at 8 X 10(-4) Gy/min showed 7 times the effectiveness of chronic gamma irradiation. Administration of tritiated water (from 37 to 37 X 10(2) kBq/g b.w.) to rats entailed a risk of the same order of magnitude as external chronic gamma irradiation. Reduction of genetic risk was achieved by pretreatment with either AFT-, ATP-serotonin mixtures or the molecular combinations, Adeturon and Cytriphos. Study of interspecies differences in genetic radiosensitivity showed decline in the following order: rat-rabbit-mouse-Syrian hamster. A dose-rate effect was most clearly seen in the rat, and least clearly in the rabbit. In female mice, examination of oocyte depletion indicated primary follicles to be highly susceptible to acute gamma irradiation; decrease in sensitivity was observed beginning with stage 4. Chronic gamma irradiation was found to be less effective. PMID:4007485

  2. Effect of genetic variants associated with plasma homocysteine levels on stroke risk

    PubMed Central

    Cotlarciuc, Ioana; Malik, Rainer; Holliday, Elizabeth G.; Ahmadi, Kourosh R; Pare, Guillaume; Psaty, Bruce M.; Fornage, Myriam; Hasan, Nazeeha; Rinne, Paul E.; Ikram, M. Arfan; Markus, Hugh S; Rosand, Jonathan; Mitchell, Braxton D.; Kittner, Steven J.; Meschia, James F.; van Meurs, Joyce BJ; Uitterlinden, Andre G; Worrall, Bradford B.; Dichgans, Martin; Sharma, Pankaj

    2014-01-01

    Background and Purpose Elevated homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. Methods Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were utilized to assess association of the 18 tHcy associated SNPs in 12,389 IS cases and 62,004 controls. We also investigated the associations in regions located within 50kb from the 18 tHcy related SNPs, and the association of a genetic risk score including the 18 SNPs. Results One SNP located in the RASIP1 gene and a cluster of three SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with SVD (small vessel disease) (P=0.0022), while one SNP located in MTHFR was significantly associated with LVD (large vessel disease) (P=0.00019). A genetic risk score including the 18 SNPs did not show significant association with IS or its subtypes. Conclusions This study found several potential associations with IS and its subtypes: an association of an MUT variant with SVD, an MTHFR variant with LVD, and associations of RASIP1 and SLC17A3 variants with overall IS. PMID:24846872

  3. Falling through the cracks. Women's experiences of ineligibility for genetic testing for risk of breast cancer.

    PubMed Central

    Bottorff, J. L.; Balneaves, L. G.; Buxton, J.; Ratner, P. A.; McCullum, M.; Chalmers, K.; Hack, T.

    2000-01-01

    OBJECTIVE: To describe experiences of women seeking information about their risk of hereditary breast cancer who fail to meet strict eligibility criteria for genetic counseling and testing. DESIGN: Qualitative descriptive study. SETTING: Hereditary cancer program in western Canada. PARTICIPANTS: Women who had received notification of their ineligibility for referral for hereditary breast cancer risk assessment (n = 20) and some of their referring physicians (n = 10). Of 28 attempted contacts, five women had moved, one declined the invitation to participate, and two could not be interviewed because of scheduling conflicts. Ten of 20 physicians declined the invitation to participate. METHOD: In-depth, open-ended telephone interviews were conducted. Transcribed interviews were systematically analyzed to identify salient themes. MAIN FINDINGS: Three themes emerged. The first theme, "It's always on your mind," points to the profound concern about breast cancer that underlies women's experiences in seeking genetic testing. The second theme, "A test is a test," reflects women's beliefs that the test was relatively simple and similar to other medical tests in that it would provide a definitive answer. The third theme, "Falling through the cracks," captures the experience of ineligibility. Women reacted with a range of emotional responses and were left frustrated in their search for more specific information about their personal risk for breast cancer. Although women were encouraged to contact their physicians, few did. CONCLUSION: These findings point to the psychological consequences in women who seek genetic testing for risk of breast cancer when they are told they are ineligible and they are not given adequate information and support. PMID:10925759

  4. Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer

    PubMed Central

    2014-01-01

    Background Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk. Methods We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). The Causal Inference Test (CIT) was implemented to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype. Results Controlling for the estimated distribution of immune cells and other key covariates, our initial epigenome-wide association analysis revealed 1,993 significantly differentially methylated CpGs that between cases and controls (FDR, q < 0.05). The relationship between methylation and case-control status for these 1,993 CpGs was found to be highly consistent with the results of previously published, independent study that consisted of peripheral blood DNA methylation signatures in 131 pretreatment cases and 274 controls. Implementation of the CIT test revealed 17 CpG/SNP pairs, comprising 13 unique CpGs and 17 unique SNPs, which represent potential methylation-mediated relationships between genotype and EOC risk. Of these 13 CpGs, several are associated with immune related genes and genes that have been previously shown to exhibit altered expression in the context of cancer. Conclusions These findings provide additional insight into EOC etiology and may serve as novel biomarkers for EOC susceptibility. PMID:24479488

  5. Common genetic variants, acting additively, are a major source of risk for autism

    PubMed Central

    2012-01-01

    Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome

  6. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

    PubMed

    O'Mara, Tracy A; Glubb, Dylan M; Painter, Jodie N; Cheng, Timothy; Dennis, Joe; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Shah, Mitul; Ahmed, Shahana; Healey, Catherine S; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dürst, Matthias; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Lambrechts, Diether; Depreeuw, Jeroen; Annibali, Daniela; Amant, Frederic; Zhao, Hui; Goode, Ellen L; Dowdy, Sean C; Fridley, Brooke L; Winham, Stacey J; Salvesen, Helga B; Njølstad, Tormund S; Trovik, Jone; Werner, Henrica M J; Tham, Emma; Liu, Tao; Mints, Miriam; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Thompson, Deborah J; Spurdle, Amanda B

    2015-10-01

    Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types. PMID:26330482

  7. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

    PubMed Central

    O’Mara, Tracy A; Glubb, Dylan M; Painter, Jodie N; Cheng, Timothy; Dennis, Joe; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Shah, Mitul; Ahmed, Shahana; Healey, Catherine S; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dürst, Matthias; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Lambrechts, Diether; Depreeuw, Jeroen; Annibali, Daniela; Amant, Frederic; Zhao, Hui; Goode, Ellen L; Dowdy, Sean C; Fridley, Brooke L; Winham, Stacey J; Salvesen, Helga B; Njølstad, Tormund S; Trovik, Jone; Werner, Henrica MJ; Tham, Emma; Liu, Tao; Mints, Miriam; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Thompson, Deborah J; Spurdle, Amanda B

    2015-01-01

    Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3,633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6,607 EC cases and 37,925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P = 1.86 × 10−5), which was stronger for cancers of endometrioid subtype (P = 3.76 × 10−6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types. PMID:26330482

  8. Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk.

    PubMed

    Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, M Fatih; Scheurer, Michael E; Dorak, M Tevfik

    2015-01-01

    Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations, despite Hispanics having a greater risk. We re-examined single nucleotide polymorphisms (SNPs) of known associations with childhood ALL and known human leukocyte antigen (HLA) region lymphoma risk markers in a multi-ethnic population. Significant associations were found in two ARID5B variants (rs7089424 and rs10821936). We replicated a strong risk association in non-Hispanic White males with rs2395185, a protective marker for lymphoma. Another HLA region marker, rs2647012, showed a risk association among Hispanics only, while a strong protective association was found with rs1048456, a follicular lymphoma risk marker. Our study validated this new case-control sample by confirming genetic markers associated with childhood ALL, and yielded new associations with lymphoma markers. Despite positive results, our study did not provide any clues as to why Hispanics have a higher susceptibility to childhood leukemia, suggesting that environmental factors may have a strong contribution. PMID:24707947

  9. Tourette syndrome research highlights 2015

    PubMed Central

    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

  10. Using adult learning theory concepts to address barriers to cancer genetic risk assessment in the African American community.

    PubMed

    Kendall, Jeff; Kendall, Colleen; Catts, Zohra Ali-Khan; Radford, Cristi; Dasch, Kimberly

    2007-06-01

    Utilization of cancer genetic risk assessment can be profoundly influenced by an individuals' knowledge of risk assessment, attitudes regarding illness and healthcare, and affective reactions derived from social norms. Race and ethnicity play a powerful role in the development of an individual's attitudes and should be considered when attempting to understand a person's openness to cancer genetic risk assessment (Lannin et al., 1998). Until recently, however, cancer screening and prevention programs have been primarily based on data from studies conducted with the Caucasian population, yielding data that are not fully applicable to the African American community. In the last several years, research findings regarding African American's knowledge, attitudes, and feelings about genetic counseling and testing have grown (Matthews et al., 2000; Singer et al., 2004; Thompson et al., 2003). However, to the authors' knowledge, these data have yet to be presented in a manner that both summarizes the barriers that African Americans have reported regarding cancer genetic risk assessment, while at the same time suggesting methods individual genetic counselors can utilize during community presentations to help address these barriers. This article will first summarize previous empirical findings regarding African Americans' knowledge, attitudes, and feelings about cancer genetic risk assessment. The article will then apply adult learning theory to those findings to provide genetic counselors with practical, theory based techniques to apply toward community based educational programs with African American groups. PMID:17473964

  11. Perception of risks and benefits of in vitro fertilization, genetic engineering and biotechnology.

    PubMed

    Macer, D R

    1994-01-01

    The use of new biotechnology in medicine has become an everyday experience, but many people still express concern about biotechnology. Concerns are evoked particularly by the phrases genetic engineering and in vitro fertilization (IVF), and these concerns persist despite more than a decade of their use in medicine. Mailed nationwide opinion surveys on attitudes to biotechnology were conducted in Japan, among samples of the public (N = 551), high school biology teachers (N = 228), scientists (N = 555) and nurses (N = 301). People do see more benefits coming from science than harm when balanced against the risks. There were especially mixed perceptions of benefit and risk about IVF and genetic engineering, and a relatively high degree of worry compared to other developments of science and technology. A discussion of assisted reproductive technologies and surrogacy in Japan is also made. The opinions of people in Japan were compared to the results of previous surveys conducted in Japan, and international surveys conducted in Australia, China, Europe, New Zealand, U.K. and U.S.A. Japanese have a very high awareness of biotechnology, 97% saying that they had heard of the word. They also have a high level of awareness of IVF and genetic engineering. Genetic engineering was said to be a worthwhile research area for Japan by 76%, while 58% perceived research on IVF as being worthwhile, however 61% were worried about research on IVF or genetic engineering. Japanese expressed more concern about IVF and genetic engineering than New Zealanders. The major reason cited for rejection of genetic manipulation research in Japan and New Zealand was that it was seen as interfering with nature, playing God or as unethical. The emotions concerning these technologies are complex, and we should avoid using simplistic public opinion data as measures of public perceptions. The level of concern expressed by scientists and teachers in Japan suggest that public education "technology promotion

  12. Belief and disbelief in the existence of genetic risk factors for suicide: cross-cultural comparisons.

    PubMed

    Voracek, Martin

    2007-12-01

    There is evidence for widespread disbelief in the genetics of suicide, despite recent research progress in this area and convergent evidence supporting a role for genetic factors. This study analyzed the beliefs held in 8 samples (total N = 1224) of various types (psychology, medical, and various undergraduates, psychology graduates, and the general population) from 6 countries located on 3 continents (Austria, Canada, Malaysia, Romania, United Kingdom, and the USA). Endorsement rates for the existence of genetic risk factors for suicide ranged from 26% and 30% (Austrian psychology undergraduates and general population) to around 50% (psychology undergraduates in the USA and United Kingdom). In the 8 samples, respondents' sex, age, religiosity, political orientation, and other demographic variables were, for the most part, unrelated, but overall knowledge about suicide throughout was related positively to endorsement rates. Consistent with previous research, across a considerable variety of sample types and cultural settings there was no evidence for a clear majority believing in genetic bases for suicide. PMID:18361135

  13. RAGE Genetic Polymorphisms Are Associated with Risk, Chemotherapy Response and Prognosis in Patients with Advanced NSCLC

    PubMed Central

    Hua, Feng; Wang, Bin; Mao, Wei; Feng, Xueren

    2012-01-01

    Aim To explore the association between genetic polymorphisms of the receptor for advanced glycation end-products (RAGE) and susceptibility, chemotherapy response rate and prognosis of non-small cell lung cancer (NSCLC). Method This is a prospective study in which 562 patients with NSCLC and 764 healthy controls were enrolled. Three RAGE genetic polymorphisms, namely, −429T/C, −374T/A and 82G/S were genotyped. Platinum-based chemotherapy was given to 432 subjects with advanced inoperable NSCLC and their responses to chemotherapy were evaluated. Results All the polymorphic genotypes of RAGE polymorphisms were associated with susceptibility for NSCLC. Only the 82G/S polymorphisms denoted a significant difference between responders and non-responders to chemotherapy. The 82SS genotype and 82S allele distribution not only increased the NSCLC risk, but also was associated with a lower chemotherapy response rate and poor prognosis, indicated by overall survival and progression free survival. Conclusion The 82G/S genetic polymorphism of RAGE gene might be used as a genetic marker to screen for patients sensitive to thermotherapy and to predict the prognosis of NSCLC. PMID:23071492

  14. Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score.

    PubMed

    Eze, Ikenna C; Imboden, Medea; Kumar, Ashish; von Eckardstein, Arnold; Stolz, Daiana; Gerbase, Margaret W; Künzli, Nino; Pons, Marco; Kronenberg, Florian; Schindler, Christian; Probst-Hensch, Nicole

    2016-09-01

    Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma case-control study design. AP was estimated as 10-year mean residential particulate matter <10μm (PM10). We computed count-GRS and weighted-GRS, and applied PM10 interaction terms in mixed logistic regressions, on odds of diabetes. Analyses were stratified by pathways of diabetes pathology and by asthma status. Diabetes prevalence was 4.6% and mean exposure to PM10 was 22μg/m(3). Odds of diabetes increased by 8% (95% confidence interval: 2, 14%) per T2D risk allele and by 35% (-8, 97%) per 10μg/m(3) exposure to PM10. We observed a positive interaction between PM10 and count-GRS on diabetes [ORinteraction=1.10 (1.01, 1.20)], associations being strongest among participants at the highest quartile of count-GRS [OR: 1.97 (1.00, 3.87)]. Stronger interactions were observed with variants of the GRS involved in insulin resistance [(ORinteraction=1.22 (1.00, 1.50)] than with variants related to beta-cell function. Interactions with count-GRS were stronger among asthma cases. We observed similar results with weighted-GRS. Five single variants near GRB14, UBE2E2, PTPRD, VPS26A and KCNQ1 showed nominally significant interactions with PM10 (P<0.05). Our results suggest that genetic risk for T2D may modify susceptibility to air pollution through alterations in insulin sensitivity. These results need confirmation in diabetes cohort consortia. PMID:27281273

  15. Problems and solutions in the estimation of genetic risks from radiation and chemicals

    SciTech Connect

    Russell, W. L.

    1980-01-01

    Extensive investigations with mice on the effects of various physical and biological factors, such as dose rate, sex and cell stage, on radiation-induced mutation have provided an evaluation of the genetics hazards of radiation in man. The mutational results obtained in both sexes with progressive lowering of the radiation dose rate have permitted estimation of the mutation frequency expected under the low-level radiation conditions of most human exposure. Supplementing the studies on mutation frequency are investigations on the phenotypic effects of mutations in mice, particularly anatomical disorders of the skeleton, which allow an estimation of the degree of human handicap associated with the occurrence of parallel defects in man. Estimation of the genetic risk from chemical mutagens is much more difficult, and the research is much less advanced. Results on transmitted mutations in mice indicate a poor correlation with mutation induction in non-mammalian organisms.

  16. Genetic risks and environmental surveillance: epidemiological aspects of monitoring industrial populations for environmental mutagens

    SciTech Connect

    Buffler, P.A.; Aase, J.M.

    1982-04-01

    As industrial populations are exposed to new chemicals and other agents in their work environment, it becomes increasingly important to be able to ascertain any associated genetic risks. The characteristics of a desirable surveillance system for deleterious genetic effects are outlined and the existing or proposed surveillance systems for industrial populations are reviewed against these criteria. At present, monitoring for reproductive loss and infertility seems to be the technique best suited for surveillance of industrial populations. However, monitoring techniques based on these events do not directly assess mutagenicity. Since fetal death and infertility are strongly, but not exclusively, correlated with mutation, these methods can be considered as an early-warning system to indicate when and where more definitive studies are needed.

  17. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management

    PubMed Central

    Leoz, Maria Liz; Carballal, Sabela; Moreira, Leticia; Ocaña, Teresa; Balaguer, Francesc

    2015-01-01

    Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP. PMID:25931827

  18. An Unusual BRCA Mutation Distribution in a High Risk Cancer Genetics Clinic

    PubMed Central

    Nelson-Moseke, Anna C.; Jeter, Joanne M.; Cui, Haiyan; Roe, Denise J.; Chambers, Setsuko K.; Laukaitis, Christina M.

    2012-01-01

    The Database of Individuals at High Risk for Breast, Ovarian, or Other Hereditary Cancers at the Arizona Cancer Center in Tucson, Arizona, assesses cancer risk factors and outcomes in patients with a family history of cancer or a known genetic mutation. We analyzed the subset of clinic probands who carry deleterious BRCA gene mutations to identify factors that could explain why mutations in BRCA2 out number those in BRCA1. Medical, family, social, ethnic and genetic mutation histories were collected from consenting patients’ electronic medical records. Differences between BRCA1 and BRCA2 probands from this database were analyzed for statistical significance and compared to published analyses.. A significantly higher proportion of our clinic probands carry mutations in BRCA2 than BRCA1, compared with previous reports of mutation prevalence. This also holds true for the Hispanic sub-group. Probands with BRCA2 mutations were significantly more likely than their BRCA1 counterparts to present to the high risk clinic without adiagnosis of cancer. Other differences between the groups were not significant. Six previously unreported BRCA2 mutations appear in our clinic population. The increased proportion of probands carrying deleterious BRCA2 mutations is likely multifactorial, but may reflect aspects of Southern Arizona’s unique ethnic heritage. PMID:23179792

  19. Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children

    PubMed Central

    Lundbo, Lene F.; Harboe, Zitta Barrella; Clausen, Louise N.; Hollegaard, Mads V.; Sørensen, Henrik T.; Hougaard, David M.; Konradsen, Helle B.; Nørgaard, Mette; Benfield, Thomas

    2015-01-01

    Background Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). Methods Cases with IPD and IMD and controls were identified by linking Danish national registries. DNA was obtained from the Danish Neonatal Screening Biobank. The association between SNPs and susceptibility to IPD and IMD, mortality and pneumococcal serotypes was investigated. Results 372 children with pneumococcal meningitis, 907 with pneumococcal bacteremia and 1273 controls were included. We included 406 cases with meningococcal meningitis, 272 with meningococcal bacteremia, and 672 controls. The NFKBIE SNP was associated with increased risk of pneumococcal meningitis (aOR 1.68; 95% CI: 1.20–2.36), but not bacteremia (aOR 1.08; 95% CI: 0.86–1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. Conclusions A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis. PMID:26870821

  20. Host Genetic Risk Factors for West Nile Virus Infection and Disease Progression

    PubMed Central

    Bigham, Abigail W.; Buckingham, Kati J.; Husain, Sofia; Emond, Mary J.; Bofferding, Kathryn M.; Gildersleeve, Heidi; Rutherford, Ann; Astakhova, Natalia M.; Perelygin, Andrey A.; Busch, Michael P.; Murray, Kristy O.; Sejvar, James J.; Green, Sharone; Kriesel, John; Brinton, Margo A.; Bamshad, Michael

    2011-01-01

    West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035) and MX1, (OR 0.19, p = 0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression. PMID:21935451

  1. Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.

    PubMed

    Walsh, Kyle M; Whitehead, Todd P; de Smith, Adam J; Smirnov, Ivan V; Park, Minsun; Endicott, Alyson A; Francis, Stephen S; Codd, Veryan; Samani, Nilesh J; Metayer, Catherine; Wiemels, Joseph L

    2016-06-01

    Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood. PMID:27207662

  2. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

    PubMed Central

    Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  3. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    PubMed

    Du, Mengmeng; Jiao, Shuo; Bien, Stephanie A; Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J; Carlson, Christopher S; Casey, Graham; Chang-Claude, Jenny; Conti, David V; Curtis, Keith R; Duggan, David; Gallinger, Steven; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Jenkins, Mark A; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M; Newcomb, Polly A; Nickerson, Deborah A; Potter, John D; Schoen, Robert E; Schumacher, Fredrick R; Seminara, Daniela; Slattery, Martha L; Hsu, Li; Chan, Andrew T; White, Emily; Berndt, Sonja I; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  4. Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model.

    PubMed

    Marcus, Michael W; Raji, Olaide Y; Duffy, Stephen W; Young, Robert P; Hopkins, Raewyn J; Field, John K

    2016-07-01

    Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing P<0.0001. The apparent AUC of the epidemiological model was 0.75 (95% CI 0.73-0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79-0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID:27121382

  5. Genetic polymorphisms in obesity-related genes and endometrial cancer risk

    PubMed Central

    Chen, Xiaoli; Xiang, Yong-Bing; Long, Ji-Rong; Cai, Hui; Cai, Qiuyin; Cheng, Jiarong; Wen, Wanqing; Gao, Yu-Tang; Zheng, Wei; Shu, Xiao-Ou

    2011-01-01

    Background Obesity is associated with circulating levels of adiponectin and leptin and endometrial cancer risk. Little is known about whether single nucleotide polymorphisms (SNPs) in the genes that encode adiponectin (ADIPOQ), leptin (LEP), adiponectin receptor 1 (ADIPOR1), adiponectin receptor 2 (ADIPOR2), and leptin receptor (LEPR) are associated with endometrial cancer. Methods We selected 87 tagging SNPs to capture common genetic variants in these five genes. These SNPs were evaluated in 1,028 endometrial cancer cases and 1,932 community controls recruited from Chinese women. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results Three of the 10 SNPs evaluated in the ADIPOQ gene were significantly associated with reduced cancer risk. The OR for women homozygous for the minor allele (A/A) for rs3774262 was 0.68 (95% CI: 0.48-0.97) compared with women homozygous for the major allele (G/G). Similar results were found for SNPs rs1063539 and rs12629945 in ADIPOQ, which were in linkage disequilibrium with rs3774262. These associations became non-significant after Bonferroni correction was applied. Controls with the minor allele A at rs3774262 had lower weight, waist circumference, hip circumference, and BMI than controls with the major allele G (all P<0.05). Women homozygous for the minor allele (T/T) of rs2071045 in the LEP gene also had significantly lower risk (OR=0.70 (0.54-0.90)) than women homozygous for the major allele (C/C). No other SNPs in the LEP, ADIPOR1, ADIPOR2, or LEPR genes were found to be associated with cancer risk. Conclusions Although a chance finding cannot be ruled out, the consistency of findings for gene-endometrial cancer risk and gene-obesity measurements suggests that genetic polymorphisms in the ADIPOQ genes may play a role in endometrial cancer development. PMID:22038736

  6. Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model

    PubMed Central

    MARCUS, MICHAEL W.; RAJI, OLAIDE Y.; DUFFY, STEPHEN W.; YOUNG, ROBERT P.; HOPKINS, RAEWYN J.; FIELD, JOHN K.

    2016-01-01

    Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing P<0.0001. The apparent AUC of the epidemiological model was 0.75 (95% CI 0.73–0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79–0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID:27121382

  7. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    PubMed

    Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

    2016-03-01

    The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress. PMID:26243271

  8. Genetic Variation in the PNPLA3 Gene and Hepatocellular Carcinoma in USA: Risk and Prognosis Prediction

    PubMed Central

    Hassan, Manal M.; Kaseb, Ahmed; Etzel, Carol J.; El-Serag, Hashem; Spitz, Margaret R.; Chang, Ping; Hale, Katherine S.; Liu, Mei; Rashid, Asif; Shama, Mohamed; Abbruzzese, James L.; Loyer, Evelyne M.; Kaur, Harmeet; Hassabo, Hesham M.; Vauthey, Jean-Nicolas; Wray, Curtis J.; Hassan, Basmah S.; Patt, Yehuda Z.; Hawk, Ernest; Soliman, Khalid M.; Li, Donghui

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case–control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68–6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13–71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05–5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26–3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3. PMID:23776098

  9. Genetic polymorphisms involved in folate metabolism and maternal risk for down syndrome: a meta-analysis.

    PubMed

    Balduino Victorino, Daniella; de Godoy, Moacir Fernandes; Goloni-Bertollo, Eny Maria; Pavarino, Érika Cristina

    2014-01-01

    Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I (2) statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS. PMID:25544792

  10. Genetic Polymorphisms Involved in Folate Metabolism and Maternal Risk for Down Syndrome: A Meta-Analysis

    PubMed Central

    Balduino Victorino, Daniella; de Godoy, Moacir Fernandes; Goloni-Bertollo, Eny Maria; Pavarino, Érika Cristina

    2014-01-01

    Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I2 statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS. PMID:25544792

  11. Genetic variations of the ADIPOQ gene and risk of prostate cancer in Chinese Han men

    PubMed Central

    Gu, Cheng-Yuan; Li, Qiao-Xin; Zhu, Yao; Wang, Meng-Yun; Shi, Ting-Yan; Yang, Ya-Yun; Wang, Jiu-Cun; Jin, Li; Wei, Qing-Yi; Ye, Ding-Wei

    2014-01-01

    Adiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQ are thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hospital-based case-control study of 917 prostate cancer (PCa) cases and 1036 cancer-free controls, we evaluated the association of single nucleotide polymorphisms in ADIPOQ with risk of PCa and adiponectin levels in Chinese Han men. Variants of ADIPOQ were genotyped by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in a subset of cases and controls. We found that the ADIPOQ rs3774262 variant AA genotype was associated with both decreased PCa risk [adjusted odds ratio (OR): 0.66, 95% confidence interval (CI) =0.48–0.92] and increased plasma adiponectin levels (P = 0.036 and 0.043), with significant difference by tumor grade, clinical stage, and aggressiveness. A significant interaction between ADIPOQ rs3774262 and body mass index was observed in modifying the risk of PCa (P = 6.7 × 10−3). ADIPOQ rs266729 and rs182052 were not related to PCa risk or plasma adiponectin levels. Our data support that ADIPOQ rs3774262 may affect PCa risk in combination with plasma adiponectin levels in Chinese Han men. It may contribute to the molecular basis for the association between obesity and PCa. PMID:25038177

  12. Considerations for Using Genetic and Epigenetic Information in Occupational Health Risk Assessment and Standard Setting

    PubMed Central

    Schulte, P. A.; Whittaker, C.; Curran, C. P.

    2015-01-01

    Risk assessment forms the basis for both occupational health decision-making and the development of occupational exposure limits (OELs). Although genetic and epigenetic data have not been widely used in risk assessment and ultimately, standard setting, it is possible to envision such uses. A growing body of literature demonstrates that genetic and epigenetic factors condition biological responses to occupational and environmental hazards or serve as targets of them. This presentation addresses the considerations for using genetic and epigenetic information in risk assessments, provides guidance on using this information within the classic risk assessment paradigm, and describes a framework to organize thinking about such uses. The framework is a 4 × 4 matrix involving the risk assessment functions (hazard identification, dose-response modeling, exposure assessment, and risk characterization) on one axis and inherited and acquired genetic and epigenetic data on the other axis. The cells in the matrix identify how genetic and epigenetic data can be used for each risk assessment function. Generally, genetic and epigenetic data might be used as endpoints in hazard identification, as indicators of exposure, as effect modifiers in exposure assessment and dose-response modeling, as descriptors of mode of action, and to characterize toxicity pathways. Vast amounts of genetic and epigenetic data may be generated by high-throughput technologies. These data can be useful for assessing variability and reducing uncertainty in extrapolations, and they may serve as the foundation upon which identification of biological perturbations would lead to a new paradigm of toxicity pathway-based risk assessments. PMID:26583908

  13. Genetic ancestry and risk of mortality among U.S. Latinas with breast cancer

    PubMed Central

    Fejerman, Laura; Hu, Donglei; Huntsman, Scott; John, Esther M.; Stern, Mariana C.; Haiman, Christopher A.; Pérez-Stable, Eliseo J.; Ziv, Elad

    2013-01-01

    Multiple studies have reported that Latina women in the U.S. are diagnosed with breast cancer at more advanced stages and have poorer survival than non-Latina White women. However, Latinas are a heterogeneous group with individuals having different proportions of European, Indigenous American and African genetic ancestry. In this study we evaluated the association between genetic ancestry and survival after breast cancer diagnosis among 899 Latina women from the San Francisco Bay Area. Genetic ancestry was estimated from single nucleotide polymorphisms from an Affymetrix 6.0 array and we used Cox proportional hazards models to evaluate the association between genetic ancestry and breast cancer-specific mortality (tests were two-sided). Women were followed for an average of 9 years during which 75 died from breast cancer. Our results showed that Individuals with higher Indigenous American ancestry had increased risk of breast cancer-specific mortality [hazard ratio (HR): 1.57 per 25% increase in Indigenous American ancestry; 95% confidence interval (CI): 1.08–2.29]. Adjustment for demographic factors, tumor characteristics, and some treatment information did not explain the observed association [HR: 1.75, 95%CI: 1.12–2.74]. In an analysis in which ancestry was dichotomized, the hazard of mortality showed a two-fold increase when comparing women with <50% Indigenous American ancestry to women with ≥50% [HR: 1.89, 95%CI: 1.10–3.24]. This was also reflected by Kaplan-Meier survival estimates (P for Log-Rank test of 0.003). Overall, results suggest that genetic factors and/or unmeasured differences in treatment or access to care should be further explored to understand and reduce ethnic disparities in breast cancer outcomes. PMID:24177181

  14. Relevance of Bt toxin interaction studies for environmental risk assessment of genetically modified crops.

    PubMed

    De Schrijver, Adinda; De Clercq, Patrick; de Maagd, Ruud A; van Frankenhuyzen, Kees

    2015-12-01

    In recent years, different Bacillus thuringiensis (Bt) toxin-encoding genes have been combined or 'stacked' in genetically modified (GM) crops. Synergism between Bt proteins may occur and thereby increase the impact of the stacked GM event on nontarget invertebrates compared to plants expressing a single Bt gene. On the basis of bioassay data available for Bt toxins alone or in combination, we argue that the current knowledge of Bt protein interactions is of limited relevance in environmental risk assessment (ERA). PMID:26032006

  15. Dopamine and serotonin genetic risk scores predicting substance and nicotine use in attention deficit/hyperactivity disorder.

    PubMed

    Groenman, Annabeth P; Greven, Corina U; van Donkelaar, Marjolein M J; Schellekens, Arnt; van Hulzen, Kimm J E; Rommelse, Nanda; Hartman, Catharina A; Hoekstra, Pieter J; Luman, Marjolein; Franke, Barbara; Faraone, Stephen V; Oosterlaan, Jaap; Buitelaar, Jan K

    2016-07-01

    Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders. PMID:25752199

  16. PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors

    PubMed Central

    de Quervain, Dominique J.-F.; Kolassa, Iris-Tatjana; Ackermann, Sandra; Aerni, Amanda; Boesiger, Peter; Demougin, Philippe; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hadziselimovic, Nils; Hanser, Edveena; Heck, Angela; Hieber, Petra; Huynh, Kim-Dung; Klarhöfer, Markus; Luechinger, Roger; Rasch, Björn; Scheffler, Klaus; Spalek, Klara; Stippich, Christoph; Vogler, Christian; Vukojevic, Vanja; Stetak, Attila; Papassotiropoulos, Andreas

    2012-01-01

    Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD. PMID:22586106

  17. PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors.

    PubMed

    de Quervain, Dominique J-F; Kolassa, Iris-Tatjana; Ackermann, Sandra; Aerni, Amanda; Boesiger, Peter; Demougin, Philippe; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hadziselimovic, Nils; Hanser, Edveena; Heck, Angela; Hieber, Petra; Huynh, Kim-Dung; Klarhöfer, Markus; Luechinger, Roger; Rasch, Björn; Scheffler, Klaus; Spalek, Klara; Stippich, Christoph; Vogler, Christian; Vukojevic, Vanja; Stetak, Attila; Papassotiropoulos, Andreas

    2012-05-29

    Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity--including aversive memory--in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD. PMID:22586106

  18. Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease.

    PubMed

    Ghanbari, Mohsen; Darweesh, Sirwan K L; de Looper, Hans W J; van Luijn, Marvin M; Hofman, Albert; Ikram, M Arfan; Franco, Oscar H; Erkeland, Stefan J; Dehghan, Abbas

    2016-03-01

    MicroRNAs (miRNAs) are small noncoding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA-binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA-related genetic variants with Parkinson disease (PD) using data from the largest GWAS on PD. Of 243 miRNA variants, we identified rs897984:T>C in miR-4519 (P value = 1.3×10(-5) and OR = 0.93) and rs11651671:A>G in miR-548at-5p (P value = 1.1×10(-6) and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR-4519 and miR-548at-5p on PD. Among them, we experimentally showed that NSF is a direct target of miR-4519. Furthermore, among 48,844 miRNA-binding site variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B, and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA-binding site variants on miRNA-mediated regulation of their host genes. PMID:26670097

  19. Project 6: Cumulative Risk Assessment Methods and Applications: Task 6.3. Applying Genetic and Epigenetic Data to Inform Susceptibility

    EPA Science Inventory

    Susceptibility is defined by the NRC (2009) as the capacity to be affected. A person can be at greater or less risk relative to population median risk because of susceptibility factors such as life stage, sex, genetics, socioeconomic status, prior exposure to chemicals, and non-c...

  20. Shared Genetic Aetiology between Cognitive Ability and Cardiovascular Disease Risk Factors: Generation Scotland's Scottish Family Health Study

    ERIC Educational Resources Information Center

    Luciano, Michelle; Batty, G. David; McGilchrist, Mark; Linksted, Pamela; Fitzpatrick, Bridie; Jackson, Cathy; Pattie, Alison; Dominiczak, Anna F.; Morris, Andrew D.; Smith, Blair H.; Porteous, David; Deary, Ian J.

    2010-01-01

    People with higher general cognitive ability in early life have more favourable levels of cardiovascular disease (CVD) risk factors in adulthood and CVD itself. The mechanism of these associations is not known. Here we examine whether general cognitive ability and CVD risk factors share genetic and/or environmental aetiology. In this large,…

  1. Syndromes at risk of status epilepticus in children: genetic and pathophysiological issues.

    PubMed

    Neubauer, Bernd A; Hahn, Andreas

    2014-10-01

    Status epilepticus (SE) is a medical emergency with increased risk of morbidity and mortality in all age groups. Recent research has identified a variety of new genes implicated in disorders with severe epilepsies as a prominent feature. Autoimmune mechanisms have also been recently recognised as a cause of epilepsies with SE as a characteristic symptom. Knowledge about the aetiology potentially underlying SE may help to guide diagnostics and eventually influence treatment decisions. This review recapitulates, in brief, the risk of SE in specific clinical settings, provides an overview of paediatric epilepsy syndromes more commonly, or by definition, associated with SE, and summarizes some recent research data on genetic defects and disease mechanisms implicated in the pathogenesis of epilepsies frequently accompanied by SE. PMID:25323303

  2. A Modified Integrated Genetic Model for Risk Prediction in Younger Patients with Acute Myeloid Leukemia

    PubMed Central

    Sloan, Caroline E.; Luskin, Marlise R.; Boccuti, Anne M.; Sehgal, Alison R.; Zhao, Jianhua; Daber, Robert D.; Morrissette, Jennifer J. D.; Luger, Selina M.; Bagg, Adam

    2016-01-01

    Background Although cytogenetics-based prognostication systems are well described in acute myeloid leukemia (AML), overall survival (OS) remains highly variable within risk groups. An integrated genetic prognostic (IGP) model using cytogenetics plus mutations in nine genes was recently proposed for patients ≤60 years to improve classification. This model has not been validated in clinical practice. Methods and Findings We retrospectively studied 197 patients with newly diagnosed de novo AML. We compared OS curves among the mutational profiles defined by the IGP model. The IGP model assigned patients with intermediate cytogenetics as having favorable, intermediate or unfavorable mutational profiles. The IGP model reassigned 50 of 137 patients with intermediate cytogenetics to favorable or unfavorable mutational profiles. Median OS was 2.8 years among 14 patients with intermediate cytogenetics and favorable mutational profiles (mutant NPM1 and mutant IDH1 or IDH2) and 1.3 years among patients with intermediate mutational profiles. Among patients with intermediate cytogenetics labeled as having unfavorable mutational profiles, median OS was 0.8 years among 24 patients with FLT3-ITD positive AML and high-risk genetic changes (trisomy 8, TET2 and/or DNMT3A) and 1.7 years among 12 patients with FLT3-ITD negative AML and high-risk mutations (TET2, ASXL1 and/or PHF6). OS for patients with intermediate cytogenetics and favorable mutational profiles was similar to OS for patients with favorable cytogenetics (p = 0.697) and different from patients with intermediate cytogenetics and intermediate mutational profiles (p = 0.028). OS among patients with FLT3-ITD positive AML and high-risk genetic changes was similar to patients with unfavorable cytogenetics (p = 0.793) and different from patients with intermediate IGP profile (p = 0.022). Patients with FLT3-ITD negative AML and high-risk mutations, defined as ‘unfavorable’ in the IGP model, had OS similar to patients with

  3. Genetic variants in lncRNA SRA and risk of breast cancer

    PubMed Central

    Yan, Rui; Wang, Kaijuan; Peng, Rui; Wang, Shuaibing; Cao, Jingjing; Wang, Peng; Song, Chunhua

    2016-01-01

    Long non-coding RNA (lncRNA) steroid receptor RNA activator (SRA) has been identified to activate steroid receptor transcriptional activity and participate in tumor pathogenesis. This case-control study evaluated the association between two haplotype tagging SNPs (htSNPs) (rs10463297, rs801460) of the whole SRA sequence and breast cancer risk. We found that rs10463297 TC genotype significantly increased BC risk compared with CC genotype in both the codominant (TC vs. TT: OR=1.43, 95 % CI=1.02–2.00) and recessive (TC+CC vs. TT: OR=1.39, 95 % CI=1.01–1.92) genetic models. Both TC, TC + CC genotypes of rs10463297 and GA, AA, GA+AA genotypes of rs801460 were significantly associated with estrogen receptor (ER) positivity status. rs10463297 TC (2.09 ± 0.41), CC (2.42 ± 0.51) and TC + CC (2.20 ± 0.47) genotypes were associated with higher blood plasma SRA mRNA levels compared with the TT genotype(1.45 ± 0.34). Gene–reproductive interaction analysis presented a best model consisted of four factors (rs10463297, age, post-menopausal, No. of pregnancy), which could increase the BC risk with 1.58-fold (OR=1.58, 95 % CI=1.23–2.03). These findings suggest that SRA genetic variants may contribute to BC risk and have apparent interaction with reproductive factors in BC progression. PMID:26967566

  4. Are Genetic Risk Factors for Psychosis Also Associated with Dimension-Specific Psychotic Experiences in Adolescence?

    PubMed Central

    Sieradzka, Dominika; Power, Robert A.; Freeman, Daniel; Cardno, Alastair G.; McGuire, Philip; Plomin, Robert; Meaburn, Emma L.; Dudbridge, Frank; Ronald, Angelica

    2014-01-01

    Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value = 2.57×10−4) and rs9960767 (p-value = 6.23×10−4). Replication in an independent sample of 16-year-olds (N = 3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses

  5. The use of genetically modified mice in cancer risk assessment: Challenges and limitations*

    PubMed Central

    Eastmond, David A.; Vulimiri, Suryanarayana V.; French, John E.; Sonawane, Babasaheb

    2015-01-01

    The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/−, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals. PMID:23985072

  6. Investigation of the genetic association between quantitative measures of psychosis and schizophrenia: a polygenic risk score analysis.

    PubMed

    Derks, Eske M; Vorstman, Jacob A S; Ripke, Stephan; Kahn, Rene S; Ophoff, Roel A

    2012-01-01

    The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia. PMID:22761660

  7. Investigation of the Genetic Association between Quantitative Measures of Psychosis and Schizophrenia: A Polygenic Risk Score Analysis

    PubMed Central

    Ripke, Stephan; Kahn, Rene S.; Ophoff, Roel A.

    2012-01-01

    The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia. PMID:22761660

  8. Association between seven common OPG genetic polymorphisms and osteoporosis risk: a meta-analysis.

    PubMed

    Guo, Liang; Tang, Ke; Quan, Zhengxue; Zhao, Zenghui; Jiang, Dianming

    2014-01-01

    Functional polymorphisms of the osteoprotegerin (OPG) gene are known to be involved in bone mineral density and the development of osteoporosis; however, some conflicting results have been reported. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the relationship between seven common OPG genetic polymorphisms (T149C, A163G, G209A, T245G, T950C, G1181C, and C1217T) and osteoporosis risk. A literature search for eligible studies published before August 1st, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI (China National Knowledge Infrastructure) databases. Pooled odds ratios and their corresponding 95% confidence intervals were used to evaluate the strength of the association under fixed- or random-effect models according to a heterogeneity test. All analyses were performed using the STATA software, version 12.0. Fourteen case-control studies with a total of 2383 osteoporosis cases and 2280 healthy controls were included in this meta-analysis. Among the seven polymorphisms, A163G and G1181C revealed significant associations with osteoporosis risk. For A163G (rs3102735), the combined results showed that the G allele of the A163G polymorphism may be associated with an increased risk of osteoporosis. Stratified analyses showed that the magnitude of the effect was similar in Caucasian and postmenopausal woman subgroups. For G1181C (rs2073618), however, we found that individuals with the C allele of the G1181C polymorphism had a decreased risk of osteoporosis, especially in Asian and postmenopausal woman subgroups. In summary, this meta-analysis indicated that the G allele of the OPG A163G polymorphism might increase osteoporosis risk in Caucasians, whereas individuals with the C allele of the G1181C polymorphism had a decreased risk of osteoporosis, especially in Asians. Both of these effects were observed in postmenopausal women. These polymorphisms could probably be used with other genetic markers

  9. The decision-making process of genetically at-risk couples considering preimplantation genetic diagnosis: initial findings from a grounded theory study.

    PubMed

    Hershberger, Patricia E; Gallo, Agatha M; Kavanaugh, Karen; Olshansky, Ellen; Schwartz, Alan; Tur-Kaspa, Ilan

    2012-05-01

    Exponential growth in genomics has led to public and private initiatives worldwide that have dramatically increased the number of procreative couples who are aware of their ability to transmit genetic disorders to their future children. Understanding how couples process the meaning of being genetically at-risk for their procreative life lags far behind the advances in genomic and reproductive sciences. Moreover, society, policy makers, and clinicians are not aware of the experiences and nuances involved when modern couples are faced with using Preimplantation Genetic Diagnosis (PGD). The purpose of this study was to discover the decision-making process of genetically at-risk couples as they decide whether to use PGD to prevent the transmission of known single-gene or sex-linked genetic disorders to their children. A qualitative, grounded theory design guided the study in which 22 couples (44 individual partners) from the USA, who were actively considering PGD, participated. Couples were recruited from June 2009 to May 2010 from the Internet and from a large PGD center and a patient newsletter. In-depth semi-structured interviews were completed with each individual partner within the couple dyad, separate from their respective partner. We discovered that couples move through four phases (Identify, Contemplate, Resolve, Engage) of a complex, dynamic, and iterative decision-making process where multiple, sequential decisions are made. In the Identify phase, couples acknowledge the meaning of their at-risk status. Parenthood and reproductive options are explored in the Contemplate phase, where 41% of couples remained for up to 36 months before moving into the Resolve phase. In Resolve, one of three decisions about PGD use is reached, including: Accepting, Declining, or Oscillating. Actualizing decisions occur in the Engage phase. Awareness of the decision-making process among genetically at-risk couples provides foundational work for understanding critical processes

  10. Additive Genetic Variation in Schizophrenia Risk Is Shared by Populations of African and European Descent

    PubMed Central

    de Candia, Teresa R.; Lee, S. Hong; Yang, Jian; Browning, Brian L.; Gejman, Pablo V.; Levinson, Douglas F.; Mowry, Bryan J.; Hewitt, John K.; Goddard, Michael E.; O’Donovan, Michael C.; Purcell, Shaun M.; Posthuma, Danielle; Visscher, Peter M.; Wray, Naomi R.; Keller, Matthew C.

    2013-01-01

    To investigate the extent to which the proportion of schizophrenia’s additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-rg]) between traits can be extended to estimate SNP-rg for the same trait between ethnicities. We estimated SNP-rg for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p(SNP-rg = 0) = 0.0003), but not 1 (p(SNP-rg = 1) = 0.26). We re-estimated SNP-rg between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p(SNP-rg = 0) = 0.0003, p(SNP-rg = 1) = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence. PMID:23954163

  11. Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease

    PubMed Central

    Won, Hong-Hee; Natarajan, Pradeep; Dobbyn, Amanda; Jordan, Daniel M.; Roussos, Panos; Lage, Kasper; Raychaudhuri, Soumya

    2015-01-01

    Large genome-wide association studies (GWAS) have identified many genetic loci associated with risk for myocardial infarction (MI) and coronary artery disease (CAD). Concurrently, efforts such as the National Institutes of Health (NIH) Roadmap Epigenomics Project and the Encyclopedia of DNA Elements (ENCODE) Consortium have provided unprecedented data on functional elements of the human genome. In the present study, we systematically investigate the biological link between genetic variants associated with this complex disease and their impacts on gene function. First, we examined the heritability of MI/CAD according to genomic compartments. We observed that single nucleotide polymorphisms (SNPs) residing within nearby regulatory regions show significant polygenicity and contribute between 59–71% of the heritability for MI/CAD. Second, we showed that the polygenicity and heritability explained by these SNPs are enriched in histone modification marks in specific cell types. Third, we found that a statistically higher number of 45 MI/CAD-associated SNPs that have been identified from large-scale GWAS studies reside within certain functional elements of the genome, particularly in active enhancer and promoter regions. Finally, we observed significant heterogeneity of this signal across cell types, with strong signals observed within adipose nuclei, as well as brain and spleen cell types. These results suggest that the genetic etiology of MI/CAD is largely explained by tissue-specific regulatory perturbation within the human genome. PMID:26509271

  12. Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease.

    PubMed

    Won, Hong-Hee; Natarajan, Pradeep; Dobbyn, Amanda; Jordan, Daniel M; Roussos, Panos; Lage, Kasper; Raychaudhuri, Soumya; Stahl, Eli; Do, Ron

    2015-10-01

    Large genome-wide association studies (GWAS) have identified many genetic loci associated with risk for myocardial infarction (MI) and coronary artery disease (CAD). Concurrently, efforts such as the National Institutes of Health (NIH) Roadmap Epigenomics Project and the Encyclopedia of DNA Elements (ENCODE) Consortium have provided unprecedented data on functional elements of the human genome. In the present study, we systematically investigate the biological link between genetic variants associated with this complex disease and their impacts on gene function. First, we examined the heritability of MI/CAD according to genomic compartments. We observed that single nucleotide polymorphisms (SNPs) residing within nearby regulatory regions show significant polygenicity and contribute between 59-71% of the heritability for MI/CAD. Second, we showed that the polygenicity and heritability explained by these SNPs are enriched in histone modification marks in specific cell types. Third, we found that a statistically higher number of 45 MI/CAD-associated SNPs that have been identified from large-scale GWAS studies reside within certain functional elements of the genome, particularly in active enhancer and promoter regions. Finally, we observed significant heterogeneity of this signal across cell types, with strong signals observed within adipose nuclei, as well as brain and spleen cell types. These results suggest that the genetic etiology of MI/CAD is largely explained by tissue-specific regulatory perturbation within the human genome. PMID:26509271

  13. Twins and virtual twins: Do genetic (as well as experiential) factors affect developmental risks?

    PubMed

    Segal, Nancy L; Tan, Tony Xing; Graham, Jamie L

    2015-08-01

    Factors underlying developmental delays and psychosocial risks are of interest to international adoption communities. The current study administered a Pre-Adoption Adversity (PAA) Questionnaire to mostly American parents raising (a) adopted Chinese twins or (b) same-age unrelated adopted siblings. A goal was to replicate earlier analyses of pre-adoption adversity/adjustment among adopted preschool-age Chinese girls. A second goal was to conduct genetic analyses of four content areas (Developmental Delays at Adoption, Initial Adaptation to Adoption, Crying/Clinging, and Refusal/Avoidance) derived from the PAA Questionnaire. A key finding was that age at adoption added less than other predictors to adoptees' externalizing and internalizing behaviors. Family factors (e.g., parental education) contributed significantly to behavioral outcomes among the adopted Chinese twins. Genetic effects were indicated for all four content areas, with shared environmental effects evident for Developmental Delays at Adoption and Crying/Clinging. Future investigators should consider incorporating genetically sensitive designs into developmental research programs. PMID:25900540

  14. Editing genomic DNA in cancer cells with high genetic variance: benefit or risk?

    PubMed

    Wang, Lin; Wang, Yixiang; Guo, Chuanbin

    2014-05-01

    The generation of stably-transfected cell lines is a common and very important technology in cancer science. Considerable knowledge in the field of life sciences has been gained through the modification of the genetic code. However, there is a risk in evaluating exogenous gene function through editing genomic DNA in a cancer cell with high genetic variance. In the present study, we showed that genomic DNA status should be considered when evaluating the exogenous gene function in a cancer cell line with high variant genome through stable transfection technology, immunostaining, wound healing assay, transwell invasion assay, real-time PCR, western blot and karyotyping analysis. Our results showed that the S100P expression level was not related to the migration and invasion abilities in these stably transfected cell lines derived from a human salivary adenoid cystic carcinoma cell line SACC-83. The MMP expression pattern was detected by western blot analysis which matched the biological behaviors in these cells. The genomic analysis showed that SACC-83 presented hypotetraploid karyotyping with high variance. Our data indicated that establishment of stable transgenic cancer cell lines should consider the status of genetic variance in a cancer cell to avoid any biased conclusion. PMID:24604254

  15. Digesting the Genetics of Inflammatory Bowel Disease – Insights from Studies of Autophagy Risk Genes

    PubMed Central

    Kabi, Amrita; Nickerson, Kourtney P.; Homer, Craig R.; McDonald, Christine

    2011-01-01

    The success of genetic analyses identifying multiple loci associated with IBD susceptibility has resulted in the identification of several risk genes linked to a common cellular process called autophagy. Autophagy is a process involving the encapsulation of cytosolic cellular components in double membraned vesicles, their subsequent lysosomal degradation, and recycling of the degraded components for use by the cell. It plays an important part in the innate immune response to a variety of intracellular pathogens, and it is this component of autophagy that appears to be defective in IBD. This has lead to the hypothesis that CD may result from an impaired anti-bacterial response, which leads to ineffective control of bacterial infection, dysbiosis of the intestinal microbiota, and chronic inflammation. Several recurrent themes have surfaced from studies examining the function of autophagy-related genes in the context of IBD - with cellular context, disease status, risk variant effect and risk gene interplay all affecting the interpretation of these studies. The identification of autophagy as a major risk pathway in IBD is a significant step forward and may lead to pathway-focused therapy in the future, however there is more to understand in order to unravel the complexity of this disease. PMID:21936032

  16. Genetic variation in genes involved in hormones, inflammation and energetic factors and breast cancer risk in an admixed population

    PubMed Central

    Slattery, Martha L.

    2012-01-01

    Breast cancer incidence rates are characterized by unique racial and ethnic differences. Native American ancestry has been associated with reduced breast cancer risk. We explore the biological basis of disparities in breast cancer risk in Hispanic and non-Hispanic white women by evaluating genetic variation in genes involved in inflammation, insulin and energy homeostasis in conjunction with genetic ancestry. Hispanic (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1586 controls) women enrolled in the 4-Corner’s Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study were included. Genetic admixture was determined from 104 ancestral informative markers that discriminate between European and Native American ancestry. Twenty-one genes in the CHIEF candidate pathway were evaluated. Higher Native American ancestry was associated with reduced risk of breast cancer (odds ratio = 0.79, 95% confidence interval 0.65, 0.95) but was limited to postmenopausal women (odds ratio = 0.66, 95% confidence interval 0.52, 0.85). After adjusting for genetic ancestry and multiple comparisons, four genes were significantly associated with breast cancer risk, NFκB1, NFκB1A, PTEN and STK11. Within admixture strata, breast cancer risk among women with low Native American ancestry was associated with IkBKB, NFκB1, PTEN and RPS6KA2, whereas among women with high Native American ancestry, breast cancer risk was associated with IkBKB, mTOR, PDK2, PRKAA1, RPS6KA2 and TSC1. Higher Native American ancestry was associated with reduced breast cancer risk. Breast cancer risk differed by genetic ancestry along with genetic variation in genes involved in inflammation, insulin, and energy homeostasis. PMID:22562547

  17. Genetic risk for myocardial infarction in Japanese individuals with or without chronic kidney disease.

    PubMed

    Fujimaki, Tetsuo; Kato, Kimihiko; Yokoi, Kiyoshi; Yoshida, Tetsuro; Oguri, Mitsutoshi; Watanabe, Sachiro; Metoki, Norifumi; Yoshida, Hidemi; Satoh, Kei; Aoyagi, Yukitoshi; Nozawa, Yoshinori; Yamada, Yoshiji

    2010-05-01

    Although chronic kidney disease (CKD) is recognized as an important risk factor for myocardial infarction (MI), genetic factors underlying predisposition to MI in individuals with or without CKD remain largely unknown. The aim of the present study was to identify genetic variants that confer susceptibility to MI in individuals with or without CKD in order to allow prediction of genetic risk for such individuals separately. The study population comprised a total of 4344 individuals, including 1247 individuals with CKD (506 subjects with MI and 741 controls) and 3097 individuals without CKD (833 subjects with MI and 2264 controls). The 150 polymorphisms examined in this study were selected by genome-wide association studies of ischemic stroke and MI with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix) and determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. In individuals with CKD, no polymorphism was significantly related to MI. In individuals without CKD, an initial screen by the Chi-square test revealed that the Cyright curved arrow T polymorphism of CLEC16A (rs9925481) and the Aright curved arrow G polymorphism of LAMA3 (rs12373237) were significantly (false discovery rate for allele frequencies of <0.05) associated with MI. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the Cright curved arrow T polymorphism of CLEC16A (dominant model; P=0.0003; odds ratio, 0.66) and the Aright curved arrow G polymorphism of LAMA3 (recessive model; P=0.0087; odds ratio, 0.75) were significantly (P<0.05) associated with MI. A stepwise forward selection procedure also revealed that these polymorphisms were significant and independent determinants of MI. CLEC16A and LAMA3 may be susceptibility loci for MI in Japanese individuals without CKD. Determination of genotypes for CLEC16A and LAMA3 may prove informative for

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

    PubMed

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

    2011-10-01

    Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. PMID:21909115

  19. Disease Risk Factors Identified through Shared Genetic Architecture and Electronic Medical Records

    PubMed Central

    Li, Li; Ruau, David J.; Patel, Chirag J.; Weber, Susan C.; Chen, Rong; Tatonetti, Nicholas P.; Dudley, Joel T.; Butte, Atul J.

    2015-01-01

    Genome-Wide Association Studies (GWAS) have identified genetic variants for thousands of diseases and traits. In this study, we evaluated the relationships between specific risk factors (for example, blood cholesterol level) and diseases on the basis of their shared genetic architecture in a comprehensive human disease-SNP association database (VARIMED), analyzing the findings from 8,962 published association studies. Similarity between traits and diseases was statistically evaluated based on their association with shared gene variants. We identified 120 disease-trait pairs that were statistically similar, and of these we tested and validated five previously unknown disease-trait associations by searching electronic medical records (EMR) from 3 independent medical centers for evidence of the trait appearing in patients within one year of first diagnosis of the disease. We validated that mean corpuscular volume is elevated before diagnosis of acute lymphoblastic leukemia; both have associated variants in the gene IKZF1. Platelet count is decreased before diagnosis of alcohol dependence; both are associated with variants in the gene C12orf51. Alkaline phosphatase level is elevated in patients with venous thromboembolism; both share variants in ABO. Similarly, we found prostate specific antigen and serum magnesium levels were altered before the diagnosis of lung cancer and gastric cancer, respectively. Disease-trait associations identifies traits that can potentially serve a prognostic function clinically; validating disease-trait associations through EMR can whether these candidates are risk factors for complex diseases. PMID:24786325

  20. Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk

    PubMed Central

    2011-01-01

    Blood pressure (BP) is a heritable trait1 influenced by multiple biological pathways and is responsive to environmental stimuli. Over one billion people worldwide have hypertension (BP ≥140 mm Hg systolic [SBP] or ≥90 mm Hg diastolic [DBP])2. Even small increments in BP are associated with increased risk of cardiovascular events3. This genome-wide association study of SBP and DBP, which used a multi-stage design in 200,000 individuals of European descent, identified 16 novel loci: six of these loci contain genes previously known or suspected to regulate BP (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other 10 provide new clues to BP physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke, and coronary artery disease, but not kidney disease or kidney function. We also observed associations with BP in East Asian, South Asian, and African ancestry individuals. Our findings provide new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention. PMID:21909115

  1. Association between ANKK1 (rs1800497) and LTA (rs909253) Genetic Variants and Risk of Schizophrenia

    PubMed Central

    Arab, Arwa H.; Elhawary, Nasser A.

    2015-01-01

    Limited research has assessed associations between schizophrenia and genetic variants of the ankyrin repeat and kinase domain containing 1 (ANKK1) and lymphotoxin-alpha (LTA) genes among individuals of Middle Eastern ancestry. Here we present the first association study investigating the ANKK1 rs1800497 (T>C) and LTA rs909253 (A>G) single-nucleotide polymorphisms in an Egyptian population. Among 120 patients with DSM-IV and PANSS (Positive and Negative Syndrome Scale) assessments of schizophrenia and 100 healthy controls, we determined the genotypes for the polymorphisms using endonuclease digestion of amplified genomic DNA. Results confirmed previous findings from different ethnic populations, in that the rs1800497 and rs909253 polymorphisms were both associated with risk of schizophrenia. Differences between the genotypes of cases and controls were strongly significant (P = 0.0005 for rs1800497 and P = 0.001 for rs909253). The relative risk to schizophrenia was 1.2 (P = 0.01) for the C allele and 0.8 (P = 0.04) for the G allele. The CC, GG, and combined CC/AA genotypes were all more frequent in cases than in controls. These results support an association between ANKK1 and LTA genetic markers and vulnerability to schizophrenia and show the potential influence of just one copy of the mutant C or G allele in the Egyptian population. PMID:26114114

  2. Risk assessment of multistate progression of breast tumor with state-dependent genetic and environmental covariates.

    PubMed

    Wu, Yi-Ying; Yen, Ming-Fang; Yu, Cheng-Ping; Chen, Hsiu-Hsi

    2014-02-01

    Few studies have focused on the different roles risk factors play in the multistate temporal natural course of breast cancer. We proposed a three-state Markov regression model to predict the risk from free of breast cancer (FBC) to the preclinical screen-detectable phase (PCDP) and from the PCDP to the clinical phase (CP). We searched the initiators and promoters affecting onset and subsequent progression of breast tumor to build up a three-state temporal natural history model with state-dependent genetic and environmental covariates. This risk assessment model was applied to a 1 million Taiwanese women cohort. The proposed model was verified by external validation with another independent data set. We identified three kinds of initiators, including the BRCA gene, seven single nucleotides polymorphism, and breast density. ER, Ki-67, and HER-2 were found as promoters. Body mass index and age at first pregnancy both played a role. Among women carrying the BRCA gene, the 10-year predicted risk for the transition from FBC to CP was 25.83%, 20.31%, and 13.84% for the high-, intermediate-, and low-risk group, respectively. The corresponding figures were 1.55%, 1.22%, and 0.76% among noncarriers. The mean sojourn time of staying at the PCDP ranged from 0.82 years for the highest risk group to 6.21 years for the lowest group. The lack of statistical significance for external validation (x(4)2=5.30,p=0.26) revealed the adequacy of our proposed model. The three-state model with state-dependent covariates of initiators and promoters was proposed for achieving individually tailored screening and also for personalized clinical surveillance of early breast cancer. PMID:24111840

  3. Case-control study of diabetes-related genetic variants and pancreatic cancer risk in Japan

    PubMed Central

    Kuruma, Sawako; Egawa, Naoto; Kurata, Masanao; Honda, Goro; Kamisawa, Terumi; Ueda, Junko; Ishii, Hiroshi; Ueno, Makoto; Nakao, Haruhisa; Mori, Mitsuru; Matsuo, Keitaro; Hosono, Satoyo; Ohkawa, Shinichi; Wakai, Kenji; Nakamura, Kozue; Tamakoshi, Akiko; Nojima, Masanori; Takahashi, Mami; Shimada, Kazuaki; Nishiyama, Takeshi; Kikuchi, Shogo; Lin, Yingsong

    2014-01-01

    AIM: To examine whether diabetes-related genetic variants are associated with pancreatic cancer risk. METHODS: We genotyped 7 single-nucleotide polymorphisms (SNPs) in PPARG2 (rs1801282), ADIPOQ (rs1501299), ADRB3 (rs4994), KCNQ1 (rs2237895), KCNJ11 (rs5219), TCF7L2 (rs7903146), and CDKAL1 (rs2206734), and examined their associations with pancreatic cancer risk in a multi-institute case-control study including 360 cases and 400 controls in Japan. A self-administered questionnaire was used to collect detailed information on lifestyle factors. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these diabetes-associated variants and pancreatic cancer risk. RESULTS: With the exception of rs1501299 in the ADIPOQ gene (P = 0.09), no apparent differences in genotype frequencies were observed between cases and controls. Rs1501299 in the ADPIOQ gene was positively associated with pancreatic cancer risk; compared with individuals with the AA genotype, the age- and sex-adjusted OR was 1.79 (95%CI: 0.98-3.25) among those with the AC genotype and 1.86 (95%CI: 1.03-3.38) among those with the CC genotype. The ORs remained similar after additional adjustment for body mass index and cigarette smoking. In contrast, rs2237895 in the KCNQ1 gene was inversely related to pancreatic cancer risk, with a multivariable-adjusted OR of 0.62 (0.37-1.04) among individuals with the CC genotype compared with the AA genotype. No significant associations were noted for other 5 SNPs. CONCLUSION: Our case-control study indicates that rs1501299 in the ADIPOQ gene may be associated with pancreatic cancer risk. These findings should be replicated in additional studies. PMID:25516658

  4. Functional FEN1 genetic variants and haplotypes are associated with glioma risk.

    PubMed

    Chen, Yi-Dong; Zhang, Xiaojiao; Qiu, Xiao-Guang; Li, Jinpeng; Yuan, Qipeng; Jiang, Tao; Yang, Ming

    2013-01-01

    As a tumor suppressor, FEN1 plays an essential role in keeping genomic instability and preventing tumorigenesis. There are two functional genetic variants (-69G>A and 4150G>T) in the FEN1 gene, which have been associated with DNA damage levels in coke-oven workers as well as risks of lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer in general populations. However, it is still unknown how these polymorphisms and their haplotypes are associated with glioma risk. Therefore, we investigated the role of these polymorphisms in glioma development using a case-control design in a Chinese population. The impact of the haplotypes constructed by these two polymorphisms on glioma risk was also examined. It was observed that the FEN1-69GG or 4150GG genotype were significantly associated to increased glioma risk compared with the -69AA or 4150TT genotype [Odds ratios (OR) = 1.87, 95 % confidence interval (CI) = 1.23-2.85, P = 0.003; or OR = 1.87, 95 % CI = 1.23-2.84, P = 0.003). The associations were more pronounced among female subjects (For -69AG or GG genotype: OR = 2.35, 95 % CI = 1.22-4.52; for 4150TG or GG genotype: OR = 2.33, 95 % CI = 1.21-4.48) and patients with grade 1 or 2 disease (For -69AG or GG genotype: OR = 2.21, 95 % CI = 1.20-4.05; for 4150TG or GG genotype: OR = 2.45, 95 % CI = 1.31-4.58). Additionally, the G(-69)G(4150) haplotype was also significantly associated with increased glioma risk compared with the A(-69)T(4150) haplotype. Our results suggest that FEN1 polymorphisms and haplotypes are associated with glioma risk. PMID:23184144

  5. Combined genetic and nutritional risk models of triple negative breast cancer.

    PubMed

    Lee, Eunkyung; Levine, Edward A; Franco, Vivian I; Allen, Glenn O; Gong, Feng; Zhang, Yanbin; Hu, Jennifer J

    2014-01-01

    Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and β-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01-7.64) and 10.89 (95% confidence interval = 3.50-33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women. PMID:25023197

  6. Identical twins in forensic genetics - Epidemiology and risk based estimation of weight of evidence.

    PubMed

    Tvedebrink, Torben; Morling, Niels

    2015-12-01

    The increase in the number of forensic genetic loci used for identification purposes results in infinitesimal random match probabilities. These probabilities are computed under assumptions made for rather simple population genetic models. Often, the forensic expert reports likelihood ratios, where the alternative hypothesis is assumed not to encompass close relatives. However, this approach implies that important factors present in real human populations are discarded. This approach may be very unfavourable to the defendant. In this paper, we discuss some important aspects concerning the closest familial relationship, i.e., identical (monozygotic) twins, when reporting the weight of evidence. This can be done even when the suspect has no knowledge of an identical twin or when official records hold no twin information about the suspect. The derived expressions are not original as several authors previously have published results accounting for close familial relationships. However, we revisit the discussion to increase the awareness among forensic genetic practitioners and include new information on medical and societal factors to assess the risk of not considering a monozygotic twin as the true perpetrator. If accounting for a monozygotic twin in the weight of evidence, it implies that the likelihood ratio is truncated at a maximal value depending on the prevalence of monozygotic twins and the societal efficiency of recognising a monozygotic twin. If a monozygotic twin is considered as an alternative proposition, then data relevant for the Danish society suggests that the threshold of likelihood ratios should approximately be between 150,000 and 2,000,000 in order to take the risk of an unrecognised identical, monozygotic twin into consideration. In other societies, the threshold of the likelihood ratio in crime cases may reach other, often lower, values depending on the recognition of monozygotic twins and the age of the suspect. In general, more strictly kept

  7. Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer

    PubMed Central

    Capela, Carlos; Dossou, Ange Dodji; Silva-Gomes, Rita; Sopoh, Ghislain Emmanuel; Makoutode, Michel; Menino, João Filipe; Fraga, Alexandra Gabriel; Cunha, Cristina; Carvalho, Agostinho; Rodrigues, Fernando; Pedrosa, Jorge

    2016-01-01

    Introduction Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Objective Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Methods Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. Results The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Conclusion Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes. PMID:27128681

  8. Pleiotropy between genetic markers of obesity and risk of prostate cancer

    PubMed Central

    Edwards, Todd L.; Giri, Ayush; Motley, Saundra; Duong, Wynne; Fowke, Jay H.

    2013-01-01

    Background To address inconsistent findings of obesity and prostate cancer risk, we analyzed the association between prostate cancer (PC) and genetic markers of obesity and metabolism. Methods Analyses included 176,520 single nucleotide polymorphisms (SNPs) associated with 23 metabolic traits. We examined the association between SNPs and PC in 871 cases and 906 controls, including 427 high-grade cases with Gleason ≥7. Genetic risk scores (GRSs) for body mass index (BMI) and waist-to-hip ratio (WHR) were also created by summing alleles associated with increasing BMI or WHR. Results PC was associated with 5 loci, including cyclin M2, with p-values less than 1×10−4. In addition, the WHR GRS was associated with high-grade PC versus controls (OR: 1.05; 95% CI: 1.00 – 1.11, p-value = 0.048), and high-grade PC versus low-grade PC (OR: 1.07, 95% CI 1.01 – 1.13, p-value = 0.03). None of these findings exceed the threshold for significance after correction for multiple testing. Conclusions Variants in genes known to be associated with metabolism and obesity may be associated with PC. We show evidence for pleiotropy between WHR GRS and PC grade. This finding is consistent with the function of several WHR genes, and previously described relationships with cancer traits. Impact Limitations in standard obesity measures suggest alternative characterizations of obesity may be needed to understand the role of metabolic dysregulation in PC. The underlying genetics of WHR or other Metabochip SNPs, while not statistically significant beyond multiple testing thresholds within our sample size, support the metabolic hypothesis of prostate carcinogenesis and warrant further investigation in independent samples. PMID:23810916

  9. BRCA genetic counseling among at-risk Latinas in New York City: new beliefs shape new generation.

    PubMed

    Sussner, Katarina M; Edwards, Tiffany; Villagra, Cristina; Rodriguez, M Carina; Thompson, Hayley S; Jandorf, Lina; Valdimarsdottir, Heiddis B

    2015-02-01

    Despite the life-saving information that genetic counseling can provide for women at hereditary breast and/or ovarian cancer (HBOC) risk, Latinas disproportionately underuse such services. Understanding Latinas' beliefs and attitudes about BRCA genetic counseling may be the key to better health promotion within this underserved, at-risk group. We conducted 12 focus groups (N = 54) with at-risk Latina women in New York City, followed by 30 in-depth interviews among a subset of the focus group women. Both were professionally transcribed, translated where applicable and data analysis was completed by two coders trained in qualitative methods. Results revealed personal and community knowledge about BRCA genetic counseling was relatively low, although women felt largely positive about counseling. The main motivator to undergo genetic counseling was concerns about learning family members' cancer status, while the main barrier was competing demands. Generational differences were apparent, with younger women (approximately <55 years) reporting that they were more interested in educating themselves about counseling and other ways to prevent cancer. Younger women were also less likely to ascribe to traditionally Latino-centered cultural beliefs which could serve as barriers (e.g. machismo, fatalismo, destino) to undergoing genetic counseling. Participants were largely enthusiastic about educational efforts to increase awareness of genetic counseling among Latinos. Revealing the beliefs and attitudes of underserved Latinas may help shape culturally appropriate educational materials and promotion programs to increase BRCA genetic counseling uptake within this underrepresented community. PMID:25120034

  10. BRCA Genetic Counseling Among At-Risk Latinas in New York City: New Beliefs Shape New Generation

    PubMed Central

    Edwards, Tiffany; Villagra, Cristina; Rodriguez, M. Carina; Thompson, Hayley S.; Jandorf, Lina; Valdimarsdottir, Heiddis B.

    2015-01-01

    Despite the life-saving information that genetic counseling can provide for women at hereditary breast and/or ovarian cancer (HBOC) risk, Latinas disproportionately underuse such services. Understanding Latinas’ beliefs and attitudes about BRCA genetic counseling may be the key to better health promotion within this underserved, at-risk group. We conducted 12 focus groups (N=54) with at-risk Latina women in New York City, followed by 30 in-depth interviews among a subset of the focus group women. Both were professionally transcribed, translated where applicable and data analysis was completed by two coders trained in qualitative methods. Results revealed personal and community knowledge about BRCA genetic counseling was relatively low, although women felt largely positive about counseling. The main motivator to undergo genetic counseling was concerns about learning family members’ cancer status, while the main barrier was competing demands. Generational differences were apparent, with younger women (approximately <55 years) reporting that they were more interested in educating themselves about counseling and other ways to prevent cancer. Younger women were also less likely to ascribe to traditionally Latino-centered cultural beliefs which could serve as barriers (e.g. machismo, fatalismo, destino) to undergoing genetic counseling. Participants were largely enthusiastic about educational efforts to increase awareness of genetic counseling among Latinos. Revealing the beliefs and attitudes of underserved Latinas may help shape culturally appropriate educational materials and promotion programs to increase BRCA genetic counseling uptake within this under-represented community. PMID:25120034

  11. Genetics, Genomics and Cancer Risk Assessment: State of the art and future directions in the era of personalized medicine

    PubMed Central

    Weitzel, Jeffrey N.; Blazer, Kathleen R.; MacDonald, Deborah J.; Culver, Julie O.; Offit, Kenneth

    2012-01-01

    Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently-discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease-risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine. PMID:21858794

  12. Association between vitamin D status and age-related macular degeneration by genetic risk

    PubMed Central

    Millen, Amy E.; Meyers, Kristin J; Liu, Zhe; Engelman, Corinne D; Wallace, Robert B; LeBlanc, Erin S; Tinker, Lesley F.; Iyengar, Sudha K; Robinson, Jennifer; Sarto, Gloria E.; Mares, Julie A

    2016-01-01

    Importance Deficient 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with increased odds of age-related macular degeneration (AMD). Objective We examined 1) whether this association is modified by genetic risk for AMD and 2) if there is an association between AMD and single nucleotide polymorphisms (SNPs) of genes involved in vitamin D transport, metabolism and genomic function. Design, Setting and Participants Women were postmenopausal and participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (54 to <75 years) with available serum 25(OH)D concentrations (assessed from 1994–1998), genetic data, and measures of AMD (n=142) assessed at CAREDS baseline from 2001–2004 (n=913). Main Outcomes and Measures Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for AMD by the joint effects of 25(OH)D (<30, ≥30 to <50, ≥50 to <75, and ≥75 nmol/L) and risk genotype (noncarrier, one, or two risk alleles). The referent group was noncarriers with adequate vitamin D status (≥75 nmol/L). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the Synergy Index (SI) and an interaction term, respectively. Results We observed a 6.7-fold increased odds of AMD (95% CI=1.6, 28.2) among women with deficient vitamin D status (25(OH)D<30 nmol/L) and two risk alleles for complement factor H (CFH) Y402H (SI for additive interaction=1.4, 95% CI=1.1, 1.7; p for multiplicative interaction=0.25,. A significant additive (SI=1.4, 95% CI=1.1, 1.7) and multiplicative interaction (p=0.02) was observed for deficient women with two high risk complement factor I (CFI) (rs10033900) alleles (OR=6.3, 95% CI=1.6, 24.2). The odds of AMD did not differ by genotype of candidate

  13. No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome.

    PubMed

    Vahteristo, Pia; Koski, Taru A; Näätsaari, Laura; Kiuru, Maija; Karhu, Auli; Herva, Riitta; Sallinen, Satu-Leena; Vierimaa, Outi; Björck, Erik; Richard, Stéphane; Gardie, Betty; Bessis, Didier; Van Glabeke, Emmanuel; Blanco, Ignacio; Houlston, Richard; Senter, Leigha; Hietala, Marja; Aittomäki, Kristiina; Aaltonen, Lauri A; Launonen, Virpi; Lehtonen, Rainer

    2010-06-01

    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. Cutaneous and uterine leiomyomas are the most common clinical manifestations of HLRCC, whereas only approximately 20% of the families display renal cell cancer (RCC). The number of RCC cases in these families varies from one to five. Interestingly, families with multiple RCC cases are mainly found in Finland and the USA. Such aggregation of RCC in only some families and populations has led to the hypothesis that besides FH mutations also other inherited genetic and/or environmental factors may contribute to the malignant kidney tumor formation. To search for such a genetic modifier we have performed a genome-wide linkage analysis in two and an identical by descent analysis in four Finnish HLRCC families with several RCC patients. Additional Finnish and French families were used in fine-mapping and haplotype analyses. The only region compatible with linkage was the locus surrounding the FH gene itself in chromosome 1q43. The genes in the putative candidate region were screened, but no potentially pathogenic alterations were observed. Although these data do not rule out the existence of a genetic modifier, they emphasize the contribution of the FH genotype in HLRCC related RCC. Therefore, as all FH mutation carriers may have an increased risk for developing renal cancer, counseling and genetic testing should be offered for all HLRCC family members and clinical follow-up should be organized for the mutation carriers. PMID:20091131

  14. Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study

    PubMed Central

    Martin, Joanna; Tilling, Kate; Hubbard, Leon; Stergiakouli, Evie; Thapar, Anita; Davey Smith, George; O'Donovan, Michael C.; Zammit, Stanley

    2016-01-01

    Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1–15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness. PMID:27188935

  15. PEDIATRIC CHRONIC PANCREATITIS IS ASSOCIATED WITH GENETIC RISK FACTORS AND SUBSTANTIAL DISEASE BURDEN

    PubMed Central

    Ahuja, Monika; Barth, Bradley; Davis, Heather; Durie, Peter R.; Fishman, Douglas S.; Freedman, Steven D.; Gariepy, Cheryl E.; Giefer, Matthew J.; Gonska, Tanja; Heyman, Melvin B.; Himes, Ryan; Kumar, Soma; Morinville, Veronique D.; Lowe, Mark E.; Nuehring, Neil E.; Ooi, Chee Y.; Pohl, John F.; Troendle, David; Werlin, Steven L.; Wilschanski, Michael; Yen, Elizabeth; Uc, Aliye

    2014-01-01

    Objective To determine the clinical presentation, diagnostic variables, risk factors and disease burden in children with chronic pancreatitis. Study design We performed a cross-sectional study of data from INSPPIRE (International Study Group of Pediatric Pancreatitis: In search for a cuRE), a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. Results Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were Caucasian, median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency room visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed one day of school in the past month due to chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (p=0.002), visit emergency room (p=0.01) and experience hospitalizations (p=0.03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic ERCP; one or more pancreatic surgeries were performed in 30 (39%). Conclusions Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial. PMID:25556020

  16. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

    PubMed

    Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C A; Patsopoulos, Nikolaos A; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E; Edkins, Sarah; Gray, Emma; Booth, David R; Potter, Simon C; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'alfonso, Sandra; Blackburn, Hannah; Martinelli Boneschi, Filippo; Liddle, Jennifer; Harbo, Hanne F; Perez, Marc L; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J; Barcellos, Lisa F; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P; Brassat, David; Broadley, Simon A; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M; Cavalla, Paola; Celius, Elisabeth G; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B; Cozen, Wendy; Cree, Bruce A C; Cross, Anne H; Cusi, Daniele; Daly, Mark J; Davis, Emma; de Bakker, Paul I W; Debouverie, Marc; D'hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F A; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G; Kilpatrick, Trevor J; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S; Leone, Maurizio A; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L; Ramsay, Patricia P; Reunanen, Mauri; Reynolds, Richard; Rioux, John D; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J; Sellebjerg, Finn; Selmaj, Krzysztof W; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M A; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A; Tronczynska, Ewa; Casas, Juan P; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S; Wang, Kai; Mathew, Christopher G; Wason, James; Palmer, Colin N A; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C; Yaouanq, Jacqueline; Viswanathan, Ananth C; Zhang, Haitao; Wood, Nicholas W; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R; Pericak-Vance, Margaret A; Haines, Jonathan L; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J; De Jager, Philip L; Peltonen, Leena; Stewart, Graeme J; Hafler, David A; Hauser, Stephen L; McVean, Gil; Donnelly, Peter; Compston, Alastair

    2011-08-11

    Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. PMID:21833088

  17. Network dysfunction of emotional and cognitive processes in those at genetic risk of bipolar disorder.

    PubMed

    Breakspear, Michael; Roberts, Gloria; Green, Melissa J; Nguyen, Vinh T; Frankland, Andrew; Levy, Florence; Lenroot, Rhoshel; Mitchell, Philip B

    2015-11-01

    The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder. PMID:26373604

  18. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

    PubMed Central

    Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C.A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D’alfonso, Sandra; Blackburn, Hannah; Boneschi, Filippo Martinelli; Liddle, Jennifer; Harbo, Hanne F.; Perez, Marc L.; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P.; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T.; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J.; Barcellos, Lisa F.; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E.; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P.; Brassat, David; Broadley, Simon A.; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M.; Cavalla, Paola; Celius, Elisabeth G.; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B.; Cozen, Wendy; Cree, Bruce A.C.; Cross, Anne H.; Cusi, Daniele; Daly, Mark J.; Davis, Emma; de Bakker, Paul I.W.; Debouverie, Marc; D’hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F.A.; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N.; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G.; Kilpatrick, Trevor J.; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S.; Leone, Maurizio A.; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R.; Link, Jenny; Liu, Jianjun; Lorentzen, Åslaug R.; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L.; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L.; Ramsay, Patricia P.; Reunanen, Mauri; Reynolds, Richard; Rioux, John D.; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P.; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A.; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J.; Sellebjerg, Finn; Selmaj, Krzysztof W.; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M.A.; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C.; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M.; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A.; Tronczynska, Ewa; Casas, Juan P.; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S.; Wang, Kai; Mathew, Christopher G.; Wason, James; Palmer, Colin N.A.; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C.; Yaouanq, Jacqueline; Viswanathan, Ananth C.; Zhang, Haitao; Wood, Nicholas W.; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J.; De Jager, Philip L.; Peltonen, Leena; Stewart, Graeme J.; Hafler, David A.; Hauser, Stephen L.; McVean, Gil; Donnelly, Peter; Compston, Alastair

    2011-01-01

    Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis. PMID:21833088

  19. BRCA1 and BRCA2 genetic test in high risk patients and families: counselling and management.

    PubMed

    Marchina, Eleonora; Fontana, Maria Grazia; Speziani, Michela; Salvi, Alessandro; Ricca, Giuseppe; Di Lorenzo, Diego; Gervasi, Maria; Caimi, Luigi; Barlati, Sergio

    2010-12-01

    Hereditary breast cancer accounts for 5-10% of all cases of breast cancer and 10-15% of ovarian cancer and is characterised by dominant inheritance, early onset, the severity of the disease and bilaterality. About 30% of cases with hereditary breast and ovarian cancer have mutations in the BRCA1 and BRCA2 genes. Women with a mutation in the BRCA1 gene have a 80-90% lifetime risk of developing breast cancer, and 40-65% chance of developing ovarian cancer. Most studies carried out throughout the world indicate that the prevalence of BRCA1 and BRCA2 mutation is lower than originally suggested by early studies on large families with several affected members. Studies performed in Italy have reported different prevalence of BRCA1 and BRCA2 mutations, probably due to different selection criteria and to the variability of the techniques used. In this study, we performed a screening of BRCA1 and BRCA2 in families from northern Italy with familial recurrence of breast cancer or ovarian cancer in which the individual risk of patients of being carriers of BRCA1 and BRCA2 mutation was evaluated using BRCAPRO (CAGene) software. We enrolled 27 patients of 101 unrelated families selected when they fulfilled the inclusion criteria of the American Society of Clinical Oncology (ASCO). Specific risk evaluation, genetic test administration if needed, and discussion of the results were offered during multi-disciplinary genetic, surgical and psychological counselling. Seven probands (35%) found BRCA1/2 sequence variation carriers; no BRCA1 and BRCA2 mutations were detected in the remaining 13 probands. Two (15%) patients had BRCA1 mutations and 5 (25%) patients had BRCA2 mutations. In the latter case, BRCA2 delA 9158fs+29stop mutation in exon 22, never previously described and a new sequence variation (T703N) in exon 11 were identified. PMID:21042765

  20. Genetic and environmental influences on the development of alcoholism: resilience vs. risk.

    PubMed

    Enoch, Mary-Anne

    2006-12-01

    The physiological changes of adolescence may promote risk-taking behaviors, including binge drinking. Approximately 40% of alcoholics were already drinking heavily in late adolescence. Most cases of alcoholism are established by the age of 30 years with the peak prevalence at 18-23 years of age. Therefore the key time frame for the development, and prevention, of alcoholism lies in adolescence and young adulthood. Severe childhood stressors have been associated with increased vulnerability to addiction, however, not all stress-exposed children go on to develop alcoholism. Origins of resilience can be both genetic (variation in alcohol-metabolizing genes, increased susceptibility to alcohol's sedative effects) and environmental (lack of alcohol availability, positive peer and parental support). Genetic vulnerability is likely to be conferred by multiple genes of small to modest effects, possibly only apparent in gene-environment interactions. For example, it has been shown that childhood maltreatment interacts with a monoamine oxidase A (MAOA) gene variant to predict antisocial behavior that is often associated with alcoholism, and an interaction between early life stress and a serotonin transporter promoter variant predicts alcohol abuse in nonhuman primates and depression in humans. In addition, a common Met158 variant in the catechol-O-methyltransferase (COMT) gene can confer both risk and resilience to alcoholism in different drinking environments. It is likely that a complex mix of gene(s)-environment(s) interactions underlie addiction vulnerability and development. Risk-resilience factors can best be determined in longitudinal studies, preferably starting during pregnancy. This kind of research is important for planning future measures to prevent harmful drinking in adolescence. PMID:17347351

  1. Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women

    PubMed Central

    Lin, Jennifer; Zee, Robert Y.L.; Liu, Kuang-Yu; Zhang, Shumin M.; Lee, I-Min; Manson, JoAnn E.; Giovannucci, Edward; Buring, Julie E.; Cook, Nancy R.

    2010-01-01

    Objectives Several lines of evidence have suggested that female hormones may lower risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1) and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2). Methods We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 years or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs). Results There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction ≥0.25). There was also no association with any of the haplotypes examined (p ≥0.15) and no evidence of joint effects of variants in the 5 genes (p ≥0.51). Conclusion Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and risk for developing colorectal cancer. PMID:20148360

  2. Postictal psychosis: presymptomatic risk factors and the need for further investigation of genetics and pharmacotherapy

    PubMed Central

    Morrow, Eric M; Lafayette, Jennifer M; Bromfield, Edward B; Fricchione, Gregory

    2006-01-01

    Background Postictal psychosis (PIP), an episode of psychosis occurring after a cluster of seizures, is common and may be associated with profound morbidity, including chronic psychosis. Symptoms are often pleomorphic, involving a range of psychotic symptoms, including hallucinations and disorders of thought. PIP is treatable and may be averted if presymptomatic risk factors are considered in susceptible patients and treatment is initiated. Case presentation In this report, we present an illustrative case of PIP. The patient, Mr. R, presented to our emergency room with delusions and disordered thought process following a cluster of seizures. He recovered after admission, sedation and treatment with antipsychotic medication. Discussion A list of presymptomatic risk factors is established based on review of current literature. Identification of such risk factors may potentially help with prophylactic treatment; however, little empirical research exists in this area and treatment guidelines are thus far largely based on expert opinion. Further, while the neurobiology of schizophrenia is advancing at a rapid pace, largely due to advances in genetics, the pathophysiology of PIP remains largely unknown. Considering the progress in schizophrenia research in the context of the clinical features of PIP and existing studies, potential neurobiological mechanisms for PIP are herein proposed, and further genetic analyses, which may help identify those susceptible, are warranted. Conclusion While PIP is an important problem that may present first to general hospital psychiatrists, as in the case presented, this topic is under-represented in the medical psychiatry literature. As discussed in this article, further research is needed to develop presymptomatic screens and treatment pathways to help prevent morbidity. PMID:16859554

  3. Research Highlights, 2003

    ERIC Educational Resources Information Center

    ACER Press (Australian Council for Educational Research), 2003

    2003-01-01

    "Research Highlights" is an annual publication documenting developments in the Australian Council for Educational Research's (ACER's) research programs for the previous year. The 2003 edition highlights research on the following themes: (1) Australian students excel in international study; (2) Assessing the moral and ethical outcomes of schooling;…

  4. APPA 2011 Conference Highlights

    ERIC Educational Resources Information Center

    Facilities Manager, 2011

    2011-01-01

    This article presents highlights of APPA conference that was held on July 16-18, 2011. The highlights feature photos of 2011-2012 board of directors, outgoing senior regional representatives to the board, meritorious service award, APPA fellow, president's recognition and gavel exchange, and diamond business partner award.

  5. Highlights of 1978 activities

    NASA Technical Reports Server (NTRS)

    1978-01-01

    General highlights of NASA's activities for 1978 are presented. The highlights are categorized into topics such as space science, space transportation systems, space and terrestrial applications, environment, technology utilization, aeronautics, space research and technology, energy programs, and international. A list of the 1978 launches including: (1) launch date; (2) payload designation; (3) launch vehicle; (4) launch site and (5) mission remarks is also presented.

  6. Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy

    PubMed Central

    Gilbert, Rebecca; Martin, Richard M.; Evans, David M.; Tilling, Kate; Davey Smith, George; Kemp, John P.; Lane, J. Athene; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Metcalfe, Chris

    2015-01-01

    Introduction Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. Materials and Methods Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. Results The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). Conclusion We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng

  7. Comprehensive genetic counseling for families at risk for HNPCC: impact on distress and perceptions.

    PubMed

    Keller, M; Jost, R; Haunstetter, C Mastromarino; Kienle, P; Knaebel, H P; Gebert, J; Sutter, C; Knebel-Doeberitz, M v; Cremer, F; Mazitschek, U

    2002-01-01

    The aim of the study was to explore distress and health beliefs before and after comprehensive interdisciplinary counseling in families at risk for hereditary non-polyposis colorectal cancer (HNPCC). Results reported here were derived from a consecutive sample of 65 counselees [31 patients with colorectal cancer (CRC) and 34 unaffected at-risk persons] who participated in interdisciplinary counseling provided by human geneticists, surgeons, and psycho-oncologists before genetic testing. Data were collected from self-administered questionnaires before, as well as 4-6 weeks after, counseling. Distress and perceptions specific to HNPCC were assessed at both timepoints using standardized as well as author-derived instruments. Distress declined after counseling, as did worries related to HNPCC. An increase was found in personal belief in control of cancer risk, for instance, in the perceived efficacy of early detection of CRC. We also observed a trend toward greater anticipated ability to cope with a positive gene test after counseling. Changes after counseling were generally more pronounced for persons at risk, as compared to patients with cancer. The decrease in distress was partly attributable to an increase in personal self-confidence. One-third of the sample reported enhanced communication specific to hereditary disease within the family after counseling. A substantial minority, however, said they experienced increased worry and physical symptoms after counseling. Overall, counselees demonstrated less stress and perceived cancer threat as well as enhanced beliefs regarding personal control over cancer, suggesting an overall beneficial impact of comprehensive counseling. Further research is needed to identify those individuals most at risk for increased fear and worry related to HNPCC so that they may be most appropriately counseled. PMID:12537653

  8. Psychological and behavioural impact of genetic testing smokers for lung cancer risk: a phase II exploratory trial.

    PubMed

    Sanderson, Saskia C; Humphries, Steve E; Hubbart, Christina; Hughes, Eluned; Jarvis, Martin J; Wardle, Jane

    2008-05-01

    The behavioural and psychological impact of genetic testing for lung cancer susceptibility was examined among smokers (N = 61) who were randomly allocated to a GSTM1 genetic testing group (with GSTM1-missing or GSTM1-present result) or no-test control group. The GSTM1-missing (higher risk) group reported greater motivation to quit smoking, and both genetic testing groups reported lower depression than the control group at one-week follow-up (p < .05 for all). Differences were not significant at two months follow-up. This study indicates the feasibility of much-needed research into the risks and benefits for individuals of emerging lifestyle-related genetic susceptibility tests. PMID:18420756

  9. The conceptual imperfection of aquatic risk assessment tests: highlighting the need for tests designed to detect therapeutic effects of pharmaceutical contaminants

    NASA Astrophysics Data System (ADS)

    Klaminder, J.; Jonsson, M.; Fick, J.; Sundelin, A.; Brodin, T.

    2014-08-01

    Standardized ecotoxicological tests still constitute the fundamental tools when doing risk-assessment of aquatic contaminants. These protocols are managed towards minimal mortality in the controls, which is not representative for natural systems where mortality is often high. This methodological bias, generated from assays where mortality in the control group is systematically disregarded, makes it difficult to measure therapeutic effects of pharmaceutical contaminants leading to lower mortality. This is of concern considering that such effects on exposed organisms still may have substantial ecological consequences. In this paper, we illustrate this conceptual problem by presenting empirical data for how the therapeutic effect of Oxazepam—a common contaminant of surface waters—lower mortality rates among exposed Eurasian perch (Perca fluviatilis) from wild populations, at two different life stages. We found that fry hatched from roe that had been exposed to dilute concentrations (1.1 ± 0.3 μg l-1) of Oxazepam for 24 h 3-6 days prior to hatching showed lower mortality rates and increased activity 30 days after hatching. Similar effects, i.e. increased activity and lower mortality rates were also observed for 2-year old perch exposed to dilute Oxazepam concentrations (1.2 ± 0.4 μg l-1). We conclude that therapeutic effects from pharmaceutical contaminants need to be considered in risk assessment assays to avoid that important ecological effects from aquatic contaminants are systematically missed.

  10. Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity

    PubMed Central

    Ahmed, Mahbubl; Dorling, Leila; Kerns, Sarah; Fachal, Laura; Elliott, Rebecca; Partliament, Matt; Rosenstein, Barry S; Vega, Ana; Gómez-Caamaño, Antonio; Barnett, Gill; Dearnaley, David P; Hall, Emma; Sydes, Matt; Burnet, Neil; Pharoah, Paul D P; Eeles, Ros; West, Catharine M L

    2016