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Sample records for additional genetic risk

  1. Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

    PubMed Central

    Chowdhury, Susmita; Henneman, Lidewij; Dent, Tom; Hall, Alison; Burton, Alice; Pharoah, Paul; Pashayan, Nora; Burton, Hilary

    2015-01-01

    There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention. PMID:26068647

  2. Additive Genetic Risk from Five Serotonin System Polymorphisms Interacts with Interpersonal Stress to Predict Depression

    PubMed Central

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

    2016-01-01

    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 (GxE). 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 GxE predicting depression, we created an additive multilocus profile score from five serotonin system polymorphisms (one each in the genes HTR1A, HTR2A, HTR2C, and two in TPH2). Analyses focused on two forms of interpersonal stress as environmental risk factors. Using five 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 (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 GxE 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 GxE 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

  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. [Food additives and genetically modified food--a risk for allergic patients?].

    PubMed

    Wüthrich, B

    1999-04-01

    Adverse reactions to food and food additives must be classified according to pathogenic criteria. It is necessary to strictly differentiate between an allergy, triggered by a substance-specific immunological mechanism, and an intolerance, in which no specific immune reaction can be established. In contrast to views expressed in the media, by laymen and patients, adverse reactions to additives are less frequent than is believed. Due to frequently "alternative" methods of examination, an allergy to food additives is often wrongly blamed as the cause of a wide variety of symptoms and illness. Diagnosing an allergy or intolerance to additives normally involves carrying out double-blind, placebo-controlled oral provocation tests with food additives. Allergic reactions to food additives occur particularly against additives which are organic in origin. In principle, it is possible that during the manufacture of genetically modified plants and food, proteins are transferred which potentially create allergies. However, legislation exists both in the USA (Federal Drug Administration, FDA) and in Switzerland (Ordinance on the approval process for GM food, GM food additives and GM accessory agents for processing) which require a careful analysis before a genetically modified product is launched, particularly where foreign genes are introduced. Products containing genetically modified organisms (GMO) as additives must be declared. In addition, the source of the foreign protein must be identified. The "Round-up ready" (RR) soya flour introduced in Switzerland is no different from natural soya flour in terms of its allergenic potential. Genetically modified food can be a blessing for allergic individuals if gene technology were to succeed in removing the allergen (e.g. such possibilities exist for rice). The same caution shown towards genetically modified food might also be advisable for foreign food in our diet. Luckily, the immune system of the digestive tract in healthy people

  5. [Food additives and genetically modified food--a risk for allergic patients?].

    PubMed

    Wüthrich, B

    1999-04-01

    Adverse reactions to food and food additives must be classified according to pathogenic criteria. It is necessary to strictly differentiate between an allergy, triggered by a substance-specific immunological mechanism, and an intolerance, in which no specific immune reaction can be established. In contrast to views expressed in the media, by laymen and patients, adverse reactions to additives are less frequent than is believed. Due to frequently "alternative" methods of examination, an allergy to food additives is often wrongly blamed as the cause of a wide variety of symptoms and illness. Diagnosing an allergy or intolerance to additives normally involves carrying out double-blind, placebo-controlled oral provocation tests with food additives. Allergic reactions to food additives occur particularly against additives which are organic in origin. In principle, it is possible that during the manufacture of genetically modified plants and food, proteins are transferred which potentially create allergies. However, legislation exists both in the USA (Federal Drug Administration, FDA) and in Switzerland (Ordinance on the approval process for GM food, GM food additives and GM accessory agents for processing) which require a careful analysis before a genetically modified product is launched, particularly where foreign genes are introduced. Products containing genetically modified organisms (GMO) as additives must be declared. In addition, the source of the foreign protein must be identified. The "Round-up ready" (RR) soya flour introduced in Switzerland is no different from natural soya flour in terms of its allergenic potential. Genetically modified food can be a blessing for allergic individuals if gene technology were to succeed in removing the allergen (e.g. such possibilities exist for rice). The same caution shown towards genetically modified food might also be advisable for foreign food in our diet. Luckily, the immune system of the digestive tract in healthy people

  6. Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An additive genetic risk score (GRS) for coronary heart disease (CHD) has previously been associated with incident CHD in the population-based Greek European Prospective Investigation into Cancer and nutrition (EPIC) cohort. In this study, we explore GRS-‘environment’ joint actions on CHD for severa...

  7. PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing.

    PubMed

    Rechitsky, Svetlana; Verlinsky, Oleg; Kuliev, Anver

    2013-05-01

    Preimplantation genetic diagnosis (PGD) for inherited disorders is presently applied for more than 300 different conditions. The most frequent PGD indication is cystic fibrosis (CF), the largest series of which is reviewed here, totalling 404 PGD cycles. This involved testing for 52 different CFTR mutations with almost half of the cases (195/404 cycles) performed for ΔF508 mutation, one-quarter (103/404 cycles) for six other frequent mutations and only a few for the remaining 45 CFTR mutations. There were 44 PGD cycles performed for 25 CF-affected homozygous or double-heterozygous CF patients (18 male and seven female partners), which involved testing simultaneously for three mutations, resulting in birth of 13 healthy CF-free children and no misdiagnosis. PGD was also performed for six couples at a combined risk of producing offspring with CF and another genetic disorder. Concomitant testing for CFTR and other mutations resulted in birth of six healthy children, free of both CF and another genetic disorder in all but one cycle. A total of 96 PGD cycles for CF were performed with simultaneous aneuploidy testing, including microarray-based 24-chromosome analysis, as a comprehensive PGD for two or more conditions in the same biopsy material.

  8. Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece

    PubMed Central

    Yiannakouris, Nikos; Katsoulis, Michail; Trichopoulou, Antonia; Ordovas, Jose M; Trichopoulos, Dimitrios

    2014-01-01

    Objectives An additive genetic risk score (GRS) for coronary heart disease (CHD) has previously been associated with incident CHD in the population-based Greek European Prospective Investigation into Cancer and nutrition (EPIC) cohort. In this study, we explore GRS-‘environment’ joint actions on CHD for several conventional cardiovascular risk factors (ConvRFs), including smoking, hypertension, type-2 diabetes mellitus (T2DM), body mass index (BMI), physical activity and adherence to the Mediterranean diet. Design A case–control study. Setting The general Greek population of the EPIC study. Participants and outcome measures 477 patients with medically confirmed incident CHD and 1271 controls participated in this study. We estimated the ORs for CHD by dividing participants at higher or lower GRS and, alternatively, at higher or lower ConvRF, and calculated the relative excess risk due to interaction (RERI) as a measure of deviation from additivity. Results The joint presence of higher GRS and higher risk ConvRF was in all instances associated with an increased risk of CHD, compared with the joint presence of lower GRS and lower risk ConvRF. The OR (95% CI) was 1.7 (1.2 to 2.4) for smoking, 2.7 (1.9 to 3.8) for hypertension, 4.1 (2.8 to 6.1) for T2DM, 1.9 (1.4 to 2.5) for lower physical activity, 2.0 (1.3 to 3.2) for high BMI and 1.5 (1.1 to 2.1) for poor adherence to the Mediterranean diet. In all instances, RERI values were fairly small and not statistically significant, suggesting that the GRS and the ConvRFs do not have effects beyond additivity. Conclusions Genetic predisposition to CHD, operationalised through a multilocus GRS, and ConvRFs have essentially additive effects on CHD risk. PMID:24500614

  9. 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...

  10. Explaining additional genetic variation in complex traits

    PubMed Central

    Robinson, Matthew R.; Wray, Naomi R.; Visscher, Peter M.

    2015-01-01

    Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits, discovering >6000 variants associated with >500 quantitative traits and common complex diseases in humans. The associations identified so far represent only a fraction of those which influence phenotype, as there are likely to be very many variants across the entire frequency spectrum, each of which influences multiple traits, with only a small average contribution to the phenotypic variance. This presents a considerable challenge to further dissection of the remaining unexplained genetic variance within populations, which limits our ability to predict disease risk, identify new drug targets, improve and maintain food sources, and understand natural diversity. This challenge will be met within the current framework through larger sample size, better phenotyping including recording of non-genetic risk factors, focused study designs, and an integration of multiple sources of phenotypic and genetic information. The current evidence supports the application of quantitative genetic approaches, and we argue that one should retain simpler theories until simplicity can be traded for greater explanatory power. PMID:24629526

  11. 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.

  12. Unnatural reactive amino acid genetic code additions

    DOEpatents

    Deiters, Alexander; Cropp, Ashton T; Chin, Jason W; Anderson, Christopher J; Schultz, Peter G

    2013-05-21

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  13. Unnatural reactive amino acid genetic code additions

    DOEpatents

    Deiters, Alexander; Cropp, T. Ashton; Chin, Jason W.; Anderson, J. Christopher; Schultz, Peter G.

    2014-08-26

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  14. Unnatural reactive amino acid genetic code additions

    SciTech Connect

    Deiters, Alexander; Cropp, T. Ashton; Chin, Jason W.; Anderson, J. Christopher; Schultz, Peter G.

    2011-02-15

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  15. Unnatural reactive amino acid genetic code additions

    SciTech Connect

    Deiters, Alexander; Cropp, T. Ashton; Chin, Jason W.; Anderson, J. Christopher; Schultz, Peter G.

    2011-08-09

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNAsyn-thetases, pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  16. 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

  17. Genetic Testing for Lung Cancer Risk

    PubMed Central

    Marcy, Theodore W; Stefanek, Michael; Thompson, Kimberly M

    2002-01-01

    Advances in genetics have increased our ability to assess an individual's genetic risk for disease. There is a hypothesis that genetic test results will motivate high-risk individuals to reduce harmful exposures, to increase their surveillance for disease, or to seek preventive treatments. However, genetic testing for genes associated with an increased risk of lung cancer would not change physicians' recommendations regarding smoking cessation. Limited studies suggest that test results that demonstrate an increased risk of lung cancer do not improve smoking cessation success. These test results may even distort an individual's risk perceptions. Before recommending genetic testing to assess risk for disease, physicians need to consider whether knowledge about genetic susceptibility will alter patient management. PMID:12472931

  18. 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

  19. Genetic factors affecting dental caries risk.

    PubMed

    Opal, S; Garg, S; Jain, J; Walia, I

    2015-03-01

    This article reviews the literature on genetic aspects of dental caries and provides a framework for the rapidly changing disease model of caries. The scope is genetic aspects of various dental factors affecting dental caries. The PubMed database was searched for articles with keywords 'caries', 'genetics', 'taste', 'diet' and 'twins'. This was followed by extensive handsearching using reference lists from relevant articles. The post-genomic era will present many opportunities for improvement in oral health care but will also present a multitude of challenges. We can conclude from the literature that genes have a role to play in dental caries; however, both environmental and genetic factors have been implicated in the aetiology of caries. Additional studies will have to be conducted to replicate the findings in a different population. Identification of genetic risk factors will help screen and identify susceptible patients to better understand the contribution of genes in caries aetiopathogenesis. Information derived from these diverse studies will provide new tools to target individuals and/or populations for a more efficient and effective implementation of newer preventive measures and diagnostic and novel therapeutic approaches in the management of this disease.

  20. 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 ...

  1. 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.

  2. Integrating genetics and social science: genetic risk scores.

    PubMed

    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.

  3. 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.

  4. 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. PMID:27630453

  5. Common genetic risk for melanoma encourages preventive behavior change.

    PubMed

    Diseati, Lori; Scheinfeldt, Laura B; Kasper, Rachel S; Zhaoyang, Ruixue; Gharani, Neda; Schmidlen, Tara J; Gordon, Erynn S; Sessions, Cecili K; Delaney, Susan K; Jarvis, Joseph P; Gerry, Norman; Christman, Michael

    2015-01-01

    There is currently great interest in using genetic risk estimates for common disease in personalized healthcare. Here we assess melanoma risk-related preventive behavioral change in the context of the Coriell Personalized Medicine Collaborative (CPMC). As part of on-going reporting activities within the project, participants received a personalized risk assessment including information related to their own self-reported family history of melanoma and a genetic risk variant showing a moderate effect size (1.7, 3.0 respectively for heterozygous and homozygous individuals). Participants who opted to view their report were sent an optional outcome survey assessing risk perception and behavioral change in the months that followed. Participants that report family history risk, genetic risk, or both risk factors for melanoma were significantly more likely to increase skin cancer preventive behaviors when compared to participants with neither risk factor (ORs = 2.04, 2.79, 4.06 and p-values = 0.02, 2.86 × 10-5, 4.67 × 10-5, respectively), and we found the relationship between risk information and behavior to be partially mediated by anxiety. Genomic risk assessments appear to encourage positive behavioral change in a manner that is complementary to family history risk information and therefore may represent a useful addition to standard of care for melanoma prevention. PMID:25695399

  6. 46 CFR 308.104 - Additional war risk insurance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Additional war risk insurance. 308.104 Section 308.104 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Hull and Disbursements Insurance § 308.104 Additional war risk insurance. Owners or charterers...

  7. 46 CFR 308.104 - Additional war risk insurance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 8 2012-10-01 2012-10-01 false Additional war risk insurance. 308.104 Section 308.104 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Hull and Disbursements Insurance § 308.104 Additional war risk insurance. Owners or charterers...

  8. 46 CFR 308.104 - Additional war risk insurance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 8 2011-10-01 2011-10-01 false Additional war risk insurance. 308.104 Section 308.104 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Hull and Disbursements Insurance § 308.104 Additional war risk insurance. Owners or charterers...

  9. 46 CFR 308.104 - Additional war risk insurance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

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  10. 46 CFR 308.104 - Additional war risk insurance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

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  11. Additive and nonadditive genetic variation in avian personality traits.

    PubMed

    van Oers, K; Drent, P J; de Jong, G; van Noordwijk, A J

    2004-11-01

    Individuals of all vertebrate species differ consistently in their reactions to mildly stressful challenges. These typical reactions, described as personalities or coping strategies, have a clear genetic basis, but the structure of their inheritance in natural populations is almost unknown. We carried out a quantitative genetic analysis of two personality traits (exploration and boldness) and the combination of these two traits (early exploratory behaviour). This study was carried out on the lines resulting from a two-directional artificial selection experiment on early exploratory behaviour (EEB) of great tits (Parus major) originating from a wild population. In analyses using the original lines, reciprocal F(1) and reciprocal first backcross generations, additive, dominance, maternal effects ands sex-dependent expression of exploration, boldness and EEB were estimated. Both additive and dominant genetic effects were important determinants of phenotypic variation in exploratory behaviour and boldness. However, no sex-dependent expression was observed in either of these personality traits. These results are discussed with respect to the maintenance of genetic variation in personality traits, and the expected genetic structure of other behavioural and life history traits in general.

  12. 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.

  13. Improving genetic risk prediction by leveraging pleiotropy

    PubMed Central

    Li, Cong; Yang, Can; Gelernter, Joel

    2014-01-01

    An important task of human genetics studies is to predict accurately disease risks in individuals based on genetic markers, which allows for identifying individuals at high disease risks, and facilitating their disease treatment and prevention. Although hundreds of genome-wide association studies (GWAS) have been conducted on many complex human traits in recent years, there has been only limited success in translating these GWAS data into clinically useful risk prediction models. The predictive capability of GWAS data is largely bottlenecked by the available training sample size due to the presence of numerous variants carrying only small to modest effects. Recent studies have shown that different human traits may share common genetic bases. Therefore, an attractive strategy to increase the training sample size and hence improve the prediction accuracy is to integrate data from genetically correlated phenotypes. Yet the utility of genetic correlation in risk prediction has not been explored in the literature. In this paper, we analyzed GWAS data for bipolar and related disorders (BARD) and schizophrenia (SZ) with a bivariate ridge regression method, and found that jointly predicting the two phenotypes could substantially increase prediction accuracy as measured by the AUC (area under the receiver operating characteristic curve). We also found similar prediction accuracy improvements when we jointly analyzed GWAS data for Crohn’s disease (CD) and ulcerative colitis (UC). The empirical observations were substantiated through our comprehensive simulation studies, suggesting that a gain in prediction accuracy can be obtained by combining phenotypes with relatively high genetic correlations. Through both real data and simulation studies, we demonstrated pleiotropy can be leveraged as a valuable asset that opens up a new opportunity to improve genetic risk prediction in the future. PMID:24337655

  14. [Risk assessment of genetically modified organisms].

    PubMed

    Costa, Thadeu Estevam Moreira Maramaldo; Dias, Aline Peçanha Muzy; Scheidegger, Erica Miranda Damasio; Marin, Victor Augustus

    2011-01-01

    Since the commercial approve in 1996, the global area of transgenic crops has raised more than 50 times. In the last two decades, governments have been planning strategies and protocols for safety assessment of food and feed genetically modified (GM). Evaluation of food safety should be taken on a case-by-case analysis depending on the specific traits of the modified crops and the changes introduced by the genetic modification, using for this the concept of substantial equivalence. This work presents approaches for the risk assessment of GM food, as well as some problems related with the genetic construction or even with the expression of the inserted gene.

  15. Multilocus Genetic Risk Scores for Venous Thromboembolism Risk Assessment

    PubMed Central

    Soria, José Manuel; Morange, Pierre‐Emmanuel; Vila, Joan; Souto, Juan Carlos; Moyano, Manel; Trégouët, David‐Alexandre; Mateo, José; Saut, Noémi; Salas, Eduardo; Elosua, Roberto

    2014-01-01

    Background Genetics plays an important role in venous thromboembolism (VTE). Factor V Leiden (FVL or rs6025) and prothrombin gene G20210A (PT or rs1799963) are the genetic variants currently tested for VTE risk assessment. We hypothesized that primary VTE risk assessment can be improved by using genetic risk scores with more genetic markers than just FVL‐rs6025 and prothrombin gene PT‐rs1799963. To this end, we have designed a new genetic risk score called Thrombo inCode (TiC). Methods and Results TiC was evaluated in terms of discrimination (Δ of the area under the receiver operating characteristic curve) and reclassification (integrated discrimination improvement and net reclassification improvement). This evaluation was performed using 2 age‐ and sex‐matched case–control populations: SANTPAU (248 cases, 249 controls) and the Marseille Thrombosis Association study (MARTHA; 477 cases, 477 controls). TiC was compared with other literature‐based genetic risk scores. TiC including F5 rs6025/rs118203906/rs118203905, F2 rs1799963, F12 rs1801020, F13 rs5985, SERPINC1 rs121909548, and SERPINA10 rs2232698 plus the A1 blood group (rs8176719, rs7853989, rs8176743, rs8176750) improved the area under the curve compared with a model based only on F5‐rs6025 and F2‐rs1799963 in SANTPAU (0.677 versus 0.575, P<0.001) and MARTHA (0.605 versus 0.576, P=0.008). TiC showed good integrated discrimination improvement of 5.49 (P<0.001) for SANTPAU and 0.96 (P=0.045) for MARTHA. Among the genetic risk scores evaluated, the proportion of VTE risk variance explained by TiC was the highest. Conclusions We conclude that TiC greatly improves prediction of VTE risk compared with other genetic risk scores. TiC should improve prevention, diagnosis, and treatment of VTE. PMID:25341889

  16. Efficient Improvement of Silage Additives by Using Genetic Algorithms

    PubMed Central

    Davies, Zoe S.; Gilbert, Richard J.; Merry, Roger J.; Kell, Douglas B.; Theodorou, Michael K.; Griffith, Gareth W.

    2000-01-01

    The enormous variety of substances which may be added to forage in order to manipulate and improve the ensilage process presents an empirical, combinatorial optimization problem of great complexity. To investigate the utility of genetic algorithms for designing effective silage additive combinations, a series of small-scale proof of principle silage experiments were performed with fresh ryegrass. Having established that significant biochemical changes occur over an ensilage period as short as 2 days, we performed a series of experiments in which we used 50 silage additive combinations (prepared by using eight bacterial and other additives, each of which was added at six different levels, including zero [i.e., no additive]). The decrease in pH, the increase in lactate concentration, and the free amino acid concentration were measured after 2 days and used to calculate a “fitness” value that indicated the quality of the silage (compared to a control silage made without additives). This analysis also included a “cost” element to account for different total additive levels. In the initial experiment additive levels were selected randomly, but subsequently a genetic algorithm program was used to suggest new additive combinations based on the fitness values determined in the preceding experiments. The result was very efficient selection for silages in which large decreases in pH and high levels of lactate occurred along with low levels of free amino acids. During the series of five experiments, each of which comprised 50 treatments, there was a steady increase in the amount of lactate that accumulated; the best treatment combination was that used in the last experiment, which produced 4.6 times more lactate than the untreated silage. The additive combinations that were found to yield the highest fitness values in the final (fifth) experiment were assessed to determine a range of biochemical and microbiological quality parameters during full-term silage

  17. Common genetic risk factors of venous thromboembolism in Western and Asian populations.

    PubMed

    Huang, S S; Liu, Y; Jing, Z C; Wang, X J; Mao, Y M

    2016-03-04

    Venous thromboembolism (VTE) is a multifactorial disorder involving both acquired and genetic risk factors. The common genetic factors in Western populations have been studied and reported for several decades, while studies on Asian populations are relatively scarce. Evidence suggests that the prevalence and genetic risk factors of VTE vary significantly among ethnic populations. In this review, we summarize the common genetic risk factors of VTE in both Western and Asian populations. In addition to the development of DNA sequencing technology, genome-wide association studies have many advantages and are becoming more important in identifying new genetic risk factors and susceptible loci. They can therefore help in the prediction and prevention of VTE.

  18. Non-additive and Additive Genetic Effects on Extraversion in 3314 Dutch Adolescent Twins and Their Parents

    PubMed Central

    Rebollo-Mesa, Irene; Hudziak, James J.; Willemsen, Gonneke; Boomsma, Dorret I.

    2012-01-01

    The influence of non-additive genetic influences on personality traits has been increasingly reported in adult populations. Less is known, however, with respect to younger samples. In this study, we examine additive and non-additive genetic contributions to the personality trait of extraversion in 1,689 Dutch twin pairs, 1,505 mothers and 1,637 fathers of the twins. The twins were on average 15.5 years (range 12–18 years). To increase statistical power to detect non-additive genetic influences, data on extraversion were also collected in parents and simultaneously analyzed. Genetic modeling procedures incorporating age as a potential modifier of heritability showed significant influences of additive (20–23%) and non-additive genetic factors (31–33%) in addition to unshared environment (46–48%) for adolescents and for their parents. The additive genetic component was slightly and positively related to age. No significant sex differences were found for either extraversion means or for the magnitude of the genetic and environmental influences. There was no evidence of non-random mating for extraversion in the parental generation. Results show that in addition to additive genetic influences, extraversion in adolescents is influenced by non-additive genetic factors. PMID:18240014

  19. Estimating Additive and Non-Additive Genetic Variances and Predicting Genetic Merits Using Genome-Wide Dense Single Nucleotide Polymorphism Markers

    PubMed Central

    Su, Guosheng; Christensen, Ole F.; Ostersen, Tage; Henryon, Mark; Lund, Mogens S.

    2012-01-01

    Non-additive genetic variation is usually ignored when genome-wide markers are used to study the genetic architecture and genomic prediction of complex traits in human, wild life, model organisms or farm animals. However, non-additive genetic effects may have an important contribution to total genetic variation of complex traits. This study presented a genomic BLUP model including additive and non-additive genetic effects, in which additive and non-additive genetic relation matrices were constructed from information of genome-wide dense single nucleotide polymorphism (SNP) markers. In addition, this study for the first time proposed a method to construct dominance relationship matrix using SNP markers and demonstrated it in detail. The proposed model was implemented to investigate the amounts of additive genetic, dominance and epistatic variations, and assessed the accuracy and unbiasedness of genomic predictions for daily gain in pigs. In the analysis of daily gain, four linear models were used: 1) a simple additive genetic model (MA), 2) a model including both additive and additive by additive epistatic genetic effects (MAE), 3) a model including both additive and dominance genetic effects (MAD), and 4) a full model including all three genetic components (MAED). Estimates of narrow-sense heritability were 0.397, 0.373, 0.379 and 0.357 for models MA, MAE, MAD and MAED, respectively. Estimated dominance variance and additive by additive epistatic variance accounted for 5.6% and 9.5% of the total phenotypic variance, respectively. Based on model MAED, the estimate of broad-sense heritability was 0.506. Reliabilities of genomic predicted breeding values for the animals without performance records were 28.5%, 28.8%, 29.2% and 29.5% for models MA, MAE, MAD and MAED, respectively. In addition, models including non-additive genetic effects improved unbiasedness of genomic predictions. PMID:23028912

  20. The ecological risks of genetically engineered organisms

    NASA Astrophysics Data System (ADS)

    Wolfenbarger, Lareesa

    2001-03-01

    Highly publicized studies have suggested environmental risks of releasing genetically engineered organisms (GEOs) and have renewed concerns over the evaluation and regulation of these products in domestic and international arenas. I present an overview of the risks of GEOs and the available evidence addressing these and discuss the challenges for risk assessment. Main categories of risk include non-target effects from GEOs, emergence of new viral diseases, and the spread of invasive (weedy) characteristics. Studies have detected non-target effects in some cases but not all; however, much less information exists on other risks, in part due to a lack of conceptual knowledge. For example, general models for predicting invasiveness are not well developed for any introduced organism. The risks of GEOs appear comparable to those for any introduced species or organism, but the magnitude of the risk or the pathway of exposure to the risk can differ among introduced organisms. Therefore, assessing the risks requires a case-by-case analysis so that any differences can be identified. Challenges to assessing risks to valued ecosystems include variability in effects and ecosystem complexity. Ecosystems are a dynamic and complex network of biological and physical interactions. Introducing a new biological entity, such as a GEO, may potentially alter any of these interactions, but evaluating all of these is unrealistic. Effects on a valued ecosystem could vary greatly depending on the geographical location of the experimental site, the GEO used, the plot size of the experiment (scaling effects), and the biological and physical parameters used in the experiment. Experiments that address these sources of variability will provide the most useful information for risk assessments.

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

    PubMed

    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

  2. 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

  3. Chemical Mixture Risk Assessment Additivity-Based Approaches

    EPA Science Inventory

    Powerpoint presentation includes additivity-based chemical mixture risk assessment methods. Basic concepts, theory and example calculations are included. Several slides discuss the use of "common adverse outcomes" in analyzing phthalate mixtures.

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

    PubMed

    Cole, Christopher B; Nikpay, Majid; Stewart, Alexandre F R; McPherson, Ruth

    2016-04-01

    There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this question in a population of 5831 early onset CAD cases without diabetes mellitus and 3832 elderly healthy control subjects, all of strictly European ancestry, with adjustment for traditional risk factors (TRFs). We then estimated the genetic correlation between these BMI and CAD (rg) by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between these two traits. GRSBMI significantly (P=2.12 × 10(-12)) associated with CAD status in a multivariate model adjusted for TRFs, with a per allele odds ratio (OR) of 1.06 (95% CI 1.042-1.076). The addition of GRSBMI to TRFs explained 0.75% of CAD variance and yielded a continuous net recombination index of 16.54% (95% CI=11.82-21.26%, P<0.0001). To test whether GRSBMI explained CAD status when adjusted for measured BMI, separate models were constructed in which the score and BMI were either included as covariates or not. The addition of BMI explained ~1.9% of CAD variance and GRSBMI plus BMI explained 2.65% of CAD variance. Finally, using bivariate restricted maximum likelihood analysis, we provide strong evidence of genome-wide pleiotropy between obesity and CAD. This analysis supports the hypothesis that obesity is a causal risk factor for CAD. PMID:26220701

  5. 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

  6. Genetic risk factors for type 1 diabetes.

    PubMed

    Pociot, Flemming; Lernmark, Åke

    2016-06-01

    Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean that the β-cell autoantibodies are pathogenic, but rather that they represent reproducible biomarkers of the pathogenesis. The primary risk factor for β-cell autoimmunity is genetic, mainly occurring in individuals with either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both, but a trigger from the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis. PMID:27302272

  7. 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

  8. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

    PubMed Central

    Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

    2014-01-01

    Background The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD. PMID:23704318

  9. 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 ( ...

  10. SATIETY MECHANISMS IN GENETIC RISK OF OBESITY

    PubMed Central

    van Jaarsveld, Cornelia Hendrika Maria; Plomin, Robert; Wardle, Jane

    2014-01-01

    IMPORTANCE A better understanding of the etiology of obesity is a clinical priority. Obesity is highly heritable and specific genes are being identified. Discovering the mechanisms through which obesity-related genes influence weight would help pinpoint novel targets for intervention. One potential mechanism is satiety responsiveness. Lack of satiety characterizes many monogenic obesity disorders, and lower satiety responsiveness is linked with weight gain in population samples. OBJECTIVE We tested the hypothesis that satiety responsiveness is an intermediate behavioral phenotype associated with genetic predisposition to obesity in children. DESIGN Cross-sectional observational study. SETTING Population-based cohort of twins born 1994–1996 (Twins Early Development Study). PARTICIPANTS 2258 unrelated children (53% female; mean age: 9.9 years, SD: 0.84); one randomly selected from each twin pair. EXPOSURE Genetic predisposition to obesity. We created a polygenic risk score (PRS) comprising 28 common obesity-related single nucleotide polymorphisms identified in a meta-analysis of obesity-related genome-wide association studies. MAIN OUTCOMES AND MEASURES Satiety responsiveness was indexed with a standard psychometric scale (the Child Eating Behavior Questionnaire). BMI standard deviation scores (BMI-SDS) and waist-SDS, using 1990 UK reference data, were calculated from parent-reported anthropometric data for the child. Information on satiety responsiveness, anthropometrics and genotype were available for 2258 children. We examined associations between the PRS, adiposity and satiety responsiveness. RESULTS The PRS was negatively related to satiety responsiveness (beta, −0.060; 95% CI, −0.019 to −0.101), and positively related to adiposity (BMI-SDS: beta, 0.177; 95% CI, 0.136 to 0.218; waist-SDS: beta, 0.167; 95% CI, 0.126 to 0.208), and more children in the top 25% of the PRS were overweight than in the lowest 25% (18.5% versus 7.2%, respectively; OR, 2.90; 95

  11. Multiple Metabolic Genetic Risk Scores and Type 2 Diabetes Risk in Three Racial/Ethnic Groups

    PubMed Central

    Wineinger, Nathan E.; Vazquez, Ana I.; de los Campos, Gustavo

    2014-01-01

    Context/Rationale: Meta-analyses of genome-wide association studies have identified many single-nucleotide polymorphisms associated with various metabolic and cardiovascular traits, offering us the opportunity to learn about and capitalize on the links between cardiometabolic traits and type 2 diabetes (T2D). Design: In multiple datasets comprising over 30 000 individuals and 3 ethnic/racial groups, we calculated 17 genetic risk scores (GRSs) for glycemic, anthropometric, lipid, hemodynamic, and other traits, based on the results of recent trait-specific meta-analyses of genome-wide association studies, and examined associations with T2D risk. Using a training-testing procedure, we evaluated whether additional GRSs could contribute to risk prediction. Results: In European Americans, we find that GRSs for T2D, fasting glucose, fasting insulin, and body mass index are associated with T2D risk. In African Americans, GRSs for T2D, fasting insulin, and waist-to-hip ratio are associated with T2D. In Hispanic Americans, GRSs for T2D and body mass index are associated with T2D. We observed a trend among European Americans suggesting that genetic risk for hyperlipidemia is inversely associated with T2D risk. The use of additional GRSs resulted in only small changes in prediction accuracy in multiple independent validation datasets. Conclusions: The analysis of multiple GRSs can shed light on T2D etiology and how it varies across ethnic/racial groups. Our findings using multiple GRSs are consistent with what is known about the differences in T2D pathogenesis across racial/ethnic groups. However, further work is needed to understand the putative inverse correlation of genetic risk for hyperlipidemia and T2D risk and to develop ethnic-specific GRSs. PMID:24905067

  12. Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study.

    PubMed

    Greenwood, Tiffany A; Lazzeroni, Laura C; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Light, Gregory A; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

    2016-01-01

    The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. PMID:26597662

  13. Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study.

    PubMed

    Greenwood, Tiffany A; Lazzeroni, Laura C; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Light, Gregory A; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

    2016-01-01

    The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.

  14. A new explained-variance based genetic risk score for predictive modeling of disease risk.

    PubMed

    Che, Ronglin; Motsinger-Reif, Alison A

    2012-09-25

    The goal of association mapping is to identify genetic variants that predict disease, and as the field of human genetics matures, the number of successful association studies is increasing. Many such studies have shown that for many diseases, risk is explained by a reasonably large number of variants that each explains a very small amount of disease risk. This is prompting the use of genetic risk scores in building predictive models, where information across several variants is combined for predictive modeling. In the current study, we compare the performance of four previously proposed genetic risk score methods and present a new method for constructing genetic risk score that incorporates explained variance information. The methods compared include: a simple count Genetic Risk Score, an odds ratio weighted Genetic Risk Score, a direct logistic regression Genetic Risk Score, a polygenic Genetic Risk Score, and the new explained variance weighted Genetic Risk Score. We compare the methods using a wide range of simulations in two steps, with a range of the number of deleterious single nucleotide polymorphisms (SNPs) explaining disease risk, genetic modes, baseline penetrances, sample sizes, relative risks (RR) and minor allele frequencies (MAF). Several measures of model performance were compared including overall power, C-statistic and Akaike's Information Criterion. Our results show the relative performance of methods differs significantly, with the new explained variance weighted GRS (EV-GRS) generally performing favorably to the other methods.

  15. 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.

  16. 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?

  17. Inherited genetic variants associated with childhood acute lymphoblastic leukemia risk.

    PubMed

    Takagi, Masatoshi; Urayama, Kevin

    2016-07-01

    Numerous efforts have been made to elucidate the roles of individual genetic background factors in the risk of childhood acute lymphoblastic leukemia. Most have taken the form of case-control studies focusing on specific candidate gene polymorphisms. Recently, a more rigorous and comprehensive approach referred to as a genome-wide association study (GWAS) has been widely utilized and has achieved success. Case-control studies evaluating candidate gene associations have shown cumulative evidence of a role for folate metabolism and xenobiotic metabolism/transport pathway genetic variants. In addition, single nucleotide polymorphism (SNP)s identified by GWAS appear to indicate a strong role for genes encoding transcription factors involved in cellular differentiation. Further studies are needed to clarify the accumulating evidence obtained from both candidate gene and genome-wide investigations. PMID:27498736

  18. 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

  19. 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

  20. A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.

    PubMed

    Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

    2015-01-01

    Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance

  1. A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana

    PubMed Central

    Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

    2015-01-01

    Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance

  2. 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

  3. GENETICS AND POPULATION-LEVEL RISK ASSESSMENT

    EPA Science Inventory

    Genetic variation defines population structure and provides the mechanism for populations to adapt to novel stressors. Despite its fundamental importance in understanding populations, genetic information has been included rarely in models of population dynamics (endangered speci...

  4. Arranging marriage; negotiating risk: genetics and society in Qatar.

    PubMed

    Kilshaw, Susie; Al Raisi, Tasneem; Alshaban, Fouad

    2015-01-01

    This paper considers how the globalized discourse of genetic risk in cousin marriage is shaped, informed and taken up in local moral worlds within the context of Qatar. This paper investigates the way Qataris are negotiating the discourse on genetics and risk. It is based on data from ongoing ethnographic research in Qatar and contributes to anthropological knowledge about this understudied country. Participants were ambivalent about genetic risks and often pointed to other theories of causation in relation to illness and disability. The discourse on genetic risk associated with marrying in the family was familiar, but for some participants the benefits of close marriage outweighed potential risks. Furthermore, the introduction of mandatory pre-marital screening gave participants confidence that risks were monitored and minimized.

  5. Risk analysis of sulfites used as food additives in China.

    PubMed

    Zhang, Jian Bo; Zhang, Hong; Wang, Hua Li; Zhang, Ji Yue; Luo, Peng Jie; Zhu, Lei; Wang, Zhu Tian

    2014-02-01

    This study was to analyze the risk of sulfites in food consumed by the Chinese people and assess the health protection capability of maximum-permitted level (MPL) of sulfites in GB 2760-2011. Sulfites as food additives are overused or abused in many food categories. When the MPL in GB 2760-2011 was used as sulfites content in food, the intake of sulfites in most surveyed populations was lower than the acceptable daily intake (ADI). Excess intake of sulfites was found in all the surveyed groups when a high percentile of sulfites in food was in taken. Moreover, children aged 1-6 years are at a high risk to intake excess sulfites. The primary cause for the excess intake of sulfites in Chinese people is the overuse and abuse of sulfites by the food industry. The current MPL of sulfites in GB 2760-2011 protects the health of most populations.

  6. Behavioral risk factors among women presenting for genetic testing.

    PubMed

    Emmons, K M; Kalkbrenner, K J; Klar, N; Light, T; Schneider, K A; Garber, J E

    2000-01-01

    Considerable research attention has been given to the impact of genetic testing on psychological outcomes. Participation in genetic testing also may impact on health behaviors that increase the risk of cancer and other chronic diseases. The purpose of this study is to describe behavioral cancer risk factors of women who requested genetic testing for breast and ovarian cancer susceptibility (BRCA1, BRCA2). Before participation in a genetic testing program, 119 women completed a series of questionnaires designed to assess their health behaviors, perception of risk, and depressive symptomatology. Eight percent of participants were current smokers, 27% did not engage in at least moderate exercise, 46% did not regularly protect themselves from the sun, 39% did not consume at least five servings of fruits and vegetables per day, and 9% drank at least one alcoholic beverage per day. Poisson regression analysis revealed that age was the only predictor of behavioral risk profiles, with older women having fewer cancer risk behaviors. These patients who presented for genetic testing generally had better health behaviors than the general population. However, given their possible high-risk status, these patients should consider further improving their preventable cancer risk factors and, in particular, their diet, sun protection, and physical activity levels. Inclusion of behavioral risk factor counseling in the context of the genetic testing process may be an important opportunity to reach this at-risk population.

  7. 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)

  8. Genetic cancer risk assessment. Putting it all together.

    PubMed

    Weitzel, J N

    1999-12-01

    Dramatic advances in our understanding of the genetic basis for cancer have led to the development of new technologies and tools for genetic cancer risk assessment. Yet, cancer is a complex disorder, and risk assessment, counseling, and management strategies need to consider several important domains: state of cancer genetics knowledge, state of mind (previous cancer experience within the family), state of technology, and state of the art in terms of management. There are several barriers to the efficient identification and counseling of patients and families at high risk for cancer because of inherited susceptibility mutations. Chief among these concerns is the lack of access to competent counseling and education services that are equipped to handle the complex and rapidly evolving medical, technological, and ethical issues. Cancer risk assessment is developing into a distinct discipline in which established empiric risk models are recast along with rapidly evolving genetic technologies for estimation of individual cancer risk. Cancer genetics consultants are an important resource for primary care physicians, gynecologists, surgeons, and oncologists. However, no formal qualification criteria exist for either physicians or allied health care professionals who subspecialize in this new field. This article covers the unique domains of cancer genetics in health care and surveys models for delivery of cancer genetics services and tools for risk assessment. Coupled with innovative cancer diagnostic and preventive services and research, we have the potential to make great strides in cancer prevention and control.

  9. 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.

  10. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  11. 26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... increased risk for breast cancer, including individuals with BRCA1 or BRCA2 gene mutations. B is 33 years... reimbursement. Following an established policy, the plan asks B for evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for...

  12. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  13. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  14. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  15. 26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... increased risk for breast cancer, including individuals with BRCA1 or BRCA2 gene mutations. B is 33 years... reimbursement. Following an established policy, the plan asks B for evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for...

  16. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  17. 26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... increased risk for breast cancer, including individuals with BRCA1 or BRCA2 gene mutations. B is 33 years... reimbursement. Following an established policy, the plan asks B for evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for...

  18. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  19. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  20. 26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... increased risk for breast cancer, including individuals with BRCA1 or BRCA2 gene mutations. B is 33 years... reimbursement. Following an established policy, the plan asks B for evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for...

  1. 26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... increased risk for breast cancer, including individuals with BRCA1 or BRCA2 gene mutations. B is 33 years... reimbursement. Following an established policy, the plan asks B for evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for...

  2. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  3. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  4. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 40, or at age 30 for those with increased risk for breast cancer, including individuals with BRCA1 or... evidence of increased risk of breast cancer, such as the results of a genetic test or a family history of breast cancer, before the claim for the mammogram is paid. This policy is applied uniformly to...

  5. Additive and non-additive genetic components of the jack male life history in Chinook salmon (Oncorhynchus tshawytscha).

    PubMed

    Forest, Adriana R; Semeniuk, Christina A D; Heath, Daniel D; Pitcher, Trevor E

    2016-08-01

    Chinook salmon, Oncorhynchus tshawytscha, exhibit alternative reproductive tactics (ARTs) where males exist in two phenotypes: large "hooknose" males and smaller "jacks" that reach sexual maturity after only 1 year in seawater. The mechanisms that determine "jacking rate"-the rate at which males precociously sexually mature-are known to involve both genetics and differential growth rates, where individuals that become jacks exhibit higher growth earlier in life. The additive genetic components have been studied and it is known that jack sires produce significantly more jack offspring than hooknose sires, and vice versa. The current study was the first to investigate both additive and non-additive genetic components underlying jacking through the use of a full-factorial breeding design using all hooknose sires. The effect of dams and sires descendant from a marker-assisted broodstock program that identified "high performance" and "low performance" lines using growth- and survival-related gene markers was also studied. Finally, the relative growth of jack, hooknose, and female offspring was examined. No significant dam, sire, or interaction effects were observed in this study, and the maternal, additive, and non-additive components underlying jacking were small. Differences in jacking rates in this study were determined by dam performance line, where dams that originated from the low performance line produced significantly more jacks. Jack offspring in this study had a significantly larger body size than both hooknose males and females starting 1 year post-fertilization. This study provides novel information regarding the genetic architecture underlying ARTs in Chinook salmon that could have implications for the aquaculture industry, where jacks are not favoured due to their small body size and poor flesh quality. PMID:27450674

  6. Additive and non-additive genetic components of the jack male life history in Chinook salmon (Oncorhynchus tshawytscha).

    PubMed

    Forest, Adriana R; Semeniuk, Christina A D; Heath, Daniel D; Pitcher, Trevor E

    2016-08-01

    Chinook salmon, Oncorhynchus tshawytscha, exhibit alternative reproductive tactics (ARTs) where males exist in two phenotypes: large "hooknose" males and smaller "jacks" that reach sexual maturity after only 1 year in seawater. The mechanisms that determine "jacking rate"-the rate at which males precociously sexually mature-are known to involve both genetics and differential growth rates, where individuals that become jacks exhibit higher growth earlier in life. The additive genetic components have been studied and it is known that jack sires produce significantly more jack offspring than hooknose sires, and vice versa. The current study was the first to investigate both additive and non-additive genetic components underlying jacking through the use of a full-factorial breeding design using all hooknose sires. The effect of dams and sires descendant from a marker-assisted broodstock program that identified "high performance" and "low performance" lines using growth- and survival-related gene markers was also studied. Finally, the relative growth of jack, hooknose, and female offspring was examined. No significant dam, sire, or interaction effects were observed in this study, and the maternal, additive, and non-additive components underlying jacking were small. Differences in jacking rates in this study were determined by dam performance line, where dams that originated from the low performance line produced significantly more jacks. Jack offspring in this study had a significantly larger body size than both hooknose males and females starting 1 year post-fertilization. This study provides novel information regarding the genetic architecture underlying ARTs in Chinook salmon that could have implications for the aquaculture industry, where jacks are not favoured due to their small body size and poor flesh quality.

  7. Breast cancer risk assessment across the risk continuum: genetic and nongenetic risk factors contributing to differential model performance

    PubMed Central

    2012-01-01

    (AUC = 63.2%, CI = 57.6% to 68.9%). In almost all covariate-specific subgroups, BCRAT mean risks were significantly lower than the observed risks, while IBIS risks showed generally good agreement with observed risks, even in the subgroups of women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative). Conclusions Models developed using extended family history and genetic data, such as the IBIS model, also perform well in women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative). Extending such models to include additional nongenetic information may improve performance in women across the breast cancer risk continuum. PMID:23127309

  8. 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

  9. 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...

  10. The Evolution of Human Intelligence and the Coefficient of Additive Genetic Variance in Human Brain Size

    ERIC Educational Resources Information Center

    Miller, Geoffrey F.; Penke, Lars

    2007-01-01

    Most theories of human mental evolution assume that selection favored higher intelligence and larger brains, which should have reduced genetic variance in both. However, adult human intelligence remains highly heritable, and is genetically correlated with brain size. This conflict might be resolved by estimating the coefficient of additive genetic…

  11. Additional risk of end-of-the-pipe geoengineering technologies

    NASA Astrophysics Data System (ADS)

    Bohle, Martin

    2014-05-01

    qualitatively from the known successes. They do not tackle the initial cause, namely the carbon-dioxide inputs that are too high. This is their additional specific risk. 'The acceptability of geoengineering will be determined as much by social, legal and political issues as by scientific and technical factors', conclude Adam Corner and Nick Pidgeon (2010) when reviewing social and ethical implications of geoengineering the climate. It is to debate in that context that most geoengineering technologies are 'end of the pipe technologies', what involves an additional specific risk. Should these technologies be part of the toolbox to tackle anthropogenic climate change? Adam Corner and Nick Pidgeon 2010, Geoengineering the climate: The social and ethical implications, Environment Vol. 52.

  12. Applying personal genetic data to injury risk assessment in athletes.

    PubMed

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

    2014-01-01

    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.

  13. 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

  14. Genetic risk factors associated with respiratory distress syndrome.

    PubMed

    Jo, Heui Seung

    2014-04-01

    Respiratory distress syndrome (RDS) among preterm infants is typically due to a quantitative deficiency of pulmonary surfactant. Aside from the degree of prematurity, diverse environmental and genetic factors can affect the development of RDS. The variance of the risk of RDS in various races/ethnicities or monozygotic/dizygotic twins has suggested genetic influences on this disorder. So far, several specific mutations in genes encoding surfactant-associated molecules have confirmed this. Specific genetic variants contributing to the regulation of pulmonary development, its structure and function, or the inflammatory response could be candidate risk factors for the development of RDS. This review summarizes the background that suggests the genetic predisposition of RDS, the identified mutations, and candidate genetic polymorphisms of pulmonary surfactant proteins associated with RDS.

  15. Epistasis Is a Major Determinant of the Additive Genetic Variance in Mimulus guttatus

    PubMed Central

    Monnahan, Patrick J.; Kelly, John K.

    2015-01-01

    The influence of genetic interactions (epistasis) on the genetic variance of quantitative traits is a major unresolved problem relevant to medical, agricultural, and evolutionary genetics. The additive genetic component is typically a high proportion of the total genetic variance in quantitative traits, despite that underlying genes must interact to determine phenotype. This study estimates direct and interaction effects for 11 pairs of Quantitative Trait Loci (QTLs) affecting floral traits within a single population of Mimulus guttatus. With estimates of all 9 genotypes for each QTL pair, we are able to map from QTL effects to variance components as a function of population allele frequencies, and thus predict changes in variance components as allele frequencies change. This mapping requires an analytical framework that properly accounts for bias introduced by estimation errors. We find that even with abundant interactions between QTLs, most of the genetic variance is likely to be additive. However, the strong dependency of allelic average effects on genetic background implies that epistasis is a major determinant of the additive genetic variance, and thus, the population’s ability to respond to selection. PMID:25946702

  16. Additive composite ABCG2, SLC2A9 and SLC22A12 scores of high-risk alleles with alcohol use modulate gout risk.

    PubMed

    Tu, Hung-Pin; Chung, Chia-Min; Min-Shan Ko, Albert; Lee, Su-Shin; Lai, Han-Ming; Lee, Chien-Hung; Huang, Chung-Ming; Liu, Chiu-Shong; Ko, Ying-Chin

    2016-09-01

    The aim of the present study was to evaluate the contribution of urate transporter genes and alcohol use to the risk of gout/tophi. Eight variants of ABCG2, SLC2A9, SLC22A12, SLC22A11 and SLC17A3 were genotyped in male individuals in a case-control study with 157 gout (33% tophi), 106 asymptomatic hyperuricaemia and 295 control subjects from Taiwan. The multilocus profiles of the genetic risk scores for urate gene variants were used to evaluate the risk of asymptomatic hyperuricaemia, gout and tophi. ABCG2 Q141K (T), SLC2A9 rs1014290 (A) and SLC22A12 rs475688 (C) under an additive model and alcohol use independently predicted the risk of gout (respective odds ratio for each factor=2.48, 2.03, 1.95 and 2.48). The additive composite Q141K, rs1014290 and rs475688 scores of high-risk alleles were associated with gout risk (P<0.0001). We observed the supramultiplicative interaction effect of genetic urate scores and alcohol use on gout and tophi risk (P for interaction=0.0452, 0.0033). The synergistic effect of genetic urate score 5-6 and alcohol use indicates that these combined factors correlate with gout and tophi occurrence.

  17. 46 CFR 308.204 - Additional war risk protection and indemnity insurance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Additional war risk protection and indemnity insurance... OPERATIONS WAR RISK INSURANCE War Risk Protection and Indemnity Insurance § 308.204 Additional war risk protection and indemnity insurance. Owners or charterers may obtain, on an excess basis, additional war...

  18. 46 CFR 308.204 - Additional war risk protection and indemnity insurance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 8 2014-10-01 2014-10-01 false Additional war risk protection and indemnity insurance... OPERATIONS WAR RISK INSURANCE War Risk Protection and Indemnity Insurance § 308.204 Additional war risk protection and indemnity insurance. Owners or charterers may obtain, on an excess basis, additional war...

  19. 46 CFR 308.204 - Additional war risk protection and indemnity insurance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 8 2011-10-01 2011-10-01 false Additional war risk protection and indemnity insurance... OPERATIONS WAR RISK INSURANCE War Risk Protection and Indemnity Insurance § 308.204 Additional war risk protection and indemnity insurance. Owners or charterers may obtain, on an excess basis, additional war...

  20. 46 CFR 308.204 - Additional war risk protection and indemnity insurance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 8 2012-10-01 2012-10-01 false Additional war risk protection and indemnity insurance... OPERATIONS WAR RISK INSURANCE War Risk Protection and Indemnity Insurance § 308.204 Additional war risk protection and indemnity insurance. Owners or charterers may obtain, on an excess basis, additional war...

  1. 46 CFR 308.204 - Additional war risk protection and indemnity insurance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 8 2013-10-01 2013-10-01 false Additional war risk protection and indemnity insurance... OPERATIONS WAR RISK INSURANCE War Risk Protection and Indemnity Insurance § 308.204 Additional war risk protection and indemnity insurance. Owners or charterers may obtain, on an excess basis, additional war...

  2. [Genetic risk factors for rheumatoid arthritis].

    PubMed

    Ikari, Katsunori

    2016-06-01

    Rheumatoid arthritis (RA), the most common autoimmune diseases, is a systemic, chronic inflammatory disease, which is primarily involves the joints affecting up to 1% of the population. RA is believed to be a complex, multifarious disease that is influenced by both genetic and environmental factors. Disease susceptibility has been estimated to have a genetic component of 60% by data from twin studies. To date, more than 100 RA susceptibility loci, including HLA-DRB1, have been identified by genome-wide association studies (GWAS) and GWAS meta-analyses. Through a big data approach using large amounts of comprehensive biologic data included GWAS, we identified important information, such as susceptible genes, pathways and cell types that contribute to RA pathogenesis. PMID:27311175

  3. 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.

  4. [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.

  5. Imaging-Genetics in Dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments

    PubMed Central

    Eicher, John D.; Gruen, Jeffrey R.

    2013-01-01

    Dyslexia is a common pediatric disorder that affects 5-17% of schoolchildren in the United States. It is marked by unexpected difficulties in fluent reading despite adequate intelligence, opportunity, and instruction. Classically, neuropsychologists have studied dyslexia using a variety of neurocognitive batteries to gain insight into the specific deficits and impairments in affected children. Since dyslexia is a complex genetic trait with high heritability, analyses conditioned on performance on these neurocognitive batteries have been used to try to identify associated genes. This has led to some successes in identifying contributing genes, although much of the heritability remains unexplained. Additionally, the lack of relevant human brain tissue for analysis and the challenges of modeling a uniquely human trait in animals are barriers to advancing our knowledge of the underlying pathophysiology. In vivo imaging technologies, however, present new opportunities to examine dyslexia and reading skills in a clearly relevant context in human subjects. Recent investigations have started to integrate these imaging data with genetic data in attempts to gain a more complete and complex understanding of reading processes. In addition to bridging the gap from genetic risk variant to a discernible neuroimaging phenotype and ultimately to the clinical impairments in reading performance, the use of neuroimaging phenotypes will reveal novel risk genes and variants. In this article, we briefly discuss the genetic and imaging investigations and take an in-depth look at the recent imaging-genetics investigations of dyslexia. PMID:23916419

  6. Parametric and Nonparametric Statistical Methods for Genomic Selection of Traits with Additive and Epistatic Genetic Architectures

    PubMed Central

    Howard, Réka; Carriquiry, Alicia L.; Beavis, William D.

    2014-01-01

    Parametric and nonparametric methods have been developed for purposes of predicting phenotypes. These methods are based on retrospective analyses of empirical data consisting of genotypic and phenotypic scores. Recent reports have indicated that parametric methods are unable to predict phenotypes of traits with known epistatic genetic architectures. Herein, we review parametric methods including least squares regression, ridge regression, Bayesian ridge regression, least absolute shrinkage and selection operator (LASSO), Bayesian LASSO, best linear unbiased prediction (BLUP), Bayes A, Bayes B, Bayes C, and Bayes Cπ. We also review nonparametric methods including Nadaraya-Watson estimator, reproducing kernel Hilbert space, support vector machine regression, and neural networks. We assess the relative merits of these 14 methods in terms of accuracy and mean squared error (MSE) using simulated genetic architectures consisting of completely additive or two-way epistatic interactions in an F2 population derived from crosses of inbred lines. Each simulated genetic architecture explained either 30% or 70% of the phenotypic variability. The greatest impact on estimates of accuracy and MSE was due to genetic architecture. Parametric methods were unable to predict phenotypic values when the underlying genetic architecture was based entirely on epistasis. Parametric methods were slightly better than nonparametric methods for additive genetic architectures. Distinctions among parametric methods for additive genetic architectures were incremental. Heritability, i.e., proportion of phenotypic variability, had the second greatest impact on estimates of accuracy and MSE. PMID:24727289

  7. Estimation of Additive, Dominance, and Imprinting Genetic Variance Using Genomic Data

    PubMed Central

    Lopes, Marcos S.; Bastiaansen, John W. M.; Janss, Luc; Knol, Egbert F.; Bovenhuis, Henk

    2015-01-01

    Traditionally, exploration of genetic variance in humans, plants, and livestock species has been limited mostly to the use of additive effects estimated using pedigree data. However, with the development of dense panels of single-nucleotide polymorphisms (SNPs), the exploration of genetic variation of complex traits is moving from quantifying the resemblance between family members to the dissection of genetic variation at individual loci. With SNPs, we were able to quantify the contribution of additive, dominance, and imprinting variance to the total genetic variance by using a SNP regression method. The method was validated in simulated data and applied to three traits (number of teats, backfat, and lifetime daily gain) in three purebred pig populations. In simulated data, the estimates of additive, dominance, and imprinting variance were very close to the simulated values. In real data, dominance effects account for a substantial proportion of the total genetic variance (up to 44%) for these traits in these populations. The contribution of imprinting to the total phenotypic variance of the evaluated traits was relatively small (1–3%). Our results indicate a strong relationship between additive variance explained per chromosome and chromosome length, which has been described previously for other traits in other species. We also show that a similar linear relationship exists for dominance and imprinting variance. These novel results improve our understanding of the genetic architecture of the evaluated traits and shows promise to apply the SNP regression method to other traits and species, including human diseases. PMID:26438289

  8. The contribution of additive genetic variation to personality variation: heritability of personality.

    PubMed

    Dochtermann, Ned A; Schwab, Tori; Sih, Andrew

    2015-01-01

    Individual animals frequently exhibit repeatable differences from other members of their population, differences now commonly referred to as 'animal personality'. Personality differences can arise, for example, from differences in permanent environmental effects--including parental and epigenetic contributors--and the effect of additive genetic variation. Although several studies have evaluated the heritability of behaviour, less is known about general patterns of heritability and additive genetic variation in animal personality. As overall variation in behaviour includes both the among-individual differences that reflect different personalities and temporary environmental effects, it is possible for personality to be largely genetically influenced even when heritability of behaviour per se is quite low. The relative contribution of additive genetic variation to personality variation can be estimated whenever both repeatability and heritability are estimated for the same data. Using published estimates to address this issue, we found that approximately 52% of animal personality variation was attributable to additive genetic variation. Thus, while the heritability of behaviour is often moderate or low, the heritability of personality is much higher. Our results therefore (i) demonstrate that genetic differences are likely to be a major contributor to variation in animal personality and (ii) support the phenotypic gambit: that evolutionary inferences drawn from repeatability estimates may often be justified.

  9. 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

  10. Living with Genetic Risk: Effect on Adolescent Self-Concept

    PubMed Central

    McConkie-Rosell, Allyn; Spiridigliozzi, Gail A.; Melvin, Elizabeth; Dawson, Deborah V.; Lachiewicz, Ave M.

    2009-01-01

    The purpose of this study is to describe the interplay of adolescent girls’ self-concept, coping behaviors, and adjustment associated with knowledge of genetic risk for fragile X syndrome. We will report here findings on self concept. Using a multi-group cross-sectional design this study focused on girls ages 14–25 years from families previously diagnosed with fragile X syndrome, who knew they were 1) carriers (n = 20; mean age 18.35 years s.d. 2.5), or 2) noncarriers (n =18; mean age 17.78 years s.d. 2.69), or 3) at-risk to be carriers (n = 15; mean age 17.87 s.d. 3.18). The girls completed the Tennessee Self Concept Scale (TSCS:2), a visual analog scale, and a guided interview. Total and all subscale scores on the TSCS:2 were in the normal range for all three groups. However, threats to self concept were found in personal self (physical self, genetic identity, and parental role), social self, and family self (family genetic identity) as they specifically related to the meaning of genetic information and varied based on risk status. Our findings suggest that risk information itself is threatening and for some girls, may be as threatening as learning one is a carrier. Certainty related to genetic risk status appears to make a positive difference for some girls by allowing them the opportunity to face the challenge of their genetic risk status and to begin to consider the meaning of this information. PMID:18200514

  11. 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.

  12. Hazard identification and risk assessment procedure for genetically modified plants in the field--GMHAZID.

    PubMed

    Koivisto, Raija A; Törmäkangas, Kirsi M; Kauppinen, Veli S

    2002-01-01

    The safe application of genetically modified organisms (GMOs) requires a risk assessment prior to their proposed use. Based on methods from the chemical industry, we developed a hazard identification procedure for the risk assessment of field tests with genetically modified plants. This risk assessment method, GMHAZID, is carried out in the form of guided brainstorm sessions. GMHAZID was tested with a case study for which a risk assessment had previously been made, and the results of the assessments were compared. The results showed that some new hazards potentially leading to uncontrolled spreading, in addition to those from the previous assessment, were identified using GMHAZID. GMHAZID also recognised some hazards leading to failures in the field experiments. We suggest that GMHAZID provides systematics, reliability, and transparency to the risk assessment procedure.

  13. Additive and nonadditive genetic variances for milk yield, fertility, and lifetime performance traits of dairy cattle.

    PubMed

    Fuerst, C; Sölkner, J

    1994-04-01

    Additive and nonadditive genetic variances were estimated for yield traits and fertility for three subsequent lactations and for lifetime performance traits of purebred and crossbred dairy cattle populations. Traits were milk yield, energy-corrected milk yield, fat percentage, protein percentage, calving interval, length of productive life, and lifetime FCM of purebred Simmental, Simmental including crossbreds, and Braunvieh crossed with Brown Swiss. Data files ranged from 66,740 to 375,093 records. An approach based on pedigree information for sire and maternal grandsire was used and included additive, dominance, and additive by additive genetic effects. Variances were estimated using the tildehat approximation to REML. Heritability estimated without nonadditive effects in the model was overestimated, particularly in presence of additive by additive variance. Dominance variance was important for most traits; for the lifetime performance traits, dominance was clearly higher than additive variance. Additive by additive variance was very high for milk yield and energy-corrected milk yield, especially for data including crossbreds. Effect of inbreeding was low in most cases. Inclusion of nonadditive effects in genetic evaluation models might improve estimation of additive effects and may require consideration for dairy cattle breeding programs.

  14. Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer

    PubMed Central

    Garcia-Closas, Montserrat; Rothman, Nathaniel; Figueroa, Jonine D.; Prokunina-Olsson, Ludmila; Han, Summer S.; Baris, Dalsu; Jacobs, Eric J; Malats, Nuria; De Vivo, Immaculata; Albanes, Demetrius; Purdue, Mark P; Sharma, Sapna; Fu, Yi-Ping; Kogevinas, Manolis; Wang, Zhaoming; Tang, Wei; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Johnson, Alison; Schwenn, Molly; Karagas, Margaret R; Schned, Alan; Andriole, Gerald; Grubb, Robert; Black, Amanda; Gapstur, Susan M; Thun, Michael; Diver, W Ryan; Weinstein, Stephanie J; Virtamo, Jarmo; Hunter, David J; Caporaso, Neil; Landi, Maria Teresa; Hutchinson, Amy; Burdett, Laurie; Jacobs, Kevin B; Yeager, Meredith; Fraumeni, Joseph F; Chanock, Stephen J; Silverman, Debra T; Chatterjee, Nilanjan

    2013-01-01

    Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to evaluate the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for US-males aged 50-years. Six out of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P=7×10-4) and UGT1A6 (P=8×10-4). The 30-year absolute risk of bladder cancer in US males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile, compared to 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive =1×10-4). The impact of eliminating smoking the on number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. PMID:23536561

  15. Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer.

    PubMed

    Garcia-Closas, Montserrat; Rothman, Nathaniel; Figueroa, Jonine D; Prokunina-Olsson, Ludmila; Han, Summer S; Baris, Dalsu; Jacobs, Eric J; Malats, Nuria; De Vivo, Immaculata; Albanes, Demetrius; Purdue, Mark P; Sharma, Sapna; Fu, Yi-Ping; Kogevinas, Manolis; Wang, Zhaoming; Tang, Wei; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Johnson, Alison; Schwenn, Molly; Karagas, Margaret R; Schned, Alan; Andriole, Gerald; Grubb, Robert; Black, Amanda; Gapstur, Susan M; Thun, Michael; Diver, William Ryan; Weinstein, Stephanie J; Virtamo, Jarmo; Hunter, David J; Caporaso, Neil; Landi, Maria Teresa; Hutchinson, Amy; Burdett, Laurie; Jacobs, Kevin B; Yeager, Meredith; Fraumeni, Joseph F; Chanock, Stephen J; Silverman, Debra T; Chatterjee, Nilanjan

    2013-04-01

    Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 × 10(-4)) and UGT1A6 (P = 8 × 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P(additive) = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.

  16. 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

  17. Are centenarians genetically predisposed to lower disease risk?

    PubMed

    Ruiz, Jonatan R; Fiuza-Luces, Carmen; Buxens, Amaya; Cano-Nieto, Amalia; Gómez-Gallego, Félix; Santiago, Catalina; Rodríguez-Romo, Gabriel; Garatachea, Nuria; Lao, José I; Morán, María; Lucia, Alejandro

    2012-10-01

    Our study purpose was to compare a disease-related polygenic profile that combined a total of 62 genetic variants among (i) people reaching exceptional longevity, i.e., centenarians (n = 54, 100-108 years, 48 women) and (ii) ethnically matched healthy controls (n = 87, 19-43 years, 47 women). We computed a 'global' genotype score (GS) for 62 genetic variants (mutations/polymorphisms) related to cardiometabolic diseases, cancer or exceptional longevity, and also specific GS for main disease categories (cardiometabolic risk and cancer risk, including 36 and 24 genetic variations, respectively) and for exceptional longevity (7 genetic variants). The 'global' GS was similar among groups (centenarians: 31.0 ± 0.6; controls 32.0 ± 0.5, P = 0.263). We observed that the GS for hypertension, cancer (global risk), and other types of cancer was lower in the centenarians group compared with the control group (all P < 0.05), yet the difference became non significant after adjusting for sex. We observed significant between-group differences in the frequency of GSTT1 and GSTM1 (presence/absence) genotypes after adjusting for multiple comparisons. The likelihood of having the GSTT1 low-risk (functional) allele was higher in centenarians (odds ratio [OR] 5.005; 95% confidence interval [CI], 1.810-13.839), whereas the likelihood of having the GSTMI low-risk (functional) allele was similar in both groups (OR 1.295; 95% CI, 0.868 -1.931). In conclusion, we found preliminary evidence that Spanish centenarians have a lower genetic predisposition for cancer risk. The wild-type (i.e., functional) genotype of GSTT1, which is associated with lower cancer risk, might be associated with exceptional longevity, yet further studies with larger sample sizes must confirm these findings.

  18. Genetics and alcoholism among at-risk relatives I: perceptions of cause, risk, and control.

    PubMed

    Gamm, Jennifer L; Nussbaum, Robert L; Biesecker, Barbara Bowles

    2004-07-15

    Genetic factors influence a person's risk for developing alcoholism. In other common disorders with a genetic component, a belief in a genetic cause can lead to less perceived control or fatalism among those at risk that may adversely affect undertaking health-promoting behaviors. This study explores beliefs about the cause of alcoholism and risk perception among individuals with affected relatives. In-depth interviews including both open-ended questions and several quantitative measures were conducted with participants to explore the relationships between causal beliefs and perceptions of personal risk and control. Twenty-seven individuals with at least one first-degree relative affected with alcoholism participated. Transcript analysis of interviews revealed that all participants attribute multiple factors to the cause of alcoholism in their families, often as a combination of biological, genetic, environmental factors, and personal characteristics. Many perceived themselves as being 'at-risk,' and this concern often stemmed from a belief in a genetic or biological cause of alcoholism. However, participants also had a strong sense of personal control, rooted in beliefs about environmental causes or personal characteristics influencing alcoholism risk. A participant's strong belief in a genetic cause was associated with a significantly increased risk perception, but not a fatalistic outlook towards developing alcoholism.

  19. Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations

    PubMed Central

    Saigi-Morgui, Núria; Quteineh, Lina; Bochud, Pierre-Yves; Crettol, Severine; Kutalik, Zoltán; Wojtowicz, Agnieszka; Bibert, Stéphanie; Beckmann, Sonja; Mueller, Nicolas J; Binet, Isabelle; van Delden, Christian; Steiger, Jürg; Mohacsi, Paul; Stirnimann, Guido; Soccal, Paola M.; Pascual, Manuel; Eap, Chin B

    2016-01-01

    Background Polygenic obesity in Solid Organ Transplant (SOT) populations is considered a risk factor for the development of metabolic abnormalities and graft survival. Few studies to date have studied the genetics of weight gain in SOT recipients. We aimed to determine whether weighted genetic risk scores (w-GRS) integrating genetic polymorphisms from GWAS studies (SNP group#1 and SNP group#2) and from Candidate Gene studies (SNP group#3) influence BMI in SOT populations and if they predict ≥10% weight gain (WG) one year after transplantation. To do so, two samples (nA = 995, nB = 156) were obtained from naturalistic studies and three w-GRS were constructed and tested for association with BMI over time. Prediction of 10% WG at one year after transplantation was assessed with models containing genetic and clinical factors. Results w-GRS were associated with BMI in sample A and B combined (BMI increased by 0.14 and 0.11 units per additional risk allele in SNP group#1 and #2, respectively, p-values<0.008). w-GRS of SNP group#3 showed an effect of 0.01 kg/m2 per additional risk allele when combining sample A and B (p-value 0.04). Models with genetic factors performed better than models without in predicting 10% WG at one year after transplantation. Conclusions This is the first study in SOT evaluating extensively the association of w-GRS with BMI and the influence of clinical and genetic factors on 10% of WG one year after transplantation, showing the importance of integrating genetic factors in the final model. Genetics of obesity among SOT recipients remains an important issue and can contribute to treatment personalization and prediction of WG after transplantation. PMID:27788139

  20. Experiences of genetic risk: disclosure and the gendering of responsibility.

    PubMed

    d'Agincourt-Canning, L

    2001-06-01

    The question of 'who owns genetic information' is increasingly a focus of ethical inquiry. Applied to predictive testing, several recent critiques suggest that persons with a genetic disorder have a moral duty to disclose that information to other family members. The justification for this obligation is that genetic information belongs to and may benefit not only a single individual, but also members of a biological kinship. This paper considers this issue from a different vantage point: How does gender intersect with the moral duty to disclose genetic information? Scholars have argued that gender is partly comprised of distinct assignments and assumptions of responsibility. Thus, there is a danger that gendered patterns of socialization will make women feel that they should take primary responsibility for disclosing genetic information to others. This article explores issues of responsibility and disclosure of risk information by drawing on an empirical study of women and men who have undergone genetic testing for hereditary breast/ovarian cancer. The research study suggests that disclosure of genetic information is a gendered activity, with both the benefits and burdens of this task falling primarily on women. It also illustrates that when disclosure is understood contextually, it is a far more complicated matter than when viewed through a theoretical lens. The article considers the relevance of these findings on ethical debate and genetic counselling practices.

  1. Health risks of genetically modified foods.

    PubMed

    Dona, Artemis; Arvanitoyannis, Ioannis S

    2009-02-01

    As genetically modified (GM) foods are starting to intrude in our diet concerns have been expressed regarding GM food safety. These concerns as well as the limitations of the procedures followed in the evaluation of their safety are presented. Animal toxicity studies with certain GM foods have shown that they may toxically affect several organs and systems. The review of these studies should not be conducted separately for each GM food, but according to the effects exerted on certain organs it may help us create a better picture of the possible health effects on human beings. The results of most studies with GM foods indicate that they may cause some common toxic effects such as hepatic, pancreatic, renal, or reproductive effects and may alter the hematological, biochemical, and immunologic parameters. However, many years of research with animals and clinical trials are required for this assessment. The use of recombinant GH or its expression in animals should be re-examined since it has been shown that it increases IGF-1 which may promote cancer.

  2. Heritability Estimates Identify a Substantial Genetic Contribution to Risk and Outcome of Intracerebral Hemorrhage

    PubMed Central

    Devan, William J.; Falcone, Guido J.; Anderson, Christopher D.; Jagiella, Jeremiasz M.; Schmidt, Helena; Hansen, Björn M.; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Cuadrado-Godia, Elisa; Soriano, Carolina; Ayres, Alison M.; Schwab, Kristin; Kassis, Sylvia Baedorf; Valant, Valerie; Pera, Joanna; Urbanik, Andrzej; Viswanathan, Anand; Rost, Natalia S.; Goldstein, Joshua N.; Freudenberger, Paul; Stögerer, Eva-Maria; Norrving, Bo; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Chelsea S.; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Greenberg, Steven M.; Roquer, Jaume; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Woo, Daniel; Rosand, Jonathan; Biffi, Alessandro

    2013-01-01

    Background and Purpose Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOE loci and at 12% (SE, 4%) for APOE. Conclusions Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified. PMID:23559261

  3. Diffusion of information about genetic risk within families.

    PubMed

    Ayme, Ségolène; Macquart-Moulin, Geneviève; Julian-Reynier, Claire; Chabal, Françoise; Giraud, Francis

    1993-01-01

    Recent developments in genetics are likely to exacerbate the ethical issues in clinical practice, especially with regard to privacy and disclosure of genetic information. To evaluate the behaviour of patients with respect to transmitting carrier information, we undertook a survey of 283 families with a balanced chromosomal rearrangement as a model. In these families, 1816 relatives were considered at risk and 806 of them were karyotyped (44.4%). The percentage of karyotypes performed is significantly related to the number of living children of the index couple, the reason for referral, the nature of the anomaly, the training of the counsellor and the age of the index case. This study shows the limits of the screening of at risk individuals within families, based on the willingness of the patients, and addresses practical and ethical issues around family disclosure in medical genetics.

  4. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  5. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders.

    PubMed

    Ligthart, Lannie; Hottenga, Jouke-Jan; Lewis, Cathryn M; Farmer, Anne E; Craig, Ian W; Breen, Gerome; Willemsen, Gonneke; Vink, Jacqueline M; Middeldorp, Christel M; Byrne, Enda M; Heath, Andrew C; Madden, Pamela A F; Pergadia, Michele L; Montgomery, Grant W; Martin, Nicholas G; Penninx, Brenda W J H; McGuffin, Peter; Boomsma, Dorret I; Nyholt, Dale R

    2014-02-01

    Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study (N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study (N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR-NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the 'pure' forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD.

  6. [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.

  7. [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

  8. Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants

    PubMed Central

    Sayols-Baixeras, Sergi; Lluís-Ganella, Carla; Lucas, Gavin; Elosua, Roberto

    2014-01-01

    Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and its prevalence is expected to increase in the coming years. CAD events are caused by the interplay of genetic and environmental factors, the effects of which are mainly mediated through cardiovascular risk factors. The techniques used to study the genetic basis of these diseases have evolved from linkage studies to candidate gene studies and genome-wide association studies. Linkage studies have been able to identify genetic variants associated with monogenic diseases, whereas genome-wide association studies have been more successful in determining genetic variants associated with complex diseases. Currently, genome-wide association studies have identified approximately 40 loci that explain 6% of the heritability of CAD. The application of this knowledge to clinical practice is challenging, but can be achieved using various strategies, such as genetic variants to identify new therapeutic targets, personal genetic information to improve disease risk prediction, and pharmacogenomics. The main aim of this narrative review is to provide a general overview of our current understanding of the genetics of coronary artery disease and its potential clinical utility. PMID:24520200

  9. 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

  10. Identification of genetic risk factors for maxillary lateral incisor agenesis.

    PubMed

    Alves-Ferreira, M; Pinho, T; Sousa, A; Sequeiros, J; Lemos, C; Alonso, I

    2014-05-01

    Tooth agenesis affects 20% of the world population, and maxillary lateral incisors agenesis (MLIA) is one of the most frequent subtypes, characterized by the absence of formation of deciduous or permanent lateral incisors. Odontogenesis is a complex mechanism regulated by sequential and reciprocal epithelial-mesenchymal interactions, controlled by activators and inhibitors involved in several pathways. Disturbances in these signaling cascades can lead to abnormalities in odontogenesis, resulting in alterations in the formation of the normal teeth number. Our aim was to study a large number of genes encoding either transcription factors or key components in signaling pathways shown to be involved in tooth odontogenesis. We selected 8 genes-MSX1, PAX9, AXIN2, EDA, SPRY2, TGFA, SPRY4, and WNT10A-and performed one of the largest case-control studies taking into account the number of genes and variants assessed, aiming at the identification of MLIA susceptibility factors. We show the involvement of PAX9, EDA, SPRY2, SPRY4, and WNT10A as risk factors for MLIA. Additionally, we uncovered 3 strong synergistic interactions between MLIA liability and MSX1-TGFA, AXIN2-TGFA, and SPRY2-SPRY4 gene pairs. We report the first evidence of the involvement of sprouty genes in MLIA susceptibility. This large study results in a better understanding of the genetic components and mechanisms underlying this trait.

  11. Precursors of literacy delay among children at genetic risk of dyslexia.

    PubMed

    Gallagher, A; Frith, U; Snowling, M J

    2000-02-01

    This paper reports the literacy skills of 63 children selected as being at genetic risk of dyslexia compared with 34 children from families reporting no history of reading impairment. Fifty-seven per cent of the at-risk group were delayed in literacy development at 6 years compared with only 12% of controls. The "unimpaired" at-risk group were not statistically different from controls on most cognitive and language measures at 45 months, whereas the literacy-delayed group showed significantly slower speech and language development, although they did not differ from controls in nonverbal ability. Letter knowledge at 45 months was the strongest predictor of literacy level at 6 years. In addition, early speech and language skills predicted individual differences in literacy outcome and genetic risk accounted for unique variance over and above these other factors. The results are discussed in terms of an interactive developmental model in which semantic and phonological skills support early reading acquisition. PMID:10750546

  12. MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor

    PubMed Central

    Peng, Yun; Huentelman, Matthew; Smith, Christopher; Qiu, Shenfeng

    2014-01-01

    In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions. PMID:24290385

  13. 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

  14. 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.

  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. 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

  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. 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.

  19. Genetic determinants of risk and progression in multiple sclerosis

    PubMed Central

    Didonna, Alessandro; Oksenberg, Jorge R.

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune disease that represents a primary cause of neurological disability in the young adult population. Converging evidence support the importance of genetic determinants for MS etiology. However, with the exception of the major histocompatibility complex, their nature has been elusive for more than 20 years. In the last decade, the advent of large genome-wide association studies has significantly improved our understanding of the disease, leading to the golden era of MS genetic research. To date more than 110 genetic variants have been firmly associated to an increased risk of developing MS. A large part of these variants tag genes involved in the regulation of immune response and several of them are shared with other autoimmune diseases, suggesting a common etiological root for this class of disorders. Despite the impressive body of data obtained in the last years, we are still far from fully decoding MS genetic complexity. For example, we ignore how these genetic factors interact with each other and with the environment. Thus, the biggest challenge for the next era of MS research will consist in identifying and characterizing the molecular mechanisms and the cellular pathways in which these risk variants play a role. PMID:25661088

  20. 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

  1. Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis.

    PubMed

    Musunuru, Kiran; Kathiresan, Sekar

    2016-02-19

    Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.

  2. Planning additional drilling campaign using two-space genetic algorithm: A game theoretical approach

    NASA Astrophysics Data System (ADS)

    Kumral, Mustafa; Ozer, Umit

    2013-03-01

    Grade and tonnage are the most important technical uncertainties in mining ventures because of the use of estimations/simulations, which are mostly generated from drill data. Open pit mines are planned and designed on the basis of the blocks representing the entire orebody. Each block has different estimation/simulation variance reflecting uncertainty to some extent. The estimation/simulation realizations are submitted to mine production scheduling process. However, the use of a block model with varying estimation/simulation variances will lead to serious risk in the scheduling. In the medium of multiple simulations, the dispersion variances of blocks can be thought to regard technical uncertainties. However, the dispersion variance cannot handle uncertainty associated with varying estimation/simulation variances of blocks. This paper proposes an approach that generates the configuration of the best additional drilling campaign to generate more homogenous estimation/simulation variances of blocks. In other words, the objective is to find the best drilling configuration in such a way as to minimize grade uncertainty under budget constraint. Uncertainty measure of the optimization process in this paper is interpolation variance, which considers data locations and grades. The problem is expressed as a minmax problem, which focuses on finding the best worst-case performance i.e., minimizing interpolation variance of the block generating maximum interpolation variance. Since the optimization model requires computing the interpolation variances of blocks being simulated/estimated in each iteration, the problem cannot be solved by standard optimization tools. This motivates to use two-space genetic algorithm (GA) approach to solve the problem. The technique has two spaces: feasible drill hole configuration with minimization of interpolation variance and drill hole simulations with maximization of interpolation variance. Two-space interacts to find a minmax solution

  3. 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

  4. Genetic determinants of quantitative traits associated with cardiovascular disease risk.

    PubMed

    Smolková, Božena; Bonassi, Stefano; Buociková, Verona; Dušinská, Mária; Horská, Alexandra; Kuba, Daniel; Džupinková, Zuzana; Rašlová, Katarína; Gašparovič, Juraj; Slíž, Ivan; Ceppi, Marcello; Vohnout, Branislav; Wsólová, Ladislava; Volkovová, Katarína

    2015-08-01

    Established risk factors for cardiovascular diseases (CVD) may be moderated by genetic variants. In 2403 unrelated individuals from general practice (mean age 40.5 years), we evaluated the influence of 15 variants in 12 candidate genes on quantitative traits (QT) associated with CVD (body mass index, abdominal obesity, glucose, serum lipids, and blood pressure). Prior to multiple testing correction, univariate analysis associated APOE rs429358, rs7412 and ATG16L1 rs2241880 variants with serum lipid levels, while LEPR rs1137100 and ATG16L1 rs2241880 variants were linked to obesity related QTs. After taking into account confounding factors and correcting for multiple comparisons only APOE rs429358 and rs7412 variants remained significantly associated with risk of dyslipidemia. APOE rs429358 variant almost tripled the risk in homozygous subjects (OR = 2.97; 95% CI 1.09-8.10, p < 0.03) and had a lesser but still highly significant association also in heterozygous individuals (OR = 1.67; 95% CI 1.24-2.10; p < 0.001). Associations with hypertension, diabetes mellitus, and metabolic syndrome were not significant after Bonferroni correction. The influence of genetic variation is more evident in dyslipidemia than in other analyzed QTs. These results may contribute to strategic research aimed at including genetic variation in the set of data required to identify subjects at high risk of CVD. PMID:26043189

  5. 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

  6. Additional safety risk to exceptionally approved drugs in Europe?

    PubMed Central

    Arnardottir, Arna H; Haaijer-Ruskamp, Flora M; Straus, Sabine M J; Eichler, Hans-Georg; de Graeff, Pieter A; Mol, Peter G M

    2011-01-01

    AIMS Regulatory requirements for new drugs have increased. Special approval procedures with priority assessment are possible for drugs with clear ‘unmet medical need’. We question whether these Exceptional Circumstances (EC) or Conditional Approval (CA) procedures have led to a higher probability of serious safety issues. METHODS A retrospective cohort study was performed of new drugs approved in Europe between 1999 and 2009. The determinant was EC/CA vs. standard procedure approval. Outcome variables were frequency and timing of a first Direct Healthcare Professional Communication (DHPC). An association between approval procedure and the time from market approval to DHPC was assessed using Kaplan-Meyer survival analysis and Cox-regression to correct for covariates. RESULTS In total 289 new drugs were approved. Forty-six (16.4%) were approved under EC or CA, of which seven received a DHPC (15%). This was similar to the standard approval drugs (243), of which 33 received one or more DHPC (14%, P = 0.77). The probability of acquiring a DHPC for standard approval drugs vs. EC/CA drugs during 11-year follow-up is 22% (95% CI 14%, 29%) and 26% (95% CI 8%, 44%), respectively (log-rank P = 0.726). This difference remained not significant in the Cox-regression model: hazard ratio 0.94 (95% CI 0.40, 2.20). Only drug type was identified as a confounding covariate. CONCLUSION The EC/CA procedure is not associated with a higher probability of DHPCs despite limited clinical development data. These data do not support the view that early drug approval increases the risk of serious safety issues emerging after market approval. PMID:21501215

  7. Genetically modified foods: hazard identification and risk assessment. Session summary.

    PubMed

    Ito, Nobuyuki

    2002-07-01

    During a Joint Society of Toxicologic Pathology (STP)/International Federation of Societies of Toxicologic Pathologists (IFSTP) International Symposium, held between June 24 and 28, 2001, in Orlando, FL, USA, there was a session entitled as "Genetically Modified Foods: Hazard Identification and Risk Assessment". The purpose of this session was to present and discuss the current situations in the US, European Union and Japan for the public concerns, safety assessments and regulations on genetically modified (GM) products used as foods or food ingredients. Assuming the wide and fast growing of the usage of GM products, it is the duty for us as toxicologic pathologists, to supply reliable data on their safety and possible risks or hazards as a world-wide basis to not only governments or regulatory agencies but also general public of our countries.

  8. 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

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

    PubMed

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

    2013-06-01

    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. PMID:27625842

  10. 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. PMID:27625842

  11. 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

  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. 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

  15. 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

  16. Identification of new genetic risk factors for prostate cancer.

    PubMed

    Guy, Michelle; Kote-Jarai, Zsofia; Giles, Graham G; Al Olama, Ali Amin; Jugurnauth, Sarah K; Mulholland, Shani; Leongamornlert, Daniel A; Edwards, Stephen M; Morrison, Jonathan; Field, Helen I; Southey, Melissa C; Severi, Gianluca; Donovan, Jenny L; Hamdy, Freddie C; Dearnaley, David P; Muir, Kenneth R; Smith, Charmaine; Bagnato, Melisa; Ardern-Jones, Audrey T; Hall, Amanda L; O'Brien, Lynne T; Gehr-Swain, Beatrice N; Wilkinson, Rosemary A; Cox, Angela; Lewis, Sarah; Brown, Paul M; Jhavar, Sameer G; Tymrakiewicz, Malgorzata; Lophatananon, Artitaya; Bryant, Sarah L; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Woodhouse, Christopher J; Thompson, Alan; Christmas, Tim; Ogden, Chris; Fisher, Cyril; Jameson, Charles; Cooper, Colin S; English, Dallas R; Hopper, John L; Neal, David E; Easton, Douglas F; Eeles, Rosalind A

    2009-01-01

    There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

  17. 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

  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. No Additional Prognostic Value of Genetic Information in the Prediction of Vascular Events after Cerebral Ischemia of Arterial Origin: The PROMISe Study

    PubMed Central

    Achterberg, Sefanja; Kappelle, L. Jaap; de Bakker, Paul I. W.; Traylor, Matthew; Algra, Ale

    2015-01-01

    Background Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events. PMID:25906364

  20. 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

  1. Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer’s Disease

    PubMed Central

    Chouraki, Vincent; Reitz, Christiane; Maury, Fleur; Bis, Joshua C.; Bellenguez, Celine; Yu, Lei; Jakobsdottir, Johanna; Mukherjee, Shubhabrata; Adams, Hieab H.; Choi, Seung Hoan; Larson, Eric B.; Fitzpatrick, Annette; Uitterlinden, Andre G.; de Jager, Philip L.; Hofman, Albert; Gudnason, Vilmundur; Vardarajan, Badri; Ibrahim-Verbaas, Carla; van der Lee, Sven J.; Lopez, Oscar; Dartigues, Jean-François; Berr, Claudine; Amouyel, Philippe; Bennett, David A.; van Duijn, Cornelia; DeStefano, Anita L.; Launer, Lenore J.; Ikram, M. Arfan; Crane, Paul K.; Lambert, Jean-Charles; Mayeux, Richard; Seshadri, Sudha

    2016-01-01

    Effective prevention of Alzheimer’s disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ε4. In eight prospective cohorts included in the International Genomics of Alzheimer’s Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ–C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95%CI = [1.13–1.21] per standard deviation increase in GRS; p-value = 2.86 × 10−16). This association was stronger among persons with at least one APOE ε4 allele (HRGRS = 1.24; 95%CI = [1.15–1.34]) than in others (HRGRS = 1.13; 95%CI = [1.08–1.18]; pinteraction = 3.45 × 10−2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ε4, and education (Δ–Cindex = 0.0043 [0.0019–0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ε4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials. PMID:27340842

  2. 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

  3. Genetic risk factors for sclerotic graft-versus-host disease.

    PubMed

    Inamoto, Yoshihiro; Martin, Paul J; Flowers, Mary E D; Lee, Stephanie J; Carpenter, Paul A; Warren, Edus H; Geraghty, Daniel E; Lee, Ni; Boeckh, Michael J; Storer, Barry E; Levine, David M; Fan, Wenhong; Zhao, Lue-Ping; Hansen, John A

    2016-09-15

    Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation, characterized by fibrosis of skin or fascia. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. We examined 13 candidate single-nucleotide polymorphisms (SNPs) that have a well-documented association with systemic sclerosis to determine whether these SNPs are also associated with the risk of sclerotic GVHD. The study cohort included 847 consecutive patients who were diagnosed with chronic GVHD. Genotyping was performed using microarrays, followed by imputation of unobserved SNPs. The donor rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1) TT genotype was associated with lower risk of sclerotic GVHD (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.21-0.87; P = .02). Donor and recipient rs2056626 (CD247: T-cell receptor ζ subunit) GG or GT genotypes were associated with higher risk of sclerotic GVHD (HR, 1.57; 95% CI, 1.13-2.18; P = .007 and HR, 1.66; 95% CI, 1.19-2.32; P = .003, respectively). Donor and recipient rs987870 (5'-flanking region of HLA-DPA1) CC genotypes were associated with higher risk of sclerotic GVHD (HR, 2.50; 95% CI, 1.22-5.11; P = .01 and HR, 2.13; 95% CI, 1.00-4.54; P = .05, respectively). In further analyses, the recipient DPA1*01:03∼DPB1*04:01 haplotype and certain amino acid substitutions in the recipient P1 peptide-binding pocket of the HLA-DP heterodimer were associated with risk of sclerotic GVHD. Genetic components associated with systemic sclerosis are also associated with sclerotic GVHD. HLA-DP-mediated antigen presentation, T-cell response, and B-cell activation have important roles in the pathogenic mechanisms of both diseases. PMID:27313329

  4. 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

  5. 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

  6. 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

  7. 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.

  8. Predicting the risk of rheumatoid arthritis and its age of onset through modelling genetic risk variants with smoking.

    PubMed

    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

  9. Predicting the risk of rheumatoid arthritis and its age of onset through modelling genetic risk variants with smoking.

    PubMed

    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.

  10. 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

  11. 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.

  12. Genetic linkage analysis to identify a gene required for the addition of phosphoethanolamine to meningococcal lipopolysaccharide.

    PubMed

    Tang, Christoph M; Stroud, Dave; Mackinnon, Fiona; Makepeace, Katherine; Plested, Joyce; Moxon, E Richard; Chalmers, Ronald

    2002-02-01

    Lipopolysaccharide (LPS) is important for the virulence of Neisseria meningitidis, and is the target of immune responses. We took advantage of a monoclonal antibody (Mab B5) that recognises phosphoethanolamine (PEtn) attached to the inner core of meningococcal LPS to identify genes required for the addition of PEtn to LPS. Insertional mutants that lost Mab B5 reactivity were isolated and characterised, but failed to yield genes directly responsible for PEtn substitution. Subsequent genetic linkage analysis was used to define a region of DNA containing a single intact open reading frame which is sufficient to confer B5 reactivity to a B5 negative meningococcal isolate. The results provide an initial characterisation of the genetic basis of a key, immunodominant epitope of meningococcal LPS.

  13. 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

  14. 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

  15. A weighted genetic risk score using all known susceptibility variants to estimate rheumatoid arthritis risk

    PubMed Central

    Yarwood, Annie; Han, Buhm; Raychaudhuri, Soumya; Bowes, John; Lunt, Mark; Pappas, Dimitrios A; Kremer, Joel; Greenberg, Jeffrey D; Plenge, Robert; Worthington, Jane; Barton, Anne; Eyre, Steve

    2015-01-01

    Background There is currently great interest in the incorporation of genetic susceptibility loci into screening models to identify individuals at high risk of disease. Here, we present the first risk prediction model including all 46 known genetic loci associated with rheumatoid arthritis (RA). Methods A weighted genetic risk score (wGRS) was created using 45 RA non-human leucocyte antigen (HLA) susceptibility loci, imputed amino acids at HLA-DRB1 (11, 71 and 74), HLA-DPB1 (position 9) HLA-B (position 9) and gender. The wGRS was tested in 11 366 RA cases and 15 489 healthy controls. The risk of developing RA was estimated using logistic regression by dividing the wGRS into quintiles. The ability of the wGRS to discriminate between cases and controls was assessed by receiver operator characteristic analysis and discrimination improvement tests. Results Individuals in the highest risk group showed significantly increased odds of developing anti-cyclic citrullinated peptide-positive RA compared to the lowest risk group (OR 27.13, 95% CI 23.70 to 31.05). The wGRS was validated in an independent cohort that showed similar results (area under the curve 0.78, OR 18.00, 95% CI 13.67 to 23.71). Comparison of the full wGRS with a wGRS in which HLA amino acids were replaced by a HLA tag single-nucleotide polymorphism showed a significant loss of sensitivity and specificity. Conclusions Our study suggests that in RA, even when using all known genetic susceptibility variants, prediction performance remains modest; while this is insufficiently accurate for general population screening, it may prove of more use in targeted studies. Our study has also highlighted the importance of including HLA variation in risk prediction models. PMID:24092415

  16. Human Papillomavirus 45 Genetic Variation and Cervical Cancer Risk Worldwide

    PubMed Central

    Chen, Alyce A.; Heideman, Daniëlle A. M.; Boon, Debby; Gheit, Tarik; Snijders, Peter J. F.; Tommasino, Massimo; Franceschi, Silvia

    2014-01-01

    ABSTRACT Human papillomavirus 45 (HPV45) is a member of the HPV18-related alpha-7 species and accounts for approximately 5% of all cervical cancer cases worldwide. This study evaluated the genetic diversity of HPV45 and the association of HPV45 variants with the risk of cervical cancer by sequencing the entire E6 and E7 open reading frames of 300 HPV45-positive cervical samples from 36 countries. A total of 43 HPV45 sequence variants were identified that formed 5 phylogenetic sublineages, A1, A2, A3, B1, and B2, the distribution of which varied by geographical region. Among 192 cases of cervical cancer and 101 controls, the B2 sublineage was significantly overrepresented in cervical cancer, both overall and in Africa and Europe separately. We show that the sequence analysis of E6 and E7 allows the classification of HPV45 variants and that the risk of cervical cancer may differ by HPV45 variant sublineage. IMPORTANCE This work describes the largest study to date of human papillomavirus 45 (HPV45)-positive cervical samples and provides a comprehensive reference for phylogenetic classification for use in epidemiological studies of the carcinogenicity of HPV45 genetic variants, particularly as our findings suggest that the B2 sublineage of HPV45 is associated with a higher risk of cervical cancer. PMID:24501412

  17. 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.

  18. Genetic risk factors and Mendelian randomization in cardiovascular disease.

    PubMed

    Swerdlow, Daniel I; Hingorani, Aroon D; Humphries, Steve E

    2015-05-01

    Cardiovascular disease encompasses several diverse pathological states that place a heavy burden on individual and population health. The aetiological basis of many cardiovascular disorders is not fully understood. Growing knowledge of the genetic architecture underlying coronary heart disease, stroke, cardiac arrhythmias and peripheral vascular disease has confirmed some suspected causal pathways in these conditions but also uncovered many previously unknown mechanisms. Here, we consider the contribution of genetics to the understanding of cardiovascular disease risk. We evaluate the utility and relevance of findings from genome-wide association studies and explore the role that Mendelian randomisation has to play in exploiting these. Mendelian randomisation permits robust causal inference in an area of research where this has been hampered by bias and confounding in observational studies. In doing so, it provides evidence for causal processes in cardiovascular disease that could represent novel targets for much-needed new drugs for disease prevention and treatment. PMID:25894797

  19. Effect of multiplicative and additive noise on genetic transcriptional regulatory mechanism

    NASA Astrophysics Data System (ADS)

    Liu, Xue-Mei; Xie, Hui-Zhang; Liu, Liang-Gang; Li, Zhi-Bing

    2009-02-01

    A multiplicative noise and an additive noise are introduced in the kinetic model of Smolen-Baxter-Byrne [P. Smolen, D.A. Baxter, J.H. Byrne, Amer. J. Physiol. Cell. Physiol. 274 (1998) 531], in which the expression of gene is controlled by protein concentration of transcriptional activator. The Fokker-Planck equation is solved and the steady-state probability distribution is obtained numerically. It is found that the multiplicative noise converts the bistability to monostability that can be regarded as a noise-induced transition. The additive noise reduces the transcription efficiency. The correlation between the multiplicative noise and the additive noise works as a genetic switch and regulates the gene transcription effectively.

  20. [The application of genetic risk score in genetic studies of complex human diseases].

    PubMed

    Dayan, Niu; Weili, Yan

    2015-12-01

    Complex diseases such as cardiovascular disease, type 2 diabetes, essential hypertension, asthma, obesity and cancer have spread across the globe and become the predominant cause of death. There are growing concerns over the role of genetic susceptibility in pathogenesis of complex diseases. However, the related susceptibility genes and sequence variations are still unknown. To elucidate the genetic basis of complex diseases, researchers have identified a large number of genetic variants associated with complex diseases through genome-wide association studies (GWAS) and candidate gene studies recently. The identification of these causal and/or associated variants promotes the development of approaches for complex diseases prediction and prevention. Genetic risk score (GRS), an emerging method for exploring correlation between single nucleotide polymorphisms (SNPs) and clinical phenotypes of complex diseases, integrates weak effects of multiple SNPs and dramatically enhances predictability of complex diseases by gene polymorphisms. This method has been applied successfully in genetic studies of many complex diseases. Here we focus on the introduction of the computational methods and evaluation criteria of GRS, enumerate a series of achievements through GRS application, discuss some limitations during application, and finally prospect the future of GRS.

  1. 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.

  2. 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

  3. Genetic predisposition, Western dietary pattern, and the risk of type 2 diabetes in men123

    PubMed Central

    Qi, Lu; Cornelis, Marilyn C; Zhang, Cuilin; van Dam, Rob M; Hu, Frank B

    2009-01-01

    Background: A widely held hypothesis is that interactions between genetic predisposition and Western-type lifestyle contribute to the epidemic of type 2 diabetes (T2D). No study has tested this hypothesis. Objective: The objective was to assess whether established genetic variants, mainly from genomewide association studies, modify dietary patterns in predicting diabetes risk. Design: We determined 10 polymorphisms in a prospective, nested, case-control study of 1196 diabetic and 1337 nondiabetic men. A genetic risk score (GRS) was generated by using an allele counting method. Baseline dietary intakes were collected by using a semiquantitative food-frequency questionnaire. We used factor analysis to derive Western and “Prudent” dietary patterns from 40 food groups. Results: A significant interaction (P = 0.02) was observed between the GRS and Western dietary pattern. The multivariable odds ratios (ORs) of T2D across increasing quartiles for the Western dietary pattern were 1.00, 1.23 (95% CI: 0.88, 1.73), 1.49 (1.06,2.09), and 2.06 (1.48, 2.88) among men with a high GRS (≥12 risk alleles; P for trend = 0.01). The Western dietary pattern was not associated with diabetes risk among those with a lower GRS. In addition, we found that intakes of processed meat, red meat, and heme iron, which characterized the Western dietary pattern, showed significant interactions with GRS in relation to diabetes risk (P for interaction = 0.029, 0.02, and 0.0004, respectively). The diet-diabetes associations were more evident among men with a high GRS (≥12) than in those with a low GRS. Conclusion: Genetic predisposition may synergistically interact with a Western dietary pattern in determining diabetes risk in men. PMID:19279076

  4. 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.

  5. Geoepidemiology, Genetic and Environmental Risk Factors for PBC.

    PubMed

    Zhang, Haiyan; Carbone, Marco; Lleo, Ana; Invernizzi, Pietro

    2015-01-01

    Primary biliary cirrhosis (PBC) is the most paradigmatic autoimmune liver disease with still several controversial issues in epidemiology, diagnosis, causation, and therapy. Although we are witnessing an enormous increase in the quantum of our basic knowledge of the disease with an initial translation in clinical practice, there are still a number of key open questions in PBC. Among them are the following questions: Why are there vast geographical variations in disease frequency? What are the reasons for female preponderance? Why do only small-size bile ducts get affected: What is the real role of genetics and epigenetics in its development? In particular, the prevalence of PBC is known to vary both on an international and a regional level, suggesting the existence of substantive geographical differences in terms of genetic susceptibility and environmental factors. New theories on potential environmental triggers, such as chemical xenobiotics, which lead to the breaking of self-tolerance within a unique immunological milieu of the liver, have been suggested. On the other hand, new and solid data on the genetic architecture of PBC are now obtained from recent high-throughput studies, together with data on sex chromosomes defects, and epigenetic abnormalities, thus strongly suggesting a role of genetic and epigenetic factors in the triggering and perpetuation of the autoimmune aggression in PBC. Based on these evidences, a number of novel drugs directed against specific immune-related molecules are currently under development. In this paper, we review a comprehensive collection of current epidemiological reports from various world regions. We also discuss here the most recent data regarding candidate genetic and environmental risk factors for PBC.

  6. Public risk perception of food additives and food scares. The case in Suzhou, China.

    PubMed

    Wu, Linhai; Zhong, Yingqi; Shan, Lijie; Qin, Wei

    2013-11-01

    This study examined the factors affecting public risk perception of food additive safety and possible resulting food scares using a survey conducted in Suzhou, Jiangsu Province, China. The model was proposed based on literature relating to the role of risk perception and information perception of public purchase intention under food scares. Structural equation modeling (SEM) was used for data analysis. The results showed that attitude towards behavior, subjective norm and information perception exerted moderate to high effect on food scares, and the effects were also mediated by risk perceptions of additive safety. Significant covariance was observed between attitudes toward behavior, subjective norm and information perception. Establishing an effective mechanism of food safety risk communication, releasing information of government supervision on food safety in a timely manner, curbing misleading media reports on public food safety risk, and enhancing public knowledge of the food additives are key to the development and implementation of food safety risk management policies by the Chinese government. PMID:23831014

  7. Public risk perception of food additives and food scares. The case in Suzhou, China.

    PubMed

    Wu, Linhai; Zhong, Yingqi; Shan, Lijie; Qin, Wei

    2013-11-01

    This study examined the factors affecting public risk perception of food additive safety and possible resulting food scares using a survey conducted in Suzhou, Jiangsu Province, China. The model was proposed based on literature relating to the role of risk perception and information perception of public purchase intention under food scares. Structural equation modeling (SEM) was used for data analysis. The results showed that attitude towards behavior, subjective norm and information perception exerted moderate to high effect on food scares, and the effects were also mediated by risk perceptions of additive safety. Significant covariance was observed between attitudes toward behavior, subjective norm and information perception. Establishing an effective mechanism of food safety risk communication, releasing information of government supervision on food safety in a timely manner, curbing misleading media reports on public food safety risk, and enhancing public knowledge of the food additives are key to the development and implementation of food safety risk management policies by the Chinese government.

  8. Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: Application of the additive model for cancer

    PubMed Central

    Pérez-Morales, Rebeca; Méndez-Ramírez, Ignacio; Castro-Hernández, Clementina; Martínez-Ramírez, Ollin C.; Gonsebatt, María Eugenia; Rubio, Julieta

    2011-01-01

    Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy-Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer. PMID:22215955

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

    PubMed

    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 IRF4 rs12203592T/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 IRF4 rs12203592T 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 IRF4 rs12203592 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

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. FEMALE AND MALE GENETIC EFFECTS ON OFFSPRING PATERNITY: ADDITIVE GENETIC (CO)VARIANCES IN FEMALE EXTRA-PAIR REPRODUCTION AND MALE PATERNITY SUCCESS IN SONG SPARROWS (MELOSPIZA MELODIA)

    PubMed Central

    Reid, Jane M; Arcese, Peter; Keller, Lukas F; Losdat, Sylvain

    2014-01-01

    Ongoing evolution of polyandry, and consequent extra-pair reproduction in socially monogamous systems, is hypothesized to be facilitated by indirect selection stemming from cross-sex genetic covariances with components of male fitness. Specifically, polyandry is hypothesized to create positive genetic covariance with male paternity success due to inevitable assortative reproduction, driving ongoing coevolution. However, it remains unclear whether such covariances could or do emerge within complex polyandrous systems. First, we illustrate that genetic covariances between female extra-pair reproduction and male within-pair paternity success might be constrained in socially monogamous systems where female and male additive genetic effects can have opposing impacts on the paternity of jointly reared offspring. Second, we demonstrate nonzero additive genetic variance in female liability for extra-pair reproduction and male liability for within-pair paternity success, modeled as direct and associative genetic effects on offspring paternity, respectively, in free-living song sparrows (Melospiza melodia). The posterior mean additive genetic covariance between these liabilities was slightly positive, but the credible interval was wide and overlapped zero. Therefore, although substantial total additive genetic variance exists, the hypothesis that ongoing evolution of female extra-pair reproduction is facilitated by genetic covariance with male within-pair paternity success cannot yet be definitively supported or rejected either conceptually or empirically. PMID:24724612

  17. Female and male genetic effects on offspring paternity: additive genetic (co)variances in female extra-pair reproduction and male paternity success in song sparrows (Melospiza melodia).

    PubMed

    Reid, Jane M; Arcese, Peter; Keller, Lukas F; Losdat, Sylvain

    2014-08-01

    Ongoing evolution of polyandry, and consequent extra-pair reproduction in socially monogamous systems, is hypothesized to be facilitated by indirect selection stemming from cross-sex genetic covariances with components of male fitness. Specifically, polyandry is hypothesized to create positive genetic covariance with male paternity success due to inevitable assortative reproduction, driving ongoing coevolution. However, it remains unclear whether such covariances could or do emerge within complex polyandrous systems. First, we illustrate that genetic covariances between female extra-pair reproduction and male within-pair paternity success might be constrained in socially monogamous systems where female and male additive genetic effects can have opposing impacts on the paternity of jointly reared offspring. Second, we demonstrate nonzero additive genetic variance in female liability for extra-pair reproduction and male liability for within-pair paternity success, modeled as direct and associative genetic effects on offspring paternity, respectively, in free-living song sparrows (Melospiza melodia). The posterior mean additive genetic covariance between these liabilities was slightly positive, but the credible interval was wide and overlapped zero. Therefore, although substantial total additive genetic variance exists, the hypothesis that ongoing evolution of female extra-pair reproduction is facilitated by genetic covariance with male within-pair paternity success cannot yet be definitively supported or rejected either conceptually or empirically.

  18. 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…

  19. 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

  20. 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.

  1. Additive genetic variance and developmental plasticity in growth trajectories in a wild cooperative mammal.

    PubMed

    Huchard, E; Charmantier, A; English, S; Bateman, A; Nielsen, J F; Clutton-Brock, T

    2014-09-01

    Individual variation in growth is high in cooperative breeders and may reflect plastic divergence in developmental trajectories leading to breeding vs. helping phenotypes. However, the relative importance of additive genetic variance and developmental plasticity in shaping growth trajectories is largely unknown in cooperative vertebrates. This study exploits weekly sequences of body mass from birth to adulthood to investigate sources of variance in, and covariance between, early and later growth in wild meerkats (Suricata suricatta), a cooperative mongoose. Our results indicate that (i) the correlation between early growth (prior to nutritional independence) and adult mass is positive but weak, and there are frequent changes (compensatory growth) in post-independence growth trajectories; (ii) among parameters describing growth trajectories, those describing growth rate (prior to and at nutritional independence) show undetectable heritability while associated size parameters (mass at nutritional independence and asymptotic mass) are moderately heritable (0.09 ≤ h(2) < 0.3); and (iii) additive genetic effects, rather than early environmental effects, mediate the covariance between early growth and adult mass. These results reveal that meerkat growth trajectories remain plastic throughout development, rather than showing early and irreversible divergence, and that the weak effects of early growth on adult mass, an important determinant of breeding success, are partly genetic. In contrast to most cooperative invertebrates, the acquisition of breeding status is often determined after sexual maturity and strongly impacted by chance in many cooperative vertebrates, who may therefore retain the ability to adjust their morphology to environmental changes and social opportunities arising throughout their development, rather than specializing early.

  2. Additive genetic variance and developmental plasticity in growth trajectories in a wild cooperative mammal.

    PubMed

    Huchard, E; Charmantier, A; English, S; Bateman, A; Nielsen, J F; Clutton-Brock, T

    2014-09-01

    Individual variation in growth is high in cooperative breeders and may reflect plastic divergence in developmental trajectories leading to breeding vs. helping phenotypes. However, the relative importance of additive genetic variance and developmental plasticity in shaping growth trajectories is largely unknown in cooperative vertebrates. This study exploits weekly sequences of body mass from birth to adulthood to investigate sources of variance in, and covariance between, early and later growth in wild meerkats (Suricata suricatta), a cooperative mongoose. Our results indicate that (i) the correlation between early growth (prior to nutritional independence) and adult mass is positive but weak, and there are frequent changes (compensatory growth) in post-independence growth trajectories; (ii) among parameters describing growth trajectories, those describing growth rate (prior to and at nutritional independence) show undetectable heritability while associated size parameters (mass at nutritional independence and asymptotic mass) are moderately heritable (0.09 ≤ h(2) < 0.3); and (iii) additive genetic effects, rather than early environmental effects, mediate the covariance between early growth and adult mass. These results reveal that meerkat growth trajectories remain plastic throughout development, rather than showing early and irreversible divergence, and that the weak effects of early growth on adult mass, an important determinant of breeding success, are partly genetic. In contrast to most cooperative invertebrates, the acquisition of breeding status is often determined after sexual maturity and strongly impacted by chance in many cooperative vertebrates, who may therefore retain the ability to adjust their morphology to environmental changes and social opportunities arising throughout their development, rather than specializing early. PMID:24962704

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. eNOS Genetic Polymorphisms and Cancer Risk

    PubMed Central

    Gao, Xueren; Wang, Jie; Wang, Wenjun; Wang, Mingxi; Zhang, Jianqiong

    2015-01-01

    Abstract The association between endothelial nitric oxide synthase (eNOS) polymorphisms (intron 4a/b, -786T>C and 894G>T) and cancer risk remains elusive. In addition, no studies focused on their associations with the risk of breast cancer in Chinese Han population. Thus, a meta-analysis was conducted to determine the relationship between eNOS polymorphisms and cancer risk, and then a case–control study in Chinese Han population was performed to assess their associations with breast cancer susceptibility. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The pooled analysis indicated that eNOS intron 4a/b and -786T>C polymorphisms were significantly associated with an increased risk of overall cancer. In subgroup analyses based on cancer type, the significant association was found between eNOS intron 4a/b polymorphism and prostate cancer risk, eNOS -786T>C polymorphism and risk of prostate, bladder and breast cancers, and eNOS 894G>T polymorphism and breast cancer risk. In subgroup analyses based on ethnicity, eNOS intron 4a/b and -786T>C polymorphisms were associated with an increased risk of cancer in Caucasians. In consistent with our meta-analysis results, a case–control study in Chinese Han population showed significant associations of eNOS -786T>C and 894G>T polymorphisms with the increased risk of breast cancer. In addition, stratified analyses based on pathological type showed that eNOS 894G>T polymorphism was only associated with the risk of infiltrative ductal carcinoma. Stratified analyses by tumor stage showed that eNOS -786T>C polymorphism was only associated with the risk of tumor stage III and IV. In conclusion, our meta-analysis and case–control study suggest that eNOS -786T>C and 894G>T polymorphisms are associated with the increased risk of breast cancer. PMID:26131841

  8. Towards internationally acceptable standards for food additives and contaminants based on the use of risk analysis.

    PubMed

    Huggett, A; Petersen, B J; Walker, R; Fisher, C E; Notermans, S H; Rombouts, F M; Abbott, P; Debackere, M; Hathaway, S C; Hecker, E F; Knaap, A G; Kuznesof, P M; Meyland, I; Moy, G; Narbonne, J F; Paakkanen, J; Smith, M R; Tennant, D; Wagstaffe, P; Wargo, J; Würtzen, G

    1998-06-01

    Internationally acceptable norms need to incorporate sound science and consistent risk management principles in an open and transparent manner, as set out in the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). The process of risk analysis provides a procedure to reach these goals. The interaction between risk assessors and risk managers is considered vital to this procedure. This paper reports the outcome of a meeting of risk assessors and risk managers on specific aspects of risk analysis and its application to international standard setting for food additives and contaminants. Case studies on aflatoxins and aspartame were used to identify the key steps of the interaction process which ensure scientific justification for risk management decisions. A series of recommendations were proposed in order to enhance the scientific transparency in these critical phases of the standard setting procedure.

  9. Genetic variants influencing circulating lipid levels and risk of coronary artery disease

    PubMed Central

    Waterworth, Dawn M; Ricketts, Sally L; Song, Kijoung; Chen, Li; Zhao, Jing Hua; Ripatti, Samuli; Aulchenko, Yurii S; Zhang, Weihua; Yuan, Xin; Lim, Noha; Luan, Jian’an; Ashford, Sofie; Wheeler, Eleanor; Young, Elizabeth H; Hadley, David; Thompson, John R; Braund, Peter S; Johnson, Toby; Struchalin, Maksim; Surakka, Ida; Luben, Robert; Khaw, Kay-Tee; Rodwell, Sheila A; Loos, Ruth J F; Boekholdt, S. Matthijs; Inouye, Michael; Deloukas, Panagiotis; Elliott, Paul; Schlessinger, David; Sanna, Serena; Scuteri, Angelo; Jackson, Anne; Mohlke, Karen L; Tuomilehto, Jaako; Roberts, Robert; Stewart, Alexandre; Kesäniemi, Y Antero; Mahley, Robert W; Grundy, Scott M; Hofman, Albert; McArdle, Wendy; Cardon, Lon; Waeber, Gérard; Vollenweider, Peter; Chambers, John C; Boehnke, Michael; Abecasis, Gonçalo R; Salomaa, Veikko; Järvelin, Marjo-Riitta; Barroso, Inês; Epstein, Stephen E; Hakonarson, Hakon H; Rader, Daniel J; Reilly, Muredach P; Witteman, Jacqueline C M; Hall, Alistair S; Samani, Nilesh J; Strachan, David P; Barter, Philip; van Duijn, Cornelia M; Kooner, Jaspal S; Peltonen, Leena; Wareham, Nicholas J; McPherson, Ruth; Mooser, Vincent; Sandhu, Manjinder S

    2013-01-01

    Objectives Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides. Methods and results We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls. We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9). Conclusions We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk. PMID:20864672

  10. The apolipoprotein epsilon4 allele confers additional risk in children with familial hypercholesterolemia.

    PubMed

    Wiegman, Albert; Sijbrands, Eric J G; Rodenburg, Jessica; Defesche, Joep C; de Jongh, Saskia; Bakker, Henk D; Kastelein, John J P

    2003-06-01

    Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 +/- 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 +/- 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 allele explained 72.4% of the variance of HDL cholesterol levels (-0.15 mmol/L, 95% confidence interval -0.24 to -0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the epsilon4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children. PMID:12646733

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

    PubMed

    Wu, Yishuo; Zhang, Ning; Li, Kaiwen; Chen, Haitao; Lin, Xiaolin; Yu, Yang; Gou, Yuancheng; Hou, Jiangang; Jiang, Deke; Na, Rong; Wang, Xiang; Ding, Qiang; Xu, Jianfeng

    2016-04-01

    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.

  12. 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

  13. Extracting additional risk managers information from a risk assessment of Listeria monocytogenes in deli meats.

    PubMed

    Pérez-Rodríguez, F; van Asselt, E D; Garcia-Gimeno, R M; Zurera, G; Zwietering, M H

    2007-05-01

    The risk assessment study of Listeria monocytogenes in ready-to-eat foods conducted by the U.S. Food and Drug Administration is an example of an extensive quantitative microbiological risk assessment that could be used by risk analysts and other scientists to obtain information and by managers and stakeholders to make decisions on food safety management. The present study was conducted to investigate how detailed sensitivity analysis can be used by assessors to extract more information on risk factors and how results can be communicated to managers and stakeholders in an understandable way. The extended sensitivity analysis revealed that the extremes at the right side of the dose distribution (at consumption, 9 to 11.5 log CFU per serving) were responsible for most of the cases of listeriosis simulated. For concentration at retail, values below the detection limit of 0.04 CFU/g and the often used limit for L. monocytogenes of 100 CFU/g (also at retail) were associated with a high number of annual cases of listeriosis (about 29 and 82%, respectively). This association can be explained by growth of L. monocytogenes at both average and extreme values of temperature and time, indicating that a wide distribution can lead to high risk levels. Another finding is the importance of the maximal population density (i.e., the maximum concentration of L. monocytogenes assumed at a certain temperature) for accurately estimating the risk of infection by opportunistic pathogens such as L. monocytogenes. According to the obtained results, mainly concentrations corresponding to the highest maximal population densities caused risk in the simulation. However, sensitivity analysis applied to the uncertainty parameters revealed that prevalence at retail was the most important source of uncertainty in the model.

  14. Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder

    PubMed Central

    Dima, D; Roberts, R E; Frangou, S

    2016-01-01

    Bipolar disorder (BD) is characterized by emotional dysregulation and cognitive deficits associated with abnormal connectivity between subcortical—primarily emotional processing regions—and prefrontal regulatory areas. Given the significant contribution of genetic factors to BD, studies in unaffected first-degree relatives can identify neural mechanisms of genetic risk but also resilience, thus paving the way for preventive interventions. Dynamic causal modeling (DCM) and random-effects Bayesian model selection were used to define and assess connectomic phenotypes linked to facial affect processing and working memory in a demographically matched sample of first-degree relatives carefully selected for resilience (n=25), euthymic patients with BD (n=41) and unrelated healthy controls (n=46). During facial affect processing, patients and relatives showed similarly increased frontolimbic connectivity; resilient relatives, however, evidenced additional adaptive hyperconnectivity within the ventral visual stream. During working memory processing, patients displayed widespread hypoconnectivity within the corresponding network. In contrast, working memory network connectivity in resilient relatives was comparable to that of controls. Our results indicate that frontolimbic dysfunction during affect processing could represent a marker of genetic risk to BD, and diffuse hypoconnectivity within the working memory network a marker of disease expression. The association of hyperconnectivity within the affect-processing network with resilience to BD suggests adaptive plasticity that allows for compensatory changes and encourages further investigation of this phenotype in genetic and early intervention studies. PMID:26731443

  15. Genetic rearrangements of six wheat-agropyron cristatum 6P addition lines revealed by molecular markers.

    PubMed

    Han, Haiming; Bai, Li; Su, Junji; Zhang, Jinpeng; Song, Liqiang; Gao, Ainong; Yang, Xinming; Li, Xiuquan; Liu, Weihua; Li, Lihui

    2014-01-01

    Agropyron cristatum (L.) Gaertn. (2n = 4x = 28, PPPP) not only is cultivated as pasture fodder but also could provide many desirable genes for wheat improvement. It is critical to obtain common wheat-A. cristatum alien disomic addition lines to locate the desired genes on the P genome chromosomes. Comparative analysis of the homoeologous relationships between the P genome chromosome and wheat genome chromosomes is a key step in transferring different desirable genes into common wheat and producing the desired alien translocation line while compensating for the loss of wheat chromatin. In this study, six common wheat-A. cristatum disomic addition lines were produced and analyzed by phenotypic examination, genomic in situ hybridization (GISH), SSR markers from the ABD genomes and STS markers from the P genome. Comparative maps, six in total, were generated and demonstrated that all six addition lines belonged to homoeologous group 6. However, chromosome 6P had undergone obvious rearrangements in different addition lines compared with the wheat chromosome, indicating that to obtain a genetic compensating alien translocation line, one should recombine alien chromosomal regions with homoeologous wheat chromosomes. Indeed, these addition lines were classified into four types based on the comparative mapping: 6PI, 6PII, 6PIII, and 6PIV. The different types of chromosome 6P possessed different desirable genes. For example, the 6PI type, containing three addition lines, carried genes conferring high numbers of kernels per spike and resistance to powdery mildew, important traits for wheat improvement. These results may prove valuable for promoting the development of conventional chromosome engineering techniques toward molecular chromosome engineering. PMID:24595330

  16. Symposium overview: genetic polymorphisms in DNA repair and cancer risk.

    PubMed

    Hu, J J; Mohrenweiser, H W; Bell, D A; Leadon, S A; Miller, M S

    2002-11-15

    A symposium, Genetic Polymorphisms in DNA Repair and Cancer Risk, was presented at the 40th Annual Meeting of the Society of Toxicology, held in San Francisco, California, in March 2001. A brief report of the symposium was published (Kaiser, Science 292, 837-838, 2001). Molecular epidemiological studies have shown that polymorphic variants of genes involved in the metabolism and repair of carcinogens can act as cancer susceptibility genes. These variants of drug metabolic and DNA-repair enzymes either increase the activation of chemical carcinogens or decrease the cells' ability to detoxify/repair mutagenic damages. Although on an individual basis these variant alleles may only slightly change catalytic activity and increase cancer risk, their polymorphic frequency in the human population may contribute to a high proportion of cancer cases. Studies conducted over the past few years have identified variant alleles for a number of DNA-repair genes, some of which have been shown to change DNA-repair capacity. Identifying these genotypic alterations in DNA-repair enzymes and their association with cancer may help to elucidate the mechanisms of cancer etiology and to predict both disease risk and response to cancer therapy, since most antineoplastic treatments mediate their effects through DNA damage.

  17. Benefits and concerns associated with biotechnology-derived foods: can additional research reduce children health risks?

    PubMed

    Cantani, A

    2006-01-01

    The development of techniques devised for the genetic manipulation of foods poses new risks for children with food allergy (FA). The introduction of foreign allergenic proteins from different foods into previously tolerated foods may trigger allergic reactions, often complicating with anaphylactic shock in a subset of allergic babies. Children with FA, even if subjected to preventative diets, always challenge the risk of developing allergic manifestations after unintentional intake of a non tolerated food in restaurant settings, with relatives or schoolmates, etc, where product labelling is necessarily lacking. The introduction of potentially allergenic proteins into foods generally considered safe for allergic children can be done deliberately, by either substantially altering the food ingredients, or by genetic manipulation which change the composition or transfer allergens, or unintentionally by quality-control failures, due to contaminations in the production process, or to genetic mismanipulation. There is a controversy between multinationals often favored by governments and consumer association resistance, thus an equidistant analysis poses some unprecedented impediments. The importance of FA and the potential of transgenic plants to bring food allergens into the food supply should not be disregarded. The expression in soybeans of a Brazil nut protein resulted in a food allergen expressed in widely used infant formulas, so paving the way to an often reported multinational debacle. Genetic engineering poses innovative ethical and social concerns, as well as serious challenges to the environment, human health, animal welfare, and the future of agriculture. In this paper will be emphasized practical concepts more crucial for pediatricians.

  18. Benefits and concerns associated with biotechnology-derived foods: can additional research reduce children health risks?

    PubMed

    Cantani, A

    2009-01-01

    The development of techniques devised for the genetic manipulation of foods poses new risks for children with food allergy (FA). The introduction of foreign allergenic proteins from different foods into previously tolerated foods may trigger allergic reactions, often complicating with anaphylactic shock in a subset of allergic babies. Children with FA, even if subjected to preventative diets, always challenge the risk of developing allergic manifestations after unintentional intake of a non tolerated food in restaurant settings, with relatives or schoolmates, etc, where product labelling is necessarily lacking. The introduction of potentially allergenic proteins into foods generally considered safe for allergic children can be done deliberately, by either substantially altering the food ingredients, or by genetic manipulation which change the composition or transfer allergens, or unintentionally by qualitycontrol failures, due to contaminations in the production process, or to genetic mismanipulation. There is a controversy between multinationals often favored by governments and consumer association resistance, thus an equidistant analysis poses some unprecedented impediments. The importance of FA and the potential of transgenic plants to bring food allergens into the food supply should not be disregarded. The expression in soybeans of a Brazil nut protein resulted in a food allergen ex-pressed in widely used infant formulas, so paving the way to an often reported multinational debacle. Genetic engineering poses innovative ethical and social concerns, as well as serious challenges to the environment, human health, animal welfare, and the future of agriculture. In this paper will be emphasized practical concepts more crucial for pediatricians.

  19. Benefits and concerns associated with biotechnology-derived foods: can additional research reduce children health risks?

    PubMed

    Cantani, A

    2006-01-01

    The development of techniques devised for the genetic manipulation of foods poses new risks for children with food allergy (FA). The introduction of foreign allergenic proteins from different foods into previously tolerated foods may trigger allergic reactions, often complicating with anaphylactic shock in a subset of allergic babies. Children with FA, even if subjected to preventative diets, always challenge the risk of developing allergic manifestations after unintentional intake of a non tolerated food in restaurant settings, with relatives or schoolmates, etc, where product labelling is necessarily lacking. The introduction of potentially allergenic proteins into foods generally considered safe for allergic children can be done deliberately, by either substantially altering the food ingredients, or by genetic manipulation which change the composition or transfer allergens, or unintentionally by quality-control failures, due to contaminations in the production process, or to genetic mismanipulation. There is a controversy between multinationals often favored by governments and consumer association resistance, thus an equidistant analysis poses some unprecedented impediments. The importance of FA and the potential of transgenic plants to bring food allergens into the food supply should not be disregarded. The expression in soybeans of a Brazil nut protein resulted in a food allergen expressed in widely used infant formulas, so paving the way to an often reported multinational debacle. Genetic engineering poses innovative ethical and social concerns, as well as serious challenges to the environment, human health, animal welfare, and the future of agriculture. In this paper will be emphasized practical concepts more crucial for pediatricians. PMID:16910351

  20. Benefits and concerns associated with biotechnology-derived foods: can additional research reduce children health risks?

    PubMed

    Cantani, A

    2009-01-01

    The development of techniques devised for the genetic manipulation of foods poses new risks for children with food allergy (FA). The introduction of foreign allergenic proteins from different foods into previously tolerated foods may trigger allergic reactions, often complicating with anaphylactic shock in a subset of allergic babies. Children with FA, even if subjected to preventative diets, always challenge the risk of developing allergic manifestations after unintentional intake of a non tolerated food in restaurant settings, with relatives or schoolmates, etc, where product labelling is necessarily lacking. The introduction of potentially allergenic proteins into foods generally considered safe for allergic children can be done deliberately, by either substantially altering the food ingredients, or by genetic manipulation which change the composition or transfer allergens, or unintentionally by qualitycontrol failures, due to contaminations in the production process, or to genetic mismanipulation. There is a controversy between multinationals often favored by governments and consumer association resistance, thus an equidistant analysis poses some unprecedented impediments. The importance of FA and the potential of transgenic plants to bring food allergens into the food supply should not be disregarded. The expression in soybeans of a Brazil nut protein resulted in a food allergen ex-pressed in widely used infant formulas, so paving the way to an often reported multinational debacle. Genetic engineering poses innovative ethical and social concerns, as well as serious challenges to the environment, human health, animal welfare, and the future of agriculture. In this paper will be emphasized practical concepts more crucial for pediatricians. PMID:19364084

  1. 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

    2014-05-20

    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

  2. Heritability of heterozygosity offers a new way of understanding why dominant gene action contributes to additive genetic variance.

    PubMed

    Nietlisbach, Pirmin; Hadfield, Jarrod D

    2015-07-01

    Whenever allele frequencies are unequal, nonadditive gene action contributes to additive genetic variance and therefore the resemblance between parents and offspring. The reason for this has not been easy to understand. Here, we present a new single-locus decomposition of additive genetic variance that may give greater intuition about this important result. We show that the contribution of dominant gene action to parent-offspring resemblance only depends on the degree to which the heterozygosity of parents and offspring covary. Thus, dominant gene action only contributes to additive genetic variance when heterozygosity is heritable. Under most circumstances this is the case because individuals with rare alleles are more likely to be heterozygous, and because they pass rare alleles to their offspring they also tend to have heterozygous offspring. When segregating alleles are at equal frequency there are no rare alleles, the heterozygosities of parents and offspring are uncorrelated and dominant gene action does not contribute to additive genetic variance. PMID:26100570

  3. 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

  4. Are major behavioral and sociodemographic risk factors for mortality additive or multiplicative in their effects?

    PubMed

    Mehta, Neil; Preston, Samuel

    2016-04-01

    All individuals are subject to multiple risk factors for mortality. In this paper, we consider the nature of interactions between certain major sociodemographic and behavioral risk factors associated with all-cause mortality in the United States. We develop the formal logic pertaining to two forms of interaction between risk factors, additive and multiplicative relations. We then consider the general circumstances in which additive or multiplicative relations might be expected. We argue that expectations about interactions among socio-demographic variables, and their relation to behavioral variables, have been stated in terms of additivity. However, the statistical models typically used to estimate the relation between risk factors and mortality assume that risk factors act multiplicatively. We examine empirically the nature of interactions among five major risk factors associated with all-cause mortality: smoking, obesity, race, sex, and educational attainment. Data were drawn from the cross-sectional NHANES III (1988-1994) and NHANES 1999-2010 surveys, linked to death records through December 31, 2011. Our analytic sample comprised 35,604 respondents and 5369 deaths. We find that obesity is additive with each of the remaining four variables. We speculate that its additivity is a reflection of the fact that obese status is generally achieved later in life. For all pairings of socio-demographic variables, risks are multiplicative. For survival chances, it is much more dangerous to be poorly educated if you are black or if you are male. And it is much riskier to be a male if you are black. These traits, established at birth or during childhood, literally result in deadly combinations. We conclude that the identification of interactions among risk factors can cast valuable light on the nature of the process being studied. It also has public health implications by identifying especially vulnerable groups and by properly identifying the proportion of deaths

  5. "The Dose Makes the Poison": Informing Consumers About the Scientific Risk Assessment of Food Additives.

    PubMed

    Bearth, Angela; Cousin, Marie-Eve; Siegrist, Michael

    2016-01-01

    Intensive risk assessment is required before the approval of food additives. During this process, based on the toxicological principle of "the dose makes the poison,ˮ maximum usage doses are assessed. However, most consumers are not aware of these efforts to ensure the safety of food additives and are therefore sceptical, even though food additives bring certain benefits to consumers. This study investigated the effect of a short video, which explains the scientific risk assessment and regulation of food additives, on consumers' perceptions and acceptance of food additives. The primary goal of this study was to inform consumers and enable them to construct their own risk-benefit assessment and make informed decisions about food additives. The secondary goal was to investigate whether people have different perceptions of food additives of artificial (i.e., aspartame) or natural origin (i.e., steviolglycoside). To attain these research goals, an online experiment was conducted on 185 Swiss consumers. Participants were randomly assigned to either the experimental group, which was shown a video about the scientific risk assessment of food additives, or the control group, which was shown a video about a topic irrelevant to the study. After watching the video, the respondents knew significantly more, expressed more positive thoughts and feelings, had less risk perception, and more acceptance than prior to watching the video. Thus, it appears that informing consumers about complex food safety topics, such as the scientific risk assessment of food additives, is possible, and using a carefully developed information video is a successful strategy for informing consumers. PMID:25951078

  6. "The Dose Makes the Poison": Informing Consumers About the Scientific Risk Assessment of Food Additives.

    PubMed

    Bearth, Angela; Cousin, Marie-Eve; Siegrist, Michael

    2016-01-01

    Intensive risk assessment is required before the approval of food additives. During this process, based on the toxicological principle of "the dose makes the poison,ˮ maximum usage doses are assessed. However, most consumers are not aware of these efforts to ensure the safety of food additives and are therefore sceptical, even though food additives bring certain benefits to consumers. This study investigated the effect of a short video, which explains the scientific risk assessment and regulation of food additives, on consumers' perceptions and acceptance of food additives. The primary goal of this study was to inform consumers and enable them to construct their own risk-benefit assessment and make informed decisions about food additives. The secondary goal was to investigate whether people have different perceptions of food additives of artificial (i.e., aspartame) or natural origin (i.e., steviolglycoside). To attain these research goals, an online experiment was conducted on 185 Swiss consumers. Participants were randomly assigned to either the experimental group, which was shown a video about the scientific risk assessment of food additives, or the control group, which was shown a video about a topic irrelevant to the study. After watching the video, the respondents knew significantly more, expressed more positive thoughts and feelings, had less risk perception, and more acceptance than prior to watching the video. Thus, it appears that informing consumers about complex food safety topics, such as the scientific risk assessment of food additives, is possible, and using a carefully developed information video is a successful strategy for informing consumers.

  7. 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

  8. 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.

  9. Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma

    PubMed Central

    Rendleman, Justin; Antipin, Yevgeniy; Reva, Boris; Adaniel, Christina; Przybylo, Jennifer A.; Dutra-Clarke, Ana; Hansen, Nichole; Heguy, Adriana; Huberman, Kety; Borsu, Laetitia; Paltiel, Ora; Ben-Yehuda, Dina; Brown, Jennifer R.; Freedman, Arnold S.; Sander, Chris; Zelenetz, Andrew; Klein, Robert J.; Shao, Yongzhao; Lacher, Mortimer; Vijai, Joseph; Offit, Kenneth; Kirchhoff, Tomas

    2014-01-01

    Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL. PMID:25010664

  10. Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO, and CCFR Consortia

    PubMed Central

    Cheng, Iona; Kocarnik, Jonathan M; Dumitrescu, Logan; Lindor, Noralane M; Chang-Claude, Jenny; Avery, Christy L.; Caberto, Christian P; Love, Shelly-Ann; Slattery, Martha L; Chan, Andrew T; Baron, John A; Hindorff, Lucia A; Park, Sungshim Lani; Schumacher, Fredrick R; Hoffmeister, Michael; Kraft, Peter; Butler, Anne; Duggan, David; Hou, Lifang; Carlson, Chris S; Monroe, Kristine R; Lin, Yi; Carty, Cara L; Mann, Sue; Ma, Jing; Giovannucci, Edward L; Fuchs, Charles S; Newcomb, Polly A; Jenkins, Mark A; Hopper, John L; Haile, Robert W; Conti, David V; Campbell, Peter T; Potter, John D; Caan, Bette J; Schoen, Robert E; Hayes, Richard B; Chanock, Stephen J; Berndt, Sonja I; Kury, Sebastien; Bezieau, Stephane; Ambite, Jose Luis; Kumaraguruparan, Gowri; Richardson, Danielle; Goodloe, Robert J; Dilks, Holli H; Baker, Paxton; Zanke, Brent W; Lemire, Mathieu; Gallinger, Steven; Hsu, Li; Jiao, Shuo; Harrison, Tabitha; Seminara, Daniela; Haiman, Christopher A; Kooperberg, Charles; Wilkens, Lynne R; Hutter, Carolyn M; White, Emily; Crawford, Dana C; Heiss, Gerardo; Hudson, Thomas J; Brenner, Hermann; Bush, William S; Casey, Graham; Marchand, Loic Le; Peters, Ulrike

    2013-01-01

    Objective Genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13,338 colorectal cancer cases and 40,967 controls from three consortia: Population Architecture using Genetics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p-value of 2.92×10−4 was used to determine statistical significance of the associations. Results Two correlated SNPs— rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI: 1.07–1.18; P=1.74×10−5), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusion This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer, thus adding colorectal cancer to the list of cancer sites linked to this particular multi-cancer risk region at 8q24. PMID:23935004

  11. Very low levels of direct additive genetic variance in fitness and fitness components in a red squirrel population.

    PubMed

    McFarlane, S Eryn; Gorrell, Jamieson C; Coltman, David W; Humphries, Murray M; Boutin, Stan; McAdam, Andrew G

    2014-05-01

    A trait must genetically correlate with fitness in order to evolve in response to natural selection, but theory suggests that strong directional selection should erode additive genetic variance in fitness and limit future evolutionary potential. Balancing selection has been proposed as a mechanism that could maintain genetic variance if fitness components trade off with one another and has been invoked to account for empirical observations of higher levels of additive genetic variance in fitness components than would be expected from mutation-selection balance. Here, we used a long-term study of an individually marked population of North American red squirrels (Tamiasciurus hudsonicus) to look for evidence of (1) additive genetic variance in lifetime reproductive success and (2) fitness trade-offs between fitness components, such as male and female fitness or fitness in high- and low-resource environments. "Animal model" analyses of a multigenerational pedigree revealed modest maternal effects on fitness, but very low levels of additive genetic variance in lifetime reproductive success overall as well as fitness measures within each sex and environment. It therefore appears that there are very low levels of direct genetic variance in fitness and fitness components in red squirrels to facilitate contemporary adaptation in this population.

  12. Additive genetic variance in polyandry enables its evolution, but polyandry is unlikely to evolve through sexy or good sperm processes.

    PubMed

    Travers, L M; Simmons, L W; Garcia-Gonzalez, F

    2016-05-01

    Polyandry is widespread despite its costs. The sexually selected sperm hypotheses ('sexy' and 'good' sperm) posit that sperm competition plays a role in the evolution of polyandry. Two poorly studied assumptions of these hypotheses are the presence of additive genetic variance in polyandry and sperm competitiveness. Using a quantitative genetic breeding design in a natural population of Drosophila melanogaster, we first established the potential for polyandry to respond to selection. We then investigated whether polyandry can evolve through sexually selected sperm processes. We measured lifetime polyandry and offensive sperm competitiveness (P2 ) while controlling for sampling variance due to male × male × female interactions. We also measured additive genetic variance in egg-to-adult viability and controlled for its effect on P2 estimates. Female lifetime polyandry showed significant and substantial additive genetic variance and evolvability. In contrast, we found little genetic variance or evolvability in P2 or egg-to-adult viability. Additive genetic variance in polyandry highlights its potential to respond to selection. However, the low levels of genetic variance in sperm competitiveness suggest that the evolution of polyandry may not be driven by sexy sperm or good sperm processes.

  13. Additive genetic variance in polyandry enables its evolution, but polyandry is unlikely to evolve through sexy or good sperm processes.

    PubMed

    Travers, L M; Simmons, L W; Garcia-Gonzalez, F

    2016-05-01

    Polyandry is widespread despite its costs. The sexually selected sperm hypotheses ('sexy' and 'good' sperm) posit that sperm competition plays a role in the evolution of polyandry. Two poorly studied assumptions of these hypotheses are the presence of additive genetic variance in polyandry and sperm competitiveness. Using a quantitative genetic breeding design in a natural population of Drosophila melanogaster, we first established the potential for polyandry to respond to selection. We then investigated whether polyandry can evolve through sexually selected sperm processes. We measured lifetime polyandry and offensive sperm competitiveness (P2 ) while controlling for sampling variance due to male × male × female interactions. We also measured additive genetic variance in egg-to-adult viability and controlled for its effect on P2 estimates. Female lifetime polyandry showed significant and substantial additive genetic variance and evolvability. In contrast, we found little genetic variance or evolvability in P2 or egg-to-adult viability. Additive genetic variance in polyandry highlights its potential to respond to selection. However, the low levels of genetic variance in sperm competitiveness suggest that the evolution of polyandry may not be driven by sexy sperm or good sperm processes. PMID:26801640

  14. Very low levels of direct additive genetic variance in fitness and fitness components in a red squirrel population

    PubMed Central

    McFarlane, S Eryn; Gorrell, Jamieson C; Coltman, David W; Humphries, Murray M; Boutin, Stan; McAdam, Andrew G

    2014-01-01

    A trait must genetically correlate with fitness in order to evolve in response to natural selection, but theory suggests that strong directional selection should erode additive genetic variance in fitness and limit future evolutionary potential. Balancing selection has been proposed as a mechanism that could maintain genetic variance if fitness components trade off with one another and has been invoked to account for empirical observations of higher levels of additive genetic variance in fitness components than would be expected from mutation–selection balance. Here, we used a long-term study of an individually marked population of North American red squirrels (Tamiasciurus hudsonicus) to look for evidence of (1) additive genetic variance in lifetime reproductive success and (2) fitness trade-offs between fitness components, such as male and female fitness or fitness in high- and low-resource environments. “Animal model” analyses of a multigenerational pedigree revealed modest maternal effects on fitness, but very low levels of additive genetic variance in lifetime reproductive success overall as well as fitness measures within each sex and environment. It therefore appears that there are very low levels of direct genetic variance in fitness and fitness components in red squirrels to facilitate contemporary adaptation in this population. PMID:24963372

  15. Lobular breast cancer: incidence and genetic and non-genetic risk factors.

    PubMed

    Dossus, Laure; Benusiglio, Patrick R

    2015-01-01

    While most invasive breast cancers consist of carcinomas of the ductal type, about 10% are invasive lobular carcinomas. Invasive lobular and ductal carcinomas differ with respect to risk factors. Invasive lobular carcinoma is more strongly associated with exposure to female hormones, and therefore its incidence is more subject to variation. This is illustrated by US figures during the 1987 to 2004 period: after 12 years of increases, breast cancer incidence declined steadily from 1999 to 2004, reflecting among other causes the decreasing use of menopausal hormone therapy, and these variations were stronger for invasive lobular than for invasive ductal carcinoma. Similarly, invasive lobular carcinoma is more strongly associated with early menarche, late menopause and late age at first birth. As for genetic risk factors, four high-penetrance genes are tested in clinical practice when genetic susceptibility to breast cancer is suspected, BRCA1, BRCA2, TP53 and CDH1. Germline mutations in BRCA1 and TP53 are predominantly associated with invasive ductal carcinoma, while BRCA2 mutations are associated with both ductal and lobular cancers. CDH1, the gene coding for the E-cadherin adhesion protein, is of special interest as mutations are associated with invasive lobular carcinoma, but never with ductal carcinoma. It was initially known as the main susceptibility gene for gastric cancer of the diffuse type, but the excess of breast cancers of the lobular type in CDH1 families led researchers to identify it also as a susceptibility gene for invasive lobular carcinoma. The risk of invasive lobular carcinoma is high in female mutation carriers, as about 50% are expected to develop the disease. Carriers must therefore undergo intensive breast cancer screening, with, for example, yearly magnetic resonance imaging and mammogram starting at age 30 years. PMID:25848941

  16. Lobular breast cancer: incidence and genetic and non-genetic risk factors.

    PubMed

    Dossus, Laure; Benusiglio, Patrick R

    2015-01-01

    While most invasive breast cancers consist of carcinomas of the ductal type, about 10% are invasive lobular carcinomas. Invasive lobular and ductal carcinomas differ with respect to risk factors. Invasive lobular carcinoma is more strongly associated with exposure to female hormones, and therefore its incidence is more subject to variation. This is illustrated by US figures during the 1987 to 2004 period: after 12 years of increases, breast cancer incidence declined steadily from 1999 to 2004, reflecting among other causes the decreasing use of menopausal hormone therapy, and these variations were stronger for invasive lobular than for invasive ductal carcinoma. Similarly, invasive lobular carcinoma is more strongly associated with early menarche, late menopause and late age at first birth. As for genetic risk factors, four high-penetrance genes are tested in clinical practice when genetic susceptibility to breast cancer is suspected, BRCA1, BRCA2, TP53 and CDH1. Germline mutations in BRCA1 and TP53 are predominantly associated with invasive ductal carcinoma, while BRCA2 mutations are associated with both ductal and lobular cancers. CDH1, the gene coding for the E-cadherin adhesion protein, is of special interest as mutations are associated with invasive lobular carcinoma, but never with ductal carcinoma. It was initially known as the main susceptibility gene for gastric cancer of the diffuse type, but the excess of breast cancers of the lobular type in CDH1 families led researchers to identify it also as a susceptibility gene for invasive lobular carcinoma. The risk of invasive lobular carcinoma is high in female mutation carriers, as about 50% are expected to develop the disease. Carriers must therefore undergo intensive breast cancer screening, with, for example, yearly magnetic resonance imaging and mammogram starting at age 30 years.

  17. 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

  18. 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

  19. 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

  20. Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes

    PubMed Central

    Figueroa, Jonine D.; Malats, Núria; García-Closas, Montserrat; Real, Francisco X.; Silverman, Debra; Kogevinas, Manolis; Chanock, Stephen; Welch, Robert; Dosemeci, Mustafa; Lan, Qing; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Castaño-Vinyals, Gemma; Rothman, Nathaniel

    2008-01-01

    Aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) are carcinogens present in tobacco smoke and functional polymorphisms in NAT2 and GSTM1 metabolizing genes are associated with increased bladder cancer risk. We evaluated whether genetic variation in other candidate metabolizing genes are also associated with risk. Candidates included genes that control the transcription of metabolizing genes [aryl hydrocarbon receptor (AHR), AHRR and aryl hydrocarbon nuclear translocator (ARNT)] and genes that activate/detoxify AA or PAH (AKR1C3, CYP1A1, CYP1A2, CYP1B1, CYP3A4, EPHX1, EPHX2, NQO1, MPO, UGT1A4, SULT1A1 and SULT1A2). Using genotype data from 1150 cases of urothelial carcinomas and 1149 controls from the Spanish Bladder Cancer Study, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, region and smoking status. Based on a test for trend, we observed 10 non-redundant single-nucleotide polymorphisms (SNPs) in five genes (AKR1C3, ARNT, CYP1A1, CYP1B1 and SULT1A2) significantly associated with bladder cancer risk. We observed an inverse association with risk for the AKR1C3 promoter SNP rs1937845 [OR (95% CI) for heterozygote and homozygote variant compared with common homozygote genotype were 0.86 (0.70–1.06) and 0.74 (0.57–0.96), respectively; P for trend = 0.02]. Interestingly, genetic variation in this region has been associated with lung, non-Hodgkin lymphoma and prostate cancer risk. Analysis of additional SNPs to capture most (∼90%) of common genetic variation in AKR1C3 and haplotype walking analyses based on all AKR1C3 SNPs (n = 25) suggest two separate regions associated with bladder cancer risk. These results indicate that genetic variation in carcinogen-metabolizing genes, particularly AKR1C3, could be associated with bladder cancer risk. PMID:18632753

  1. 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

  2. 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

  3. Genetic information and life insurance: a 'real' risk?

    PubMed

    Joly, Yann; Knoppers, Bartha M; Godard, Béatrice

    2003-08-01

    Public concern about genetic discrimination, particularly access to insurance following genetic testing, has been reported in the literature. This paper aims to separate myths from realities regarding genetic discrimination in life insurance and to underline the positive aspects of allowing insurers access to relevant genetic information for underwriting purposes. We present a review of the literature pertinent to discrimination in life insurance and a comparative analysis of industries guidelines. There are few reported cases in the literature of validated genetic discrimination. However, the benefits to be gained by allowing insurers access to relevant genetic data could justify fostering a more active role in the use of genetic information by insurance companies.

  4. 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).

  5. 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

  6. 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

  7. Genetic risk prediction and neurobiological understanding of alcoholism

    PubMed Central

    Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; 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. 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-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse

  8. 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…

  9. Human Papillomavirus 18 Genetic Variation and Cervical Cancer Risk Worldwide

    PubMed Central

    Chen, Alyce A.; Gheit, Tarik; Franceschi, Silvia

    2015-01-01

    ABSTRACT Human papillomavirus 18 (HPV18) is the second most carcinogenic HPV type, after HPV16, and it accounts for approximately 12% of squamous cell carcinoma (SCC) as well as 37% of adenocarcinoma (ADC) of the cervix worldwide. We aimed to evaluate the worldwide diversity and carcinogenicity of HPV18 genetic variants by sequencing the entire long control region (LCR) and the E6 open reading frame of 711 HPV18-positive cervical samples from 39 countries, taking advantage of the International Agency for Research on Cancer biobank. A total of 209 unique HPV18 sequence variants were identified that formed three phylogenetic lineages (A, B, and C). A and B lineages each divided into four sublineages, including a newly identified candidate B4 sublineage. The distribution of lineages varied by geographical region, with B and C lineages found principally in Africa. HPV18 (sub)lineages were compared between 453 cancer cases and 236 controls, as well as between 81 ADC and 160 matched SCC cases. In region-stratified analyses, there were no significant differences in the distribution of HPV18 variant lineages between cervical cancer cases and controls or between ADC and SCC. In conclusion, our findings do not support the role of HPV18 (sub)lineages for discriminating cancer risk or explaining why HPV18 is more strongly linked with ADC than SCC. IMPORTANCE This is the largest and most geographically/ethnically diverse study of the genetic variation of HPV18 to date, providing a comprehensive reference for phylogenetic classification of HPV18 sublineages for epidemiological and biological studies. PMID:26269181

  10. 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

  11. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

    PubMed

    Lenz, Tobias L; Deutsch, Aaron J; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W J; Abecasis, Gonçalo; Becker, Jessica; Boeckxstaens, Guy E; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P; Nöthen, Markus M; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E; Tsoi, Lam C; van Heel, David A; Worthington, Jane; Wouters, Mira M; Klareskog, Lars; Elder, James T; Gregersen, Peter K; Schumacher, Johannes; Rich, Stephen S; Wijmenga, Cisca; Sunyaev, Shamil R; de Bakker, Paul I W; Raychaudhuri, Soumya

    2015-09-01

    Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10(-12); T1D, P = 2.4 × 10(-10); psoriasis, P = 5.9 × 10(-6); celiac disease, P = 1.2 × 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10(-3); T1D, P = 8.6 × 10(-27); celiac disease, P = 6.0 × 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model. PMID:26258845

  12. Toxicological safety assessment of genetically modified Bacillus thuringiensis with additional N-acyl homoserine lactonase gene.

    PubMed

    Peng, Donghai; Zhou, Chenfei; Chen, Shouwen; Ruan, Lifang; Yu, Ziniu; Sun, Ming

    2008-01-01

    The aim of the present study is to evaluate the toxicology safety to mammals of a genetically modified (GM) Bacillus thuringiensis with an additional N-acyl homoserine lactones gene (aiiA), which possesses insecticidal activity together with restraint of bacterial pathogenicity and is intended for use as a multifunctional biopesticide. Safety assessments included an acute oral toxicity test and 28-d animal feeding study in Wistar rats, primary eye and dermal irritation in Zealand White rabbits, and delayed contact hypersensitivity in guinea pigs. Tests were conducted using spray-dried powder preparation. This GM product showed toxicity neither in oral acute toxicity test nor in 28-d animal feeding test at a dose of 5,000 mg/kg body weight. During the animal feeding test, there were no significant differences in growth, food and water consumption, hematology, blood biochemical indices, organ weights, and histopathology finding between rats in controls and tested groups. Tested animals in primary eye and dermal irritation and delayed contact hypersensitivity test were also devoid of any toxicity compared to controls. All the above results demonstrated that the GM based multifunctional B. thuringiensis has low toxicity and low eye and dermal irritation and would not cause hypersensitivity to laboratory mammals and therefore could be regarded as safe for use as a pesticide.

  13. An Alzheimer’s Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults

    PubMed Central

    Mahmood, Zanjbeel; Lau, Edward P.; Karacozoff, Alexandra M.; Small, Gary W.; Bookheimer, Susan Y.

    2016-01-01

    Abstract Variants at 21 genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = −0.40; p = 0.003; WRS: r = −0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = −0.35; p = 0.009; WRS: r = −0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness. PMID:27482534

  14. Who is at risk for compassion fatigue? An investigation of genetic counselor demographics, anxiety, compassion satisfaction, and burnout.

    PubMed

    Lee, Whiwon; Veach, Patricia McCarthy; MacFarlane, Ian M; LeRoy, Bonnie S

    2015-04-01

    Compassion fatigue is a state of detachment and isolation experienced when healthcare providers repeatedly engage with patients in distress. Compassion fatigue can hinder empathy and cause extreme tension. Prior research suggests 73.8 % of genetic counselors are at moderate to high risk for compassion fatigue and approximately 1 in 4 have considered leaving the field as a result Injeyan et al. (Journal of Genetic Counseling, 20, 526-540, 2011). Empirical data to establish a reliable profile of genetic counselors at risk for compassion fatigue are limited. Thus the purpose of this study was to establish a profile by assessing relationships between state and trait anxiety, burnout, compassion satisfaction, selected demographics and compassion fatigue risk in practicing genetic counselors. Practicing genetic counselors (n = 402) completed an anonymous, online survey containing demographic questions, the State-Trait Anxiety Inventory, and the Professional Quality of Life scale. Multiple regression analysis yielded four significant predictors which increase compassion fatigue risk (accounting for 48 % of the variance): higher levels of trait anxiety, burnout, and compassion satisfaction, and ethnicity other than Caucasian. Additional findings, study limitations, practice implications, and research recommendations are provided.

  15. Empirical Bayes scan statistics for detecting clusters of disease risk variants in genetic studies.

    PubMed

    McCallum, Kenneth J; Ionita-Laza, Iuliana

    2015-12-01

    Recent developments of high-throughput genomic technologies offer an unprecedented detailed view of the genetic variation in various human populations, and promise to lead to significant progress in understanding the genetic basis of complex diseases. Despite this tremendous advance in data generation, it remains very challenging to analyze and interpret these data due to their sparse and high-dimensional nature. Here, we propose novel applications and new developments of empirical Bayes scan statistics to identify genomic regions significantly enriched with disease risk variants. We show that the proposed empirical Bayes methodology can be substantially more powerful than existing scan statistics methods especially so in the presence of many non-disease risk variants, and in situations when there is a mixture of risk and protective variants. Furthermore, the empirical Bayes approach has greater flexibility to accommodate covariates such as functional prediction scores and additional biomarkers. As proof-of-concept we apply the proposed methods to a whole-exome sequencing study for autism spectrum disorders and identify several promising candidate genes.

  16. GENETIC CONTRIBUTIONS TO POPULATION LEVEL ECOLOGICAL RISK ASSESSMENT

    EPA Science Inventory

    Genetic variation defines population structure and provides the mechanism for populations to adapt to novel stressors. Despite its fundamental importance in understanding populations, genetic information has been included rarely in models of population dynamics (endangered speci...

  17. 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

  18. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    PubMed Central

    Lenz, Tobias L.; Deutsch, Aaron J.; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W.J.; Abecasis, Goncalo; Becker, Jessica; Boeckxstaens, Guy E.; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D.; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P.; Nöthen, Markus M.; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E.; Tsoi, Lam C.; Van Heel, David A.; Worthington, Jane; Wouters, Mira M.; Klareskog, Lars; Elder, James T.; Gregersen, Peter K.; Schumacher, Johannes; Rich, Stephen S.; Wijmenga, Cisca; Sunyaev, Shamil R.; de Bakker, Paul I.W.; Raychaudhuri, Soumya

    2015-01-01

    Human leukocyte antigen (HLA) genes confer strong risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen binding repertoires between a heterozygote’s two expressed HLA variants may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, Ncases=5,337), type 1 diabetes (T1D, Ncases=5,567), psoriasis vulgaris (Ncases=3,089), idiopathic achalasia (Ncases=727), and celiac disease (Ncases=11,115). In four out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; T1D: P=2.4×10−10; psoriasis: P=5.9×10−6; celiac disease: P=1.2×10−87). In three of these diseases, the dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model). PMID:26258845

  19. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease.

    PubMed

    Holmans, Peter; Moskvina, Valentina; Jones, Lesley; Sharma, Manu; Vedernikov, Alexey; Buchel, Finja; Saad, Mohamad; Sadd, Mohamad; Bras, Jose M; Bettella, Francesco; Nicolaou, Nayia; Simón-Sánchez, Javier; Mittag, Florian; Gibbs, J Raphael; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nicholas W; Martinez, Maria; Singleton, Andrew B; Nalls, Michael A; Hardy, John; Morris, Huw R; Williams, Nigel M

    2013-03-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.

  20. 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

  1. [Chronic lymphocytic leukemia. Treatment and genetic risk profile].

    PubMed

    Stilgenbauer, S; Hallek, M

    2013-02-01

    Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Among the biological features underlying this heterogeneity, genetic lesions and the mutational status of the immunoglobulin heavy chain variable genes (IGHV) are of importance. Therapeutic options in CLL have been considerably expanded during recent years. The combination of fludarabine, cyclophosphamide and rituximab (FCR) has become gold standard in the first-line treatment of physically fit patients. Bendamustine plus rituximab (BR) is currently being compared to FCR in studies and chlorambucil is still of relevance for elderly patients with comorbidities. Alemtuzumab is an alternative for high-risk patients (refractory CLL, 17p deletion, TP53 mutation). Allogeneic stem cell transplantation (allo-SCT) offers the only chance of cure but not without substantial mortality. Innovative approaches focus on individualized, targeted therapies. A number of novel agents are in clinical trials and show marked efficacy combined with good tolerability. This review provides an overview of the current therapeutic options and of promising novel approaches.

  2. Non-genetic risk factors and their influence on the management of patients in the clinic.

    PubMed

    Álvarez, Teresa; Soto, Immaculada; Astermark, Jan

    2015-02-01

    The development of inhibitors is the most serious iatrogenic complication affecting patients with haemophilia. This complication is associated with impaired vital or functional prognosis, reduced quality of life and increased cost of treatment. The reasons why some patients develop antibodies to factor replacement and others do not remain unclear. It is however clear that inhibitor development results from a complex multifactorial interaction between genetic and non-genetic risk factors. Environmental influences implicated in increasing the risk of inhibitor formation can be viewed as modifiable risk factors. Therefore, identification of the non-genetic risk factors may offer the possibility of personalising haemophilia therapy by modifying treatment strategies in high-risk patients in the critical early phase of factor VIII exposure. In this article, we review the non-genetic factors reported as well as the potential impact of danger signals and the different scores for inhibitor development risk stratification.

  3. 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.

  4. Additive transgene expression and genetic introgression in multiple green-fluorescent protein transgenic crop x weed hybrid generations.

    PubMed

    Halfhill, M D; Millwood, R J; Weissinger, A K; Warwick, S I; Stewart, C N

    2003-11-01

    The level of transgene expression in crop x weed hybrids and the degree to which crop-specific genes are integrated into hybrid populations are important factors in assessing the potential ecological and agricultural risks of gene flow associated with genetic engineering. The average transgene zygosity and genetic structure of transgenic hybrid populations change with the progression of generations, and the green fluorescent protein (GFP) transgene is an ideal marker to quantify transgene expression in advancing populations. The homozygous T(1) single-locus insert GFP/ Bacillus thuringiensis (Bt) transgenic canola ( Brassica napus, cv Westar) with two copies of the transgene fluoresced twice as much as hemizygous individuals with only one copy of the transgene. These data indicate that the expression of the GFP gene was additive, and fluorescence could be used to determine zygosity status. Several hybrid generations (BC(1)F(1), BC(2)F(1)) were produced by backcrossing various GFP/Bt transgenic canola ( B. napus, cv Westar) and birdseed rape ( Brassica rapa) hybrid generations onto B. rapa. Intercrossed generations (BC(2)F(2) Bulk) were generated by crossing BC(2)F(1) individuals in the presence of a pollinating insect ( Musca domestica L.). The ploidy of plants in the BC(2)F(2) Bulk hybrid generation was identical to the weedy parental species, B. rapa. AFLP analysis was used to quantify the degree of B. napus introgression into multiple backcross hybrid generations with B. rapa. The F(1) hybrid generations contained 95-97% of the B. napus-specific AFLP markers, and each successive backcross generation demonstrated a reduction of markers resulting in the 15-29% presence in the BC(2)F(2) Bulk population. Average fluorescence of each successive hybrid generation was analyzed, and homozygous canola lines and hybrid populations that contained individuals homozygous for GFP (BC(2)F(2) Bulk) demonstrated significantly higher fluorescence than hemizygous hybrid

  5. Additive transgene expression and genetic introgression in multiple green-fluorescent protein transgenic crop x weed hybrid generations.

    PubMed

    Halfhill, M D; Millwood, R J; Weissinger, A K; Warwick, S I; Stewart, C N

    2003-11-01

    The level of transgene expression in crop x weed hybrids and the degree to which crop-specific genes are integrated into hybrid populations are important factors in assessing the potential ecological and agricultural risks of gene flow associated with genetic engineering. The average transgene zygosity and genetic structure of transgenic hybrid populations change with the progression of generations, and the green fluorescent protein (GFP) transgene is an ideal marker to quantify transgene expression in advancing populations. The homozygous T(1) single-locus insert GFP/ Bacillus thuringiensis (Bt) transgenic canola ( Brassica napus, cv Westar) with two copies of the transgene fluoresced twice as much as hemizygous individuals with only one copy of the transgene. These data indicate that the expression of the GFP gene was additive, and fluorescence could be used to determine zygosity status. Several hybrid generations (BC(1)F(1), BC(2)F(1)) were produced by backcrossing various GFP/Bt transgenic canola ( B. napus, cv Westar) and birdseed rape ( Brassica rapa) hybrid generations onto B. rapa. Intercrossed generations (BC(2)F(2) Bulk) were generated by crossing BC(2)F(1) individuals in the presence of a pollinating insect ( Musca domestica L.). The ploidy of plants in the BC(2)F(2) Bulk hybrid generation was identical to the weedy parental species, B. rapa. AFLP analysis was used to quantify the degree of B. napus introgression into multiple backcross hybrid generations with B. rapa. The F(1) hybrid generations contained 95-97% of the B. napus-specific AFLP markers, and each successive backcross generation demonstrated a reduction of markers resulting in the 15-29% presence in the BC(2)F(2) Bulk population. Average fluorescence of each successive hybrid generation was analyzed, and homozygous canola lines and hybrid populations that contained individuals homozygous for GFP (BC(2)F(2) Bulk) demonstrated significantly higher fluorescence than hemizygous hybrid

  6. [Questions safety and tendency of using genetically modified microorganisms in food, food additives and food derived].

    PubMed

    Khovaev, A A

    2008-01-01

    In this article analysis questions of using genetically modified microorganisms in manufacture food production, present new GMM used in manufacture -food ferments; results of medical biological appraisal/ microbiological and genetic expert examination/ of food, getting by use microorganisms or there producents with indication modern of control methods.

  7. 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

  8. Predicting stroke through genetic risk functions: The CHARGE risk score project

    PubMed Central

    Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O’Donnell, Christopher J.; Kathiresan, Sekar; Ehret, Georg B.; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F.; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G.; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; DeStefano, Anita L.; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A.; DeCarli, Charles; Ikram, M. Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, WT; van Duijn, Cornelia M; Launer, Lenore J

    2014-01-01

    Background and Purpose Beyond the Framingham Stroke Risk Score (FSRS), prediction of future stroke may improve with a genetic risk score (GRS) based on Single nucleotide polymorphisms (SNPs) associated with stroke and its risk factors. Methods The study includes four population-based cohorts with 2,047 first incident strokes from 22,720 initially stroke-free European origin participants aged 55 years and older, who were followed for up to 20 years. GRS were constructed with 324 SNPs implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with Area under the curve (AUC) statistics comparing the GRS to age sex, and FSRS models, and with reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke (IS). Results In the meta-analysis, adding the GRS to the FSRS, age and sex model resulted in a significant improvement in discrimination (All stroke: Δjoint AUC =0.016, p-value=2.3*10-6; IS: Δ joint AUC =0.021, p-value=3.7*10−7), although the overall AUC remained low. In all studies there was a highly significantly improved net reclassification index (p-values <10−4). Conclusions The SNPs associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared to the classical epidemiological risk factors for stroke. PMID:24436238

  9. Social engagement with parents in 11-month-old siblings at high and low genetic risk for autism spectrum disorder.

    PubMed

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

    2015-11-01

    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 (n = 10) were less socially engaged with their parents than were low-risk infants. Parent behavior during play did not vary by group. Within the high-risk group, ratings of social reciprocity at 11 months predicted Autism Diagnostic Observation Schedule severity scores at follow-up, suggesting that systematic observations of parent-infant play may be a useful addition to early assessments of emerging autism spectrum disorder.

  10. Genetic predisposition to higher blood pressure increases risk of incident hypertension and cardiovascular diseases in Chinese.

    PubMed

    Lu, Xiangfeng; Huang, Jianfeng; Wang, Laiyuan; Chen, Shufeng; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Li, Ying; Zhao, Liancheng; Li, Hongfan; Liu, Fangcao; Huang, Chen; Shen, Chong; Shen, Jinjin; Yu, Ling; Xu, Lihua; Mu, Jianjun; Wu, Xianping; Ji, Xu; Guo, Dongshuang; Zhou, Zhengyuan; Yang, Zili; Wang, Renping; Yang, Jun; Yan, Weili; Gu, Dongfeng

    2015-10-01

    Although multiple genetic markers associated with blood pressure have been identified by genome-wide association studies, their aggregate effect on risk of incident hypertension and cardiovascular disease is uncertain, particularly among East Asian who may have different genetic and environmental exposures from Europeans. We aimed to examine the association between genetic predisposition to higher blood pressure and risk of incident hypertension and cardiovascular disease in 26 262 individuals in 2 Chinese population-based prospective cohorts. A genetic risk score was calculated based on 22 established variants for blood pressure in East Asian. We found the genetic risk score was significantly and independently associated with linear increases in blood pressure and risk of incident hypertension and cardiovascular disease (P range from 4.57×10(-3) to 3.10×10(-6)). In analyses adjusted for traditional risk factors including blood pressure, individuals carrying most blood pressure-related risk alleles (top quintile of genetic score distribution) had 40% (95% confidence interval, 18-66) and 26% (6-45) increased risk for incident hypertension and cardiovascular disease, respectively, when compared with individuals in the bottom quintile. The genetic risk score also significantly improved discrimination for incident hypertension and cardiovascular disease and led to modest improvements in risk reclassification for cardiovascular disease (all the P<0.05). Our data indicate that genetic predisposition to higher blood pressure is an independent risk factor for blood pressure increase and incident hypertension and cardiovascular disease and provides modest incremental information to cardiovascular disease risk prediction. The potential clinical use of this panel of blood pressure-associated polymorphisms remains to be determined.

  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. Biological detoxification of the mycotoxin deoxynivalenol and its use in genetically engineered crops and feed additives.

    PubMed

    Karlovsky, Petr

    2011-08-01

    Deoxynivalenol (DON) is the major mycotoxin produced by Fusarium fungi in grains. Food and feed contaminated with DON pose a health risk to humans and livestock. The risk can be reduced by enzymatic detoxification. Complete mineralization of DON by microbial cultures has rarely been observed and the activities turned out to be unstable. The detoxification of DON by reactions targeting its epoxide group or hydroxyl on carbon 3 is more feasible. Microbial strains that de-epoxidize DON under anaerobic conditions have been isolated from animal digestive system. Feed additives claimed to de-epoxidize trichothecenes enzymatically are on the market but their efficacy has been disputed. A new detoxification pathway leading to 3-oxo-DON and 3-epi-DON was discovered in taxonomically unrelated soil bacteria from three continents; the enzymes involved remain to be identified. Arabidopsis, tobacco, wheat, barley, and rice were engineered to acetylate DON on carbon 3. In wheat expressing DON acetylation activity, the increase in resistance against Fusarium head blight was only moderate. The Tri101 gene from Fusarium sporotrichioides was used; Fusarium graminearum enzyme which possesses higher activity towards DON would presumably be a better choice. Glycosylation of trichothecenes occurs in plants, contributing to the resistance of wheat to F. graminearum infection. Marker-assisted selection based on the trichothecene-3-O-glucosyltransferase gene can be used in breeding for resistance. Fungal acetyltransferases and plant glucosyltransferases targeting carbon 3 of trichothecenes remain promising candidates for engineering resistance against Fusarium head blight. Bacterial enzymes catalyzing oxidation, epimerization, and less likely de-epoxidation of DON may extend this list in future.

  13. 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.

  14. Genetic counselling in multiple sclerosis: risks to sibs and children of affected individuals.

    PubMed

    Sadovnick, A D; Dircks, A; Ebers, G C

    1999-08-01

    Genetic factors are recognized as having important roles in both the overall etiology and the familial aggregation of multiple sclerosis (MS), leading to increased requests for genetic counselling. This paper is designed to provide familial risk data in a practical format for use during genetic counselling for MS. Depending on the amount of genetic sharing among family members, the relative risk of MS compared with that for the general population can range from 1 (adopted sibs and children of the MS proband, with whom they share no genetic material) to 190 (monozygotic co-twins of MS patients, with whom they share 100% of their genetic material). When counselling full sibs of MS patients, risks can be better calculated if information is available on the age of MS onset in the patient and whether or not one parent has MS.

  15. 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.

  16. A tiered system for assessing the risk of genetically modified plants to non-target organisms.

    PubMed

    Garcia-Alonso, Monica; Jacobs, Erik; Raybould, Alan; Nickson, Thomas E; Sowig, Peter; Willekens, Hilde; Van der Kouwe, Pier; Layton, Raymond; Amijee, Firoz; Fuentes, Angel M; Tencalla, Francesca

    2006-01-01

    Representatives of the developers of modern agricultural biotechnology are proposing a tiered approach for conducting non-target organism risk assessment for genetically modified (GM) plants in Europe. The approach was developed by the Technical Advisory Group of the EuropaBio Plant Biotechnology Unit (http://www.europabio.org/TAG.htm) and complements other international activities to harmonize risk assessment. In the European Union (EU), the principles and methods to be followed in an environmental risk assessment for the placing on the market of GM plants are laid out in Annex II of Directive 2001/18/EC on the deliberate release into the environment of GMOs, Commission Decision 2002/623/EC and Regulation (EC) No. 1829/2003. Additional information is provided in the European Food Safety Authority guidance document of 2004. However, risk assessment for effects to non-target organisms could benefit from further clarification and remains the subject of much discussion in Europe. The industry-wide approach developed by EuropaBio is based on the fundamental steps of risk evaluation, namely hazard and exposure assessment. It follows a structured scheme including assessment planning, product characterization and assessment of hazard/exposure (Tier 0), single high dose and dose response testing (Tier 1), refined hazard characterization and exposure assessment (Tier 2) and further refined risk assessment experiments (Tier 3). An additional tier (Tier 4) was included to reflect the fact that post-market activities such as monitoring are required under Directive 2001/18/EC. The approach is compatible with conditions of commercial release in the EU and around the world.

  17. Issues of concern in risk assessment, genetic counseling, and genetic testing of younger breast cancer patients in Japan.

    PubMed

    Bando, Hiroko

    2014-11-01

    About 5-10 % of breast cancer cases are considered to be hereditary, and germ line mutations in the BRCA1 and BRCA2 genes have been proven to contribute to the development of hereditary breast and/or ovarian cancer syndrome (HBOC). Breast cancer diagnosed at a young age is an indication of a higher likelihood of HBOC. Risk assessment, genetic counseling, and BRCA1/BRCA2 mutation testing, especially for younger women with breast cancer, have started to be an integral element of practice due to advances in gene sequencing technologies and accumulating evidence for the clinical implications of BRCA mutation status for not only early breast cancer management, but also for the patient's own and their family's next cancer risk, and proactive steps toward a risk-reducing approach. As yet, the cancer genetic service system is immature in Japan. There are several problems to be solved to improve cancer genetic services in clinical practice for breast cancer.

  18. Risk assessment, genetic counseling, and clinical care for hereditary breast cancer.

    PubMed

    Powers, Jacquelyn; Stopfer, Jill Elise

    2014-01-01

    During the last 30 years, key advances in the field of cancer genetics have improved identification of high-risk families in which cancer risk can be linked to mutations in cancer susceptible genes. Identification of individuals with heritable cancer risk may influence short- and long-term medical management issues. Heightened screening and risk reducing options can offer lifesaving interventions for the woman and family members who are at risk.

  19. Identifying host genetic risk factors in the context of public health surveillance for invasive pneumococcal disease.

    PubMed

    Lingappa, Jairam R; Dumitrescu, Logan; Zimmer, Shanta M; Lynfield, Ruth; McNicholl, Janet M; Messonnier, Nancy E; Whitney, Cynthia G; Crawford, Dana C

    2011-01-01

    Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p = 0.007) in EA and 5' flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p = 0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p≤0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases.

  20. 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

  1. Evolvability of individual traits in a multivariate context: partitioning the additive genetic variance into common and specific components.

    PubMed

    McGuigan, Katrina; Blows, Mark W

    2010-07-01

    Genetic covariation among multiple traits will bias the direction of evolution. Although a trait's phenotypic context is crucial for understanding evolutionary constraints, the evolutionary potential of one (focal) trait, rather than the whole phenotype, is often of interest. The extent to which a focal trait can evolve independently depends on how much of the genetic variance in that trait is unique. Here, we present a hypothesis-testing framework for estimating the genetic variance in a focal trait that is independent of variance in other traits. We illustrate our analytical approach using two Drosophila bunnanda trait sets: a contact pheromone system comprised of cuticular hydrocarbons (CHCs), and wing shape, characterized by relative warps of vein position coordinates. Only 9% of the additive genetic variation in CHCs was trait specific, suggesting individual traits are unlikely to evolve independently. In contrast, most (72%) of the additive genetic variance in wing shape was trait specific, suggesting relative warp representations of wing shape could evolve independently. The identification of genetic variance in focal traits that is independent of other traits provides a way of studying the evolvability of individual traits within the broader context of the multivariate phenotype.

  2. Possible effects of protracted exposure on the additivity of risks from space radiations

    NASA Technical Reports Server (NTRS)

    Curtis, S. B.

    1996-01-01

    Conventional radiation risk assessments are presently based on the additivity assumption. This assumption states that risks from individual components of a complex radiation field involving many different types of radiation can be added to yield the total risk of the complex radiation field. If the assumption is not correct, the summations and integrations performed to obtain the presently quoted risk estimates are not appropriate. This problem is particularly important in the area of space radiation risk evaluation because of the many different types of high- and low-LET radiation present in the galactic cosmic ray environment. For both low- and high-LET radiations at low enough dose rates, the present convention is that the addivity assumption holds. Mathematically, the total risk, Rtot is assumed to be Rtot = summation (i) Ri where the summation runs over the different types of radiation present. If the total dose (or fluence) from each component is such that the interaction between biological lesions caused by separate single track traversals is negligible within a given cell, it is presently considered to be reasonable to accept the additivity assumption. However, when the exposure is protracted over many cell doubling times (as will be the case for extended missions to the moon or Mars), the possibility exists that radiation effects that depend on multiple cellular events over a long time period, such as is probably the case in radiation-induced carcinogenesis, may not be additive in the above sense and the exposure interval may have to be included in the evaluation procedure. It is shown, however, that "inverse" dose-rate effects are not expected from intermediate LET radiations arising from the galactic cosmic ray environment due to the "sensitive-window-in-the-cell-cycle" hypothesis.

  3. Genetic variation and prediction of additive and nonadditive genetic effects for six carcass traits in an Angus-Brahman multibreed herd.

    PubMed

    Elzo, M A; West, R L; Johnson, D D; Wakeman, D L

    1998-07-01

    Estimates of covariances and sire expected progeny differences of additive and nonadditive genetic effects for six carcass traits were obtained using records from 486 straightbred and crossbred steers from 121 sires born between 1989 and 1995 in the Angus-Brahman multibreed herd of the University of Florida. Steers were slaughtered at a similar carcass composition end point. Covariances were estimated by REML procedures, using a generalized expectation-maximization algorithm applied to multibreed populations. Straightbred and crossbred estimates of heritabilities and additive genetic correlations were within ranges found in the literature for steers slaughtered on an age- or weight-constant basis for hot carcass weight, longissimus muscle area, and shear force but equal to or less than the lower bound of these ranges for fat-related traits. Maximum values of interactibilities (i.e., ratios of nonadditive variances to phenotypic variances in the F1) and nonadditive genetic correlations were smaller than heritabilities and additive genetic correlations in straightbreds and crossbred groups. Sire additive and total direct genetic predictions for longissimus muscle area, marbling, and shear force tended to decrease with the fraction of Brahman alleles, whereas those for hot carcass weight and fat thickness over the longissimus were higher, and those for kidney fat were lower in straightbreds and F1 than in other crossbred groups. Nonadditive genetic predictions were similar across sire groups of all Angus and Brahman fractions. These results suggest that slaughtering steers on a similar carcass composition basis reduces variability of fat-related traits while retaining variability for non-fat-related traits comparable to slaughtering steers on a similar age or weight basis. Selection for carcass traits within desirable (narrow) ranges and slaughter of steers at similar compositional end point seems to be a good combination to help produce meat products of consistent

  4. Genetic variation and prediction of additive and nonadditive genetic effects for six carcass traits in an Angus-Brahman multibreed herd.

    PubMed

    Elzo, M A; West, R L; Johnson, D D; Wakeman, D L

    1998-07-01

    Estimates of covariances and sire expected progeny differences of additive and nonadditive genetic effects for six carcass traits were obtained using records from 486 straightbred and crossbred steers from 121 sires born between 1989 and 1995 in the Angus-Brahman multibreed herd of the University of Florida. Steers were slaughtered at a similar carcass composition end point. Covariances were estimated by REML procedures, using a generalized expectation-maximization algorithm applied to multibreed populations. Straightbred and crossbred estimates of heritabilities and additive genetic correlations were within ranges found in the literature for steers slaughtered on an age- or weight-constant basis for hot carcass weight, longissimus muscle area, and shear force but equal to or less than the lower bound of these ranges for fat-related traits. Maximum values of interactibilities (i.e., ratios of nonadditive variances to phenotypic variances in the F1) and nonadditive genetic correlations were smaller than heritabilities and additive genetic correlations in straightbreds and crossbred groups. Sire additive and total direct genetic predictions for longissimus muscle area, marbling, and shear force tended to decrease with the fraction of Brahman alleles, whereas those for hot carcass weight and fat thickness over the longissimus were higher, and those for kidney fat were lower in straightbreds and F1 than in other crossbred groups. Nonadditive genetic predictions were similar across sire groups of all Angus and Brahman fractions. These results suggest that slaughtering steers on a similar carcass composition basis reduces variability of fat-related traits while retaining variability for non-fat-related traits comparable to slaughtering steers on a similar age or weight basis. Selection for carcass traits within desirable (narrow) ranges and slaughter of steers at similar compositional end point seems to be a good combination to help produce meat products of consistent

  5. Risk and reproductive decisions: British Pakistani couples’ responses to genetic counselling

    PubMed Central

    Shaw, Alison

    2011-01-01

    How far does ethnicity/culture/religion mediate couples’ responses to genetic risk? This paper examines the responses of 51 British Pakistani couples referred to a genetics clinic in southern England to counselling about recurrence risks for genetic problems in children. It is based on fieldwork conducted between 2000 and 2004 that combined participant observation of genetics consultations with interviews in respondents’ homes. Interviews were conducted with 62 adults in connection with these 51 cases, of which 32 were followed through two or more clinical consultations and 12 through more than one pregnancy. Risk responses were categorized as: taking the risk; postponing; exploring risk management or dismissing the risk as irrelevant to current circumstances. Responses were cross-referenced for associations with the severity of the condition, number of affected and unaffected children, availability of a prenatal test, age, gender, and migration history. I found that most couples were initially risk-takers who already had an unaffected child or children. Couples caring for living children with severe conditions were more likely to postpone. However, the risk responses of 15 couples changed over time, most towards and some away from risk management, reflecting changes in couples’ appreciation of the severity of the condition and their subsequent reproductive experiences. The study highlights the diversity and dynamism of responses within one ethnic group and challenges stereotypes about cultural and religious responses to genetic risk. PMID:21641705

  6. 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

  7. 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

  8. Genetic variability in EGFR, Src and HER2 and risk of colorectal adenoma and cancer

    PubMed Central

    Poole, Elizabeth M; Curtin, Karen; Hsu, Li; Kulmacz, Richard J; Duggan, David J; Makar, Karen W; Xiao, Liren; Carlson, Christopher S; Slattery, Martha L; Caan, Bette J; Potter, John D; Ulrich, Cornelia M

    2011-01-01

    The EGFR signaling pathway is involved in carcinogenesis at multiple sites, particularly colorectal cancer, and is a target of colorectal cancer chemotherapy. EGFR signaling is linked to pro-carcinogenic mechanisms, including cell proliferation, survival, angiogenesis, and more recently prostaglandin synthesis. Genetic variability in this pathway has not yet been studied in relation to colorectal carcinogenesis. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations between candidate SNPs, tagSNPs and haplotypes in EGFR signaling (EGFR, Src, and HER2) and risk. We also examined associations with tumor subtypes: TP53 and KRAS2 mutations, CpG island methylator phenotype, and microsatellite instability. All three studies were genotyped using an identical Illumina GoldenGate assay, allowing thorough investigation of genetic variability across stages and locations of colorectal neoplasia. The EGFR tagSNP 142572T>C (rs3752651) CC genotype was associated with a suggested increased risk for both colon (OR: 1.40; 95% CI: 1.00-1.96; p-trend=0.04) and rectal cancer (OR: 1.39; 95% CI: 0.81-2.41; p-trend=0.65). In tumor subtype analyses, the association was limited to TP53-mutated colon tumors. Using the Chatterjee 1 df Tukey test to assess gene-gene interactions, we observed a statistically significant (p<0.01) interaction between SNPs in EGFR and Src for colorectal adenoma risk. The association with EGFR 142572 should be investigated in additional studies and the significant gene-gene interaction between EGFR and Src in relation to adenoma risk suggests that these two genes are jointly affecting early stages in colorectal carcinogenesis and requires further follow-up. PMID:22199994

  9. The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.

    PubMed

    Forsberg, Simon K G; Andreatta, Matthew E; Huang, Xin-Yuan; Danku, John; Salt, David E; Carlborg, Örjan

    2015-11-01

    Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or "missing heritability". Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations.

  10. The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance

    PubMed Central

    Forsberg, Simon K. G.; Andreatta, Matthew E.; Huang, Xin-Yuan; Danku, John; Salt, David E.; Carlborg, Örjan

    2015-01-01

    Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or “missing heritability”. Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations. PMID:26599497

  11. Genome-Enabled Estimates of Additive and Nonadditive Genetic Variances and Prediction of Apple Phenotypes Across Environments.

    PubMed

    Kumar, Satish; Molloy, Claire; Muñoz, Patricio; Daetwyler, Hans; Chagné, David; Volz, Richard

    2015-12-01

    The nonadditive genetic effects may have an important contribution to total genetic variation of phenotypes, so estimates of both the additive and nonadditive effects are desirable for breeding and selection purposes. Our main objectives were to: estimate additive, dominance and epistatic variances of apple (Malus × domestica Borkh.) phenotypes using relationship matrices constructed from genome-wide dense single nucleotide polymorphism (SNP) markers; and compare the accuracy of genomic predictions using genomic best linear unbiased prediction models with or without including nonadditive genetic effects. A set of 247 clonally replicated individuals was assessed for six fruit quality traits at two sites, and also genotyped using an Illumina 8K SNP array. Across several fruit quality traits, the additive, dominance, and epistatic effects contributed about 30%, 16%, and 19%, respectively, to the total phenotypic variance. Models ignoring nonadditive components yielded upwardly biased estimates of additive variance (heritability) for all traits in this study. The accuracy of genomic predicted genetic values (GEGV) varied from about 0.15 to 0.35 for various traits, and these were almost identical for models with or without including nonadditive effects. However, models including nonadditive genetic effects further reduced the bias of GEGV. Between-site genotypic correlations were high (>0.85) for all traits, and genotype-site interaction accounted for <10% of the phenotypic variability. The accuracy of prediction, when the validation set was present only at one site, was generally similar for both sites, and varied from about 0.50 to 0.85. The prediction accuracies were strongly influenced by trait heritability, and genetic relatedness between the training and validation families.

  12. Genome-Enabled Estimates of Additive and Nonadditive Genetic Variances and Prediction of Apple Phenotypes Across Environments

    PubMed Central

    Kumar, Satish; Molloy, Claire; Muñoz, Patricio; Daetwyler, Hans; Chagné, David; Volz, Richard

    2015-01-01

    The nonadditive genetic effects may have an important contribution to total genetic variation of phenotypes, so estimates of both the additive and nonadditive effects are desirable for breeding and selection purposes. Our main objectives were to: estimate additive, dominance and epistatic variances of apple (Malus × domestica Borkh.) phenotypes using relationship matrices constructed from genome-wide dense single nucleotide polymorphism (SNP) markers; and compare the accuracy of genomic predictions using genomic best linear unbiased prediction models with or without including nonadditive genetic effects. A set of 247 clonally replicated individuals was assessed for six fruit quality traits at two sites, and also genotyped using an Illumina 8K SNP array. Across several fruit quality traits, the additive, dominance, and epistatic effects contributed about 30%, 16%, and 19%, respectively, to the total phenotypic variance. Models ignoring nonadditive components yielded upwardly biased estimates of additive variance (heritability) for all traits in this study. The accuracy of genomic predicted genetic values (GEGV) varied from about 0.15 to 0.35 for various traits, and these were almost identical for models with or without including nonadditive effects. However, models including nonadditive genetic effects further reduced the bias of GEGV. Between-site genotypic correlations were high (>0.85) for all traits, and genotype-site interaction accounted for <10% of the phenotypic variability. The accuracy of prediction, when the validation set was present only at one site, was generally similar for both sites, and varied from about 0.50 to 0.85. The prediction accuracies were strongly influenced by trait heritability, and genetic relatedness between the training and validation families. PMID:26497141

  13. Cancer Genetic Counselor Information Needs for Risk Communication: A Qualitative Evaluation of Interview Transcripts

    PubMed Central

    Overby, Casey Lynnette; Chung, Wendy K.; Hripcsak, George; Kukafka, Rita

    2013-01-01

    Personalized medicine is a model of healthcare that is predictive, personalized, preventive and participatory (“P4 Medicine”). Genetic counselors are an ideal group to study when designing tools to support cancer P4 Medicine activities more broadly. The goal for this work was to gain a better understanding of the information cancer genetic counselors seek from their patients to facilitate effective information exchange for discussing risk. This was an analysis of a qualitative data set from interviews of eight cancer genetic counselors, recruited from three institutions. Genetic counselors at each site were interviewed using a semi-structured, open-ended questionnaire. A selective coding approach was used to determine major themes associated with genetic counseling information needs for communicating risk. We generated a model for understanding categories of genetic counseling information needs to support risk communication activities. Common activities for risk communication included risk assessment and tailoring communication. Categories of information needs included: (a) clinical patient characteristics, (b) social and cognitive patient characteristics and (c) patient motivation and goals for the genetic counseling session. A logical next step is for this model to inform the design of software systems for pre-visit patient planning and delivering just-in-time educational information to facilitate cancer risk communication activities. PMID:24358447

  14. Assessing the additive risks of PSII herbicide exposure to the Great Barrier Reef.

    PubMed

    Lewis, Stephen E; Schaffelke, Britta; Shaw, Melanie; Bainbridge, Zoë T; Rohde, Ken W; Kennedy, Karen; Davis, Aaron M; Masters, Bronwyn L; Devlin, Michelle J; Mueller, Jochen F; Brodie, Jon E

    2012-01-01

    Herbicide residues have been measured in the Great Barrier Reef lagoon at concentrations which have the potential to harm marine plant communities. Monitoring on the Great Barrier Reef lagoon following wet season discharge show that 80% of the time when herbicides are detected, more than one are present. These herbicides have been shown to act in an additive manner with regards to photosystem-II inhibition. In this study, the area of the Great Barrier Reef considered to be at risk from herbicides is compared when exposures are considered for each herbicide individually and also for herbicide mixtures. Two normalisation indices for herbicide mixtures were calculated based on current guidelines and PSII inhibition thresholds. The results show that the area of risk for most regions is greatly increased under the proposed additive PSII inhibition threshold and that the resilience of this important ecosystem could be reduced by exposure to these herbicides.

  15. Risk assessment of combined photogenotoxic effects of sunlight and food additives.

    PubMed

    Salih, Fadhil M

    2006-06-01

    The presence of flavored colorants (peach and raspberry), flavors (caramel, citric acid and vanilla) and food preservatives (sodium nitrite, sodium nitrate, sodium benzoate, benzoic acid, potassium sorbate and sodium chloride) in Escherichia coli suspension during exposure to sunlight did not change the extent of cell survival. No effect on viability and mutation induction (kanamycin resistant) was also seen when cells were kept in contact with any of the additives for 80 min in the dark. However, when the relevant additive was present in cell suspension during sunlight exposure the number of induced mutations was increased to varying extents over that seen with sunlight alone. Raspberry and peach increased the number of mutations in a dose dependent manner, while vanilla produced mutations in an additive fashion. Nitrite, nitrate, benzoate, sorbate and benzoic acid increased mutation somewhat additively over that of sunlight. Sodium chloride and citric acid were not effective. The impact of this investigation reflects the significance of combination of sunlight and chemical food additives as potential risk, which requires special attention and necessitates further investigations to evaluate the risk.

  16. Association between interleukin-22 genetic polymorphisms and bladder cancer risk

    PubMed Central

    Zhao, Tao; Wu, XiaoHou; Liu, JiaJi

    2015-01-01

    OBJECTIVE: The cytokine interleukin-22 (IL-22), which is produced by T cells and natural killer cells, is associated with tumorigenesis and tumor progression in cancers. However, the role of IL-22 in bladder cancer has not been investigated. MATERIALS AND METHODS: A prospective hospital-based case-control study comprising 210 patients with pathologically proven bladder cancer and 210 age- and gender-matched healthy controls was conducted. The genotypes of 3 common polymorphisms (-429 C/T, +1046 T/A and +1995 A/C) of the IL-22 gene were determined with fluorogenic 5' exonuclease assays. RESULTS: Patients with bladder cancer had a significantly higher frequency of the IL-22 -429 TT genotype [odds ratio (OR)=2.04, 95% confidence interval (CI)=1.19, 3.49; p=0.009] and -429 T allele (OR=1.42, 95% CI=1.08, 1.87; p=0.01) than the healthy controls. These findings were still significant after a Bonferroni correction. When stratifying according to the stage of bladder cancer, we found that patients with superficial bladder cancer had a significantly lower frequency of the IL-22 -429 TT genotype (OR=0.48, 95% CI=0.23, 0.98; p=0.04). When stratifying according to the grade and histological type of bladder cancer, we found no statistical association. The IL-22 +1046 T/A and IL-22 +1995 A/C gene polymorphisms were not associated with the risk of bladder cancer. CONCLUSION: To the authors' knowledge, this is the first report documenting that the IL-22 -429 C/T gene polymorphism is associated with bladder cancer risk. Additional studies are required to confirm this finding. PMID:26598081

  17. Early Intervention Following Trauma May Mitigate Genetic Risk for PTSD in Civilians: A Pilot Prospective Emergency Department Study

    PubMed Central

    Rothbaum, Barbara O.; Kearns, Megan C.; Reiser, Emily; Davis, Jennifer S.; Kerley, Kimberly A.; Rothbaum, Alex O.; Mercer, Kristina B.; Price, Matthew; Houry, Debra; Ressler, Kerry J.

    2015-01-01

    Background Civilian posttraumatic stress disorder (PTSD) and combat PTSD are major public health concerns. Although a number of psychosocial risk factors have been identified related to PTSD risk, there are no accepted, robust biological predictors that identify who will develop PTSD or who will respond to early intervention following trauma. We wished to examine whether genetic risk for PTSD can be mitigated with an early intervention. Method 65 emergency department patients recruited in 2009–2010 at Grady Memorial Hospital in Atlanta, Georgia, who met criterion A of DSM-IV PTSD received either 3 sessions of an exposure intervention, beginning in the emergency department shortly after trauma exposure or assessment only. PTSD symptoms were assessed 4 and 12 weeks after trauma exposure. A composite additive risk score was derived from polymorphisms in 10 previously identified genes associated with stress-response (ADCYAP1R1, COMT, CRHR1, DBH, DRD2, FAAH, FKBP5, NPY, NTRK2, and PCLO), and gene x treatment effects were examined. The intervention included 3 sessions of imaginal exposure to the trauma memory and additional exposure homework. The primary outcome measure was the PTSD Symptom Scale-Interview Version or DSM-IV–based PTSD diagnosis in patients related to genotype and treatment group. Results A gene x intervention x time effect was detected for individual polymorphisms, in particular the PACAP receptor, ADCYAP1R1, as well as with a combined genotype risk score created from independent SNP markers. Subjects who did not receive treatment had higher symptoms than those who received intervention. Furthermore, subjects with the “risk” genotypes who did not receive intervention had higher PTSD symptoms compared to those with the “low-risk” or “resilience” genotypes or those who received intervention. Additionally, PTSD symptoms correlated with level of genetic risk at week 12 (P < .005) in the assessment-only group, but with no relationship in the

  18. 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

  19. 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.

  20. A Multistage Genetic Association Study Identifies Breast Cancer Risk Loci at 10q25 and 16q24

    PubMed Central

    Higginbotham, Kathryn S.; Breyer, Joan P.; McReynolds, Kate M.; Bradley, Kevin M.; Schuyler, Peggy A.; Plummer, W. Dale; Freudenthal, Marcia E.; Trentham-Dietz, Amy; Newcomb, Polly A.; Parl, Fritz F.; Sanders, Melinda E.; Page, David L.; Egan, Kathleen M.; Dupont, William D.; Smith, Jeffrey R.

    2013-01-01

    Background Heritable risk for breast cancer includes an increasing number of common, low effect risk variants. We conducted a multistage genetic association study in a series of independent epidemiologic breast cancer study populations to identify novel breast cancer risk variants. Methods We tested 1,162 SNPs of greatest nominal significance from stage I of the Cancer Genetic Markers of Susceptibility breast cancer study (CGEMS; 1,145 cases, 1,142 controls) for evidence of replicated association with breast cancer in the Nashville Breast Cohort (NBC; 599 cases, 1,161 controls), the Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls), and BioVU Breast Cancer Study (BioVU; 1,172 cases, 1,172 controls). Results Among these SNPs, a series of validated breast cancer risk variants yielded expected associations in the study populations. In addition, we observed two previously unreported loci that were significantly associated with breast cancer risk in the CGEMS, NBC, and CBCS study populations and had a consistent, although not statistically significant, risk effect in the BioVU study population. These were rs1626678 at 10q25.3 near ENO4 and KIAA1598 (meta-analysis age-adjusted OR 1.13 [1.07–1.20], P = 5.6 × 10−5), and rs8046508 at 16q23.1 in the eighth intron of WWOX (meta-analysis age-adjusted OR = 1.20 [1.10–1.31], P = 3.5 × 10−5). Conclusions Our data supports the association of two novel loci, at 10q25.3 and 16q23.1, with risk of breast cancer. Impact The expanding compendium of known breast cancer genetic risk variants holds increasing power for clinical risk prediction models of breast cancer, improving upon the Gail model. PMID:22806168

  1. 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 ...

  2. 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...

  3. [Genetic risks of intracytoplasmic sperm injection for male infertility].

    PubMed

    Shao, Fa-Ming; Zhu, Xiao-Bin; Li, Zheng

    2008-01-01

    Recently, intracytoplasmic sperm injection (ICSI) has been extremely successful in the treatment of male infertility. However, the consequent transmission of sperm cytogenetic defects and genetic defects to the offspring has aroused considerable concern. Among infertile men, those with severe spermatogenic defects, including oligozoospermia and azoospermia, are mostly the subjects for ICSI. Therefore it is very important to obtain cytogenetic and chromosomal information on these infertile patients and prevent the inheritance of these genetic defects. This review offers an analysis on the genetic defects among infertile men.

  4. 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…

  5. Molecular Genetic Evidence for Genetic Overlap between General Cognitive Ability and Risk for Schizophrenia: A Report from the Cognitive Genomics Consortium (COGENT)

    PubMed Central

    Lencz, Todd; Knowles, Emma; Davies, Gail; Guha, Saurav; Liewald, David C; Starr, John M; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; Mukherjee, Semanti; Lundervold, Astri; Steen, Vidar M.; John, Majnu; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G; Giegling, Ina; Konte, Bettina; Ikeda, Masashi; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E.; Payton, Antony; Ollier, William; Horan, Mike; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Pendleton, Neil; Iwata, Nakao; Darvasi, Ariel; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Hellard, Stephanie Le; Keller, Matthew C.; Andreassen, Ole A.; Deary, Ian J; Glahn, David C.; Malhotra, Anil K.

    2014-01-01

    It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia, evident prior to full illness onset and independent of medication. The possibility of genetic overlap between risk for schizophrenia and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with schizophrenia; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of schizophrenia have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common SNPs of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for schizophrenia. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from 9 non-clinical cohorts comprising the COGENT consortium) to four schizophrenia case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for schizophrenia were associated with lower general cognitive ability. Additionally, using our large cognitive meta-analytic dataset, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with schizophrenia susceptibility. Results provide molecular confirmation of the genetic overlap between schizophrenia and general cognitive ability, and may provide additional insight into pathophysiology of the disorder. PMID:24342994

  6. Reprogenetics, Genetic Tools and Reproductive Risk: Attitudes and Understanding Among Ethnic Groups in Israel.

    PubMed

    Simonstein, Frida; Mashiach-Eizenberg, Michal

    2016-02-01

    The present study investigated a possible relationship between the attitudes toward genetic technologies and the understanding of genetics, reproduction, and reproductive risk among Israeli Arabs and Israeli Jews. The study included 203 respondents, who answered a structured self-report questionnaire. They were recruited using a snowball method, which increased the participation of Israeli Arabs in the sample, although the sample was not representative of the Israeli population as a whole (there were more Arabs and fewer men). The respondents in this study expressed a positive attitude toward genetic technologies, but were less in favor of using genetic tools for non-medical purposes. Respondents of both groups were not knowledgeable of genetics; however, they scored higher on the items related to reproductive risk, which suggests that some awareness about genetic risk exists in both sectors of the Israeli population. Nevertheless, Israeli Arabs were less positive than Israeli Jews regarding the application of genetic tools. Moreover, although an understanding of genetics correlated positively with the attitude among Arabs, it did not affect the attitude of Jews, who remained very positive, regardless of their level of understanding. This result suggests that other social and cultural factors, besides understanding, might be at work among these two major ethnic sectors. Further studies that integrate educational, social, and cultural aspects among ethnic sectors of the population are required to improve health services and genetic counselling in Israel and in other countries. PMID:26051269

  7. Estimation of radiation risk in presence of classical additive and Berkson multiplicative errors in exposure doses.

    PubMed

    Masiuk, S V; Shklyar, S V; Kukush, A G; Carroll, R J; Kovgan, L N; Likhtarov, I A

    2016-07-01

    In this paper, the influence of measurement errors in exposure doses in a regression model with binary response is studied. Recently, it has been recognized that uncertainty in exposure dose is characterized by errors of two types: classical additive errors and Berkson multiplicative errors. The combination of classical additive and Berkson multiplicative errors has not been considered in the literature previously. In a simulation study based on data from radio-epidemiological research of thyroid cancer in Ukraine caused by the Chornobyl accident, it is shown that ignoring measurement errors in doses leads to overestimation of background prevalence and underestimation of excess relative risk. In the work, several methods to reduce these biases are proposed. They are new regression calibration, an additive version of efficient SIMEX, and novel corrected score methods.

  8. 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

  9. 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.

  10. 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.

  11. Genetic risk prediction in a small cohort of healthy adults in Atlanta.

    PubMed

    Zhao, Jing; Arafat, Dalia; Brigham, Kenneth L; Gibson, Greg

    2013-02-01

    Compared with single markers, polygenic scores that evaluate the joint effects of multiple trait-associated variants are more effective in explaining the variance of traits and risk of diseases. In total, 182 CHDWB (Emory-Georgia Tech Center for Health Discovery and Well Being study) adults were genotyped to investigate the common variant contributions to three traits (height, BMI, serum triglycerides) and three diseases (coronary artery disease (CAD), type 2 diabetes (T2D) and asthma). Association was contrasted between weighted and simple allelic sum polygenic scores with quantitative traits, and with the Framingham risk scores for CAD and T2D. Although the cohort size is two or three orders of magnitude smaller than typical discovery cohorts, we were able to detect significant associations and to explain up to 5% of the traits by the genetic risk scores, despite a strong influence of outliers. An unexpected finding was that CAD-associated single nucleotide polymorphisms (SNPs) explain a significant amount of the variation for total serum cholesterol. Forward step-wise sequential addition of SNPs into the regression model showed that the top-ranked SNPs explain a large proportion of variance, whereas inclusion of gender and ethnicity also affect the performance of polygenic scores. PMID:23442331

  12. Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

    PubMed Central

    Christensen, Kurt D.; Roberts, J. Scott; Royal, Charmaine D. M.; Fasaye, Grace-Ann; Obisesan, Thomas; Cupples, L. Adrienne; Whitehouse, Peter J.; Butson, Melissa Barber; Linnenbringer, Erin; Relkin, Norman R.; Farrer, Lindsay; Cook-Deegan, Robert; Green, Robert C.

    2008-01-01

    Purpose To describe how investigators in a multisite randomized clinical trial addressed scientific and ethical issues involved in creating risk models based on genetic testing for African American participants. Methods The following informed our decision whether to stratify risk assessment by ethnicity: evaluation of epidemiological data, appraisal of benefits and risks of incorporating ethnicity into calculations, and feasibility of creating ethnicity-specific risk curves. Once the decision was made, risk curves were created based on data from a large, diverse study of first-degree relatives of patients with Alzheimer disease. Results Review of epidemiological data suggested notable differences in risk between African Americans and whites and that Apolipoprotein E genotype predicts risk in both groups. Discussions about the benefits and risks of stratified risk assessments reached consensus that estimates based on data from whites should not preclude enrolling African Americans, but population-specific risk curves should be created if feasible. Risk models specific to ethnicity, gender, and Apolipoprotein E genotype were subsequently developed for the randomized clinical trial that oversampled African Americans. Conclusion The Risk Evaluation and Education for Alzheimer Disease study provides an instructive example of a process to develop risk assessment protocols that are sensitive to the implications of genetic testing for multiple ethnic groups with differing levels of risk. PMID:18344711

  13. Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms.

    PubMed

    Figueroa, Jonine D; Koutros, Stella; Colt, Joanne S; Kogevinas, Manolis; Garcia-Closas, Montserrat; Real, Francisco X; Friesen, Melissa C; Baris, Dalsu; Stewart, Patricia; Schwenn, Molly; Johnson, Alison; Karagas, Margaret R; Armenti, Karla R; Moore, Lee E; Schned, Alan; Lenz, Petra; Prokunina-Olsson, Ludmila; Banday, A Rouf; Paquin, Ashley; Ylaya, Kris; Chung, Joon-Yong; Hewitt, Stephen M; Nickerson, Michael L; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Malats, Núria; Fraumeni, Joseph F; Chanock, Stephen J; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T

    2015-11-01

    Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P interaction ≤ .001), rs11892031 (UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis. PMID:26374428

  14. Risk assessment of additives through soft drinks and nectars consumption on Portuguese population: a 2010 survey.

    PubMed

    Diogo, Janina S G; Silva, Liliana S O; Pena, Angelina; Lino, Celeste M

    2013-12-01

    This study investigated whether the Portuguese population is at risk of exceeding ADI levels for acesulfame-K, saccharin, aspartame, caffeine, benzoic and sorbic acid through an assessment of dietary intake of additives and specific consumption of four types of beverages, traditional soft drinks and soft drinks based on mineral waters, energetic drinks, and nectars. The highest mean levels of additives were found for caffeine in energetic drinks, 293.5mg/L, for saccharin in traditional soft drinks, 18.4 mg/L, for acesulfame-K and aspartame in nectars, with 88.2 and 97.8 mg/L, respectively, for benzoic acid in traditional soft drinks, 125.7 mg/L, and for sorbic acid in soft drinks based on mineral water, 166.5 mg/L. Traditional soft drinks presented the highest acceptable daily intake percentages (ADIs%) for acesulfame-K, aspartame, benzoic and sorbic acid and similar value for saccharin (0.5%) when compared with soft drinks based on mineral water, 0.7%, 0.08%, 7.3%, and 1.92% versus 0.2%, 0.053%, 0.6%, and 0.28%, respectively. However for saccharin the highest percentage of ADI was obtained for nectars, 0.9%, in comparison with both types of soft drinks, 0.5%. Therefore, it is concluded that the Portuguese population is not at risk of exceeding the established ADIs for the studied additives.

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

    PubMed

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

    2014-01-01

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

  16. Genetic variants in miRNAs predict bladder cancer risk and recurrence.

    PubMed

    Wang, Meilin; Chu, Haiyan; Li, Pu; Yuan, Lin; Fu, Guangbo; Ma, Lan; Shi, Danni; Zhong, Dongyan; Tong, Na; Qin, Chao; Yin, Changjun; Zhang, Zhengdong

    2012-12-01

    miRNAs play important roles in numerous cellular processes, including development, proliferation, apoptosis, and carcinogenesis. Because altered expression and function of miRNAs has been observed in bladder cancer, we investigated whether genetic variations in miRNAs are associated with bladder cancer risk and prognosis. Using bioinformatics tools, we selected five single-nucleotide polymorphisms located in miRNAs and used these to evaluate miRNA-disease associations in a two-stage model, consisting of 1,019 bladder cancer cases and 1,182 controls (683 cases and 728 controls in the training set and 336 cases and 454 controls in the test set). We found that miR-146a rs2910164 C allele was associated with significantly decreased risk of bladder cancer in both the training and test sets, as well as the combined set [OR = 0.80, 95% confidence interval (CI) = 0.71-0.90, P = 2.92 × 10(-4)]. Furthermore, the rs2910164 GC/CC genotypes conferred a significantly reduced risk of recurrence, compared with the GG genotype (P = 0.016). Functional analysis revealed that miR-146a rs2910164 C allele inhibited cell proliferation and significantly downregulated expression of IRAK1 and TRAF6 in bladder cancer cells. Additional examination of 64 bladder cancer tissues showed that individuals carrying the C allele had increased expression levels of miR-146a compared with those carrying the G allele (P = 0.010). Taken together, our findings show that miR-146a rs2910164 plays an important role in the risk and recurrence of bladder cancer, suggesting it may represent a biomarker for risk prevention and therapeutic intervention. Further larger and prospective cohorts are needed to validate our findings.

  17. Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

    PubMed Central

    Martin, Jose-Ezequiel; Broen, Jasper C.; Carmona, F. David; Teruel, Maria; Simeon, Carmen P.; Vonk, Madelon C.; van ‘t Slot, Ruben; Rodriguez-Rodriguez, Luis; Vicente, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A.; García-Hernández, Francisco J.; de la Peña, Paloma García; Carreira, Patricia; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; van Riel, Piet L.C.M.; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Airo, Paolo; Scorza, Raffaella; Lunardi, Claudio; Hunzelmann, Nicolas; Distler, Jörg H.W.; Beretta, Lorenzo; van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Ariane; Denton, Christopher; Tan, Filemon K.; Arnett, Frank C.; Assassi, Shervin; Fonseca, Carmen; Mayes, Maureen D.; Radstake, Timothy R.D.J.; Koeleman, Bobby P.C.; Martin, Javier

    2012-01-01

    Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10−12, odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10−7, OR = 1.36) and NFKB1 (P-value = 1.03 × 10−6, OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones. PMID:22407130

  18. Transgenerational genetic effects on phenotypic variation and disease risk.

    PubMed

    Nadeau, Joseph H

    2009-10-15

    Traditionally, we understand that individual phenotypes result primarily from inherited genetic variants together with environmental exposures. However, many studies showed that a remarkable variety of factors including environmental agents, parental behaviors, maternal physiology, xenobiotics, nutritional supplements and others lead to epigenetic changes that can be transmitted to subsequent generations without continued exposure. Recent discoveries show transgenerational epistasis and transgenerational genetic effects where genetic factors in one generation affect phenotypes in subsequent generation without inheritance of the genetic variant in the parents. Together these discoveries implicate a key signaling pathway, chromatin remodeling, methylation, RNA editing and microRNA biology. This exceptional mode of inheritance complicates the search for disease genes and represents perhaps an adaptation to transmit useful gene expression profiles from one generation to the next. In this review, I present evidence for these transgenerational genetic effects, identify their common features, propose a heuristic model to guide the search for mechanisms, discuss the implications, and pose questions whose answers will begin to reveal the underlying mechanisms.

  19. Population-based genetic risk prediction and stratification for ovarian cancer: views from women at high risk.

    PubMed

    Rahman, Belinda; Meisel, Susanne F; Fraser, Lindsay; Side, Lucy; Gessler, Sue; Wardle, Jane; Lanceley, Anne

    2015-03-01

    There is an opportunity to improve outcomes for ovarian cancer (OC) through advances in risk stratification, early detection and diagnosis. A population-based OC genetic risk prediction and stratification program is being developed. A previous focus group study with individuals from the general population showed support for the proposed program. This qualitative interview study explores the attitudes of women at high risk of OC. Eight women participated in one-on-one, in-depth, semi-structured interviews to explore: experiences of learning of OC risk, risk perceptions, OC knowledge and awareness, and opinions on risk stratification approach. There was evidence of strong support for the proposed program. Benefits were seen as providing reassurance to women at low risk, and reducing worry in women at high risk through appropriate clinical management. Stratification into 'low' and 'high' risk groups was well-received. Participants were more hesitant about stratification to the 'intermediate' risk group. The data suggest formats to effectively communicate OC risk estimates will require careful thought. Interactions with GPs were highlighted as a barrier to OC risk assessment and diagnosis. These results are encouraging for the possible introduction and uptake of a risk prediction and stratification program for OC in the general population.

  20. [Genetically modified organisms in food--production, detection and risks].

    PubMed

    Zeljezić, Davor

    2004-11-01

    The first genetically modified plant (GMP) was a tobacco resistant to antibiotics in 1983. In 1996, the first genetically altered crop, a delayed-ripening tomato was commercially released. In the year 2003, the estimated global area of GM crops for was 67.7 million hectares. To produce such a plant a gene of interest has to be isolated from the donor. Together with a promoter, terminator sequence and marker gene it has to be introduced into the plant cell which is then stimulated to generate a whole GMP expressing new characteristics (herbicide/insect resistance, delayed ripening). The last few months have seen a strong public debate over genetically modified organisms which has raised scientific, economic, political, and ethical issues. Some questions concerning the safety of GMPs are still to be answered, and decisions about their future should be based on scientifically validated information.

  1. 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

  2. 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

  3. Segmenting by Risk Perceptions: Predicting Young Adults’ Genetic-Belief Profiles with Health and Opinion-Leader Covariates

    PubMed Central

    Smith, Rachel A.; Greenberg, Marisa; Parrott, Roxanne L.

    2014-01-01

    With a growing interest in using genetic information to motivate young adults’ health behaviors, audience segmentation is needed for effective campaign design. Using latent class analysis, this study identifies segments based on young adults’ (N = 327) beliefs about genetic threats to their health and personal efficacy over genetic influences on their health. A four-class model was identified. The model indicators fit the risk perception attitude framework (Rimal & Real, 2003), but the covariates (e.g., current health behaviors) did not. In addition, opinion leader qualities covaried with one profile: those in this profile engaged in fewer preventative behaviors and more dangerous treatment options, and also liked to persuade others, making them a particularly salient group for campaign efforts. The implications for adult-onset disorders, like alpha-1 antitrypsin deficiency are discussed. PMID:24111749

  4. Segmenting by risk perceptions: predicting young adults' genetic-belief profiles with health and opinion-leader covariates.

    PubMed

    Smith, Rachel A; Greenberg, Marisa; Parrott, Roxanne L

    2014-01-01

    With a growing interest in using genetic information to motivate young adults' health behaviors, audience segmentation is needed for effective campaign design. Using latent class analysis, this study identifies segments based on young adults' (N = 327) beliefs about genetic threats to their health and personal efficacy over genetic influences on their health. A four-class model was identified. The model indicators fit the risk perception attitude framework (Rimal & Real, 2003), but the covariates (e.g., current health behaviors) did not. In addition, opinion leader qualities covaried with one profile: Those in this profile engaged in fewer preventative behaviors and more dangerous treatment options, and also liked to persuade others, making them a particularly salient group for campaign efforts. The implications for adult-onset disorders, like alpha-1 antitrypsin deficiency, are discussed.

  5. 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

  6. 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...

  7. Relative Importance and Additive Effects of Maternal and Infant Risk Factors on Childhood Asthma

    PubMed Central

    Rosas-Salazar, Christian; James, Kristina; Escobar, Gabriel; Gebretsadik, Tebeb; Li, Sherian Xu; Carroll, Kecia N.; Walsh, Eileen; Mitchel, Edward; Das, Suman; Kumar, Rajesh; Yu, Chang; Dupont, William D.; Hartert, Tina V.

    2016-01-01

    Background Environmental exposures that occur in utero and during early life may contribute to the development of childhood asthma through alteration of the human microbiome. The objectives of this study were to estimate the cumulative effect and relative importance of environmental exposures on the risk of childhood asthma. Methods We conducted a population-based birth cohort study of mother-child dyads who were born between 1995 and 2003 and were continuously enrolled in the PRIMA (Prevention of RSV: Impact on Morbidity and Asthma) cohort. The individual and cumulative impact of maternal urinary tract infections (UTI) during pregnancy, maternal colonization with group B streptococcus (GBS), mode of delivery, infant antibiotic use, and older siblings at home, on the risk of childhood asthma were estimated using logistic regression. Dose-response effect on childhood asthma risk was assessed for continuous risk factors: number of maternal UTIs during pregnancy, courses of infant antibiotics, and number of older siblings at home. We further assessed and compared the relative importance of these exposures on the asthma risk. In a subgroup of children for whom maternal antibiotic use during pregnancy information was available, the effect of maternal antibiotic use on the risk of childhood asthma was estimated. Results Among 136,098 singleton birth infants, 13.29% developed asthma. In both univariate and adjusted analyses, maternal UTI during pregnancy (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.18, 1.25; adjusted OR [AOR] 1.04, 95%CI 1.02, 1.07 for every additional UTI) and infant antibiotic use (OR 1.21, 95%CI 1.20, 1.22; AOR 1.16, 95%CI 1.15, 1.17 for every additional course) were associated with an increased risk of childhood asthma, while having older siblings at home (OR 0.92, 95%CI 0.91, 0.93; AOR 0.85, 95%CI 0.84, 0.87 for each additional sibling) was associated with a decreased risk of childhood asthma, in a dose-dependent manner. Compared with vaginal

  8. Intentions for risk-reducing surgery among high-risk women referred for BRCA1/BRCA2 genetic counseling

    PubMed Central

    Tong, Angie; Kelly, Scott; Nusbaum, Rachel; Graves, Kristi; Peshkin, Beth N.; Valdimarsdottir, Heiddis B.; Wood, Marie; McKinnon, Wendy; Garber, Judy; McCormick, Shelley R.; Jandorf, Lina; Schwartz, Marc D.

    2014-01-01

    Objective Genetic testing for breast and ovarian cancer susceptibility is now part of routine clinical practice. Although rates of risk-reducing surgery following genetic testing have been increasing, little is known about attitudes toward risk-reducing surgery in women prior to genetic counseling and testing. This study examines correlates of patient intentions to undergo risk-reducing mastectomy (RRM) and risk-reducing oophorectomy (RRO). Methods Participants were 696 women, ages 21–85, who sought breast cancer gene 1 and 2 (BRCA1/2) genetic counseling and had at least a 10% risk of carrying a mutation. The sample included women who were affected with breast or ovarian cancer and unaffected women with a known familial BRCA1/2 mutation. Participants completed a precounseling telephone questionnaire. Results Prior to receiving genetic counseling, 23.3% of participants were considering RRM and 42.5% were considering RRO. Variables that were independently associated with RRM intentions were cancer-specific distress (OR = 1.14, 95% CI = 1.03–1.26), perceived risk of breast cancer (OR = 1.16, 95% CI = 1.05–1.28), education (OR = 1.76, 95% CI = 1.03–2.99), and age (OR = 0.96, 95% CI = 0.95–0.98). Predictors of RRO intentions were perceived risk for ovarian cancer (OR = 1.25, 95% CI = 1.14–1.37), perceived risk of carrying a BRCA1/2 mutation (OR = 1.74, 95% CI = 1.15–2.62), marital status (OR = 1.92, 95% CI = 1.34–2.76), and age (OR = 1.02, 95% CI = 1.00–1.03). Conclusions Because precounseling intentions predict subsequent risk-reducing surgery decisions, this study identified patient factors associated with surgical intentions. These factors reinforce the critical role for pretest genetic counseling in communicating accurate risk estimates and management options, and addressing psychosocial concerns, to facilitate informed decision making regarding RRM and RRO. PMID:24839250

  9. Additive genetic variation for tolerance to estrogen pollution in natural populations of Alpine whitefish (Coregonus sp., Salmonidae)

    PubMed Central

    Brazzola, Gregory; Chèvre, Nathalie; Wedekind, Claus

    2014-01-01

    The evolutionary potential of natural populations to adapt to anthropogenic threats critically depends on whether there exists additive genetic variation for tolerance to the threat. A major problem for water-dwelling organisms is chemical pollution, and among the most common pollutants is 17α-ethinylestradiol (EE2), the synthetic estrogen that is used in oral contraceptives and that can affect fish at various developmental stages, including embryogenesis. We tested whether there is variation in the tolerance to EE2 within Alpine whitefish. We sampled spawners from two species of different lakes, bred them in vitro in a full-factorial design each, and studied growth and mortality of embryos. Exposure to EE2 turned out to be toxic in all concentrations we tested (≥1 ng/L). It reduced embryo viability and slowed down embryogenesis. We found significant additive genetic variation in EE2-induced mortality in both species, that is, genotypes differed in their tolerance to estrogen pollution. We also found maternal effects on embryo development to be influenced by EE2, that is, some maternal sib groups were more susceptible to EE2 than others. In conclusion, the toxic effects of EE2 were strong, but both species demonstrated the kind of additive genetic variation that is necessary for an evolutionary response to this type of pollution. PMID:25553069

  10. Additive genetic variation for tolerance to estrogen pollution in natural populations of Alpine whitefish (Coregonus sp., Salmonidae).

    PubMed

    Brazzola, Gregory; Chèvre, Nathalie; Wedekind, Claus

    2014-11-01

    The evolutionary potential of natural populations to adapt to anthropogenic threats critically depends on whether there exists additive genetic variation for tolerance to the threat. A major problem for water-dwelling organisms is chemical pollution, and among the most common pollutants is 17α-ethinylestradiol (EE2), the synthetic estrogen that is used in oral contraceptives and that can affect fish at various developmental stages, including embryogenesis. We tested whether there is variation in the tolerance to EE2 within Alpine whitefish. We sampled spawners from two species of different lakes, bred them in vitro in a full-factorial design each, and studied growth and mortality of embryos. Exposure to EE2 turned out to be toxic in all concentrations we tested (≥1 ng/L). It reduced embryo viability and slowed down embryogenesis. We found significant additive genetic variation in EE2-induced mortality in both species, that is, genotypes differed in their tolerance to estrogen pollution. We also found maternal effects on embryo development to be influenced by EE2, that is, some maternal sib groups were more susceptible to EE2 than others. In conclusion, the toxic effects of EE2 were strong, but both species demonstrated the kind of additive genetic variation that is necessary for an evolutionary response to this type of pollution. PMID:25553069

  11. Risk factors of allergic rhinitis: genetic or environmental?

    PubMed Central

    Wang, De-Yun

    2005-01-01

    Allergic diseases such as allergic rhinitis represent a global health problem, affecting 10%–25% of the world population. There is clear evidence to support the concept that allergic diseases are influenced by genetic predisposition and environmental exposure. Polymorphisms of candidate genes have been associated with clinical expression of these diseases. However, characterization of these susceptibility markers in discriminating an “allergic individual” from the general population has not yet been achieved, and the value of how this genetic insight leading to recognition of specific subtypes of these disorders still needs to be confirmed. Environmental factors (eg, air pollution and bacterial/viral infection) also play an important role in the development of the diseases. A number of epidemiologic studies have supported the “hygiene hypothesis”, which is based on the observations that Th1 responses induced by microbial stimulation can counterbalance allergen-induced Th2 responses. Future studies are needed to identify the key genes or their haplotypes for atopic phenotypes and to investigate the interactions between genetic and environmental factors that influence the complex trait of allergic diseases. This will help us to further understand the etiology of the diseases and develop new avenues for genetically oriented diagnosis and more effective measures of prevention and intervention. PMID:18360551

  12. Can genetic risk information enhance motivation for smoking cessation? An analogue study.

    PubMed

    Wright, Alison J; French, David P; Weinman, John; Marteau, Theresa M

    2006-11-01

    Protection motivation theory and the extended parallel processing model are used to predict the motivational impact of information regarding a genetic susceptibility to heart disease. One hundred ninety-eight smokers read 1 of 3 vignettes: gene positive, gene negative, or standard smoking risk information. Analyses examined whether the impact of type of risk information was moderated by smokers' self-efficacy (SE) levels. Key outcomes were intention to quit and intention to attend an information session about quitting. There were significant main effects of SE and of receiving gene-positive risk information on intentions to quit. There was a significant Risk x SE interaction on intentions to attend an information session. SE was not associated with intentions to attend the information session for smokers in the gene-positive group. Intentions to attend the session were negatively associated with SE for smokers in the lower risk groups. Implications for using genetic risk information to motivate smoking cessation are discussed.

  13. THE COMBINED CARCINOGENIC RISK FOR EXPOSURE TO MIXTURES OF DRINKING WATER DISINFECTION BY-PRODUCTS MAY BE LESS THAN ADDITIVE

    EPA Science Inventory

    The Combined Carcinogenic Risk for Exposure to Mixtures of Drinking Water Disinfection By-Products May be Less Than Additive

    Risk assessment methods for chemical mixtures in drinking water are not well defined. Current default risk assessments for chemical mixtures assume...

  14. A comprehensive genetic approach for improving prediction of skin cancer risk in humans.

    PubMed

    Vazquez, Ana I; de los Campos, Gustavo; Klimentidis, Yann C; Rosa, Guilherme J M; Gianola, Daniel; Yi, Nengjun; Allison, David B

    2012-12-01

    Prediction of genetic risk for disease is needed for preventive and personalized medicine. Genome-wide association studies have found unprecedented numbers of variants associated with complex human traits and diseases. However, these variants explain only a small proportion of genetic risk. Mounting evidence suggests that many traits, relevant to public health, are affected by large numbers of small-effect genes and that prediction of genetic risk to those traits and diseases could be improved by incorporating large numbers of markers into whole-genome prediction (WGP) models. We developed a WGP model incorporating thousands of markers for prediction of skin cancer risk in humans. We also considered other ways of incorporating genetic information into prediction models, such as family history or ancestry (using principal components, PCs, of informative markers). Prediction accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) estimated in a cross-validation. Incorporation of genetic information (i.e., familial relationships, PCs, or WGP) yielded a significant increase in prediction accuracy: from an AUC of 0.53 for a baseline model that accounted for nongenetic covariates to AUCs of 0.58 (pedigree), 0.62 (PCs), and 0.64 (WGP). In summary, prediction of skin cancer risk could be improved by considering genetic information and using a large number of single-nucleotide polymorphisms (SNPs) in a WGP model, which allows for the detection of patterns of genetic risk that are above and beyond those that can be captured using family history. We discuss avenues for improving prediction accuracy and speculate on the possible use of WGP to prospectively identify individuals at high risk.

  15. Breast Cancer Risk Reduction and Membrane-Bound Catechol O-Methyltransferase Genetic Polymorphisms

    PubMed Central

    Ji, Yuan; Olson, Janet; Zhang, Jianping; Hildebrandt, Michelle; Wang, Liewei; Ingle, James; Fredericksen, Zachary; Sellers, Thomas; Miller, William R.; Dixon, J. Michael; Brauch, Hiltrud; Eichelbaum, Michel; Justenhoven, Christina; Hamann, Ute; Ko, Yon; Brüning, Thomas; Chang-Claude, Jenny; Wang-Gohrke, Shan; Schaid, Daniel; Weinshilboum, Richard

    2008-01-01

    Catechol O-methyltransferase (COMT)-catalyzed methylation of catecholestrogens has been proposed to play a protective role in estrogen-induced genotoxic carcinogenesis. We have taken a comprehensive approach to test the hypothesis that genetic variation in COMT might influence breast cancer risk. Fifteen COMT SNPs selected on the basis of in-depth resequencing of the COMT gene were genotyped in 1482 DNA samples from a Mayo Clinic breast cancer case-control study. Two common SNPs in the distal promoter for membrane-bound (MB) COMT, rs2020917 and rs737865, were associated with breast cancer risk reduction in premenopausal women in the Mayo Clinic study, with allele-specific odds ratios of 0.70 (95% CI = 0.52–0.95) and 0.68 (95% CI = 0.51–0.92), respectively. These two SNPs were then subjected to functional genomic analysis and were genotyped in an additional 3683 DNA samples from two independent case-control studies (GENICA and GESBC). Functional genomic experiments showed that these SNPs could up-regulate transcription and that they altered DNA-protein binding patterns. Furthermore, substrate kinetic and exon array analyses suggested a role for MB-COMT in catecholestrogen inactivation. The GENICA results were similar to the Mayo case-control observations, with ORs of 0.85 (95% CI = 0.72–1.00) and 0.85 (95% CI = 0.72–1.01) for the two SNPs. No significant effect was observed in the GESBC study. These studies demonstrated that two SNPs in the COMT distal promoter were associated with breast cancer risk reduction in 2 of 3 case-control studies, compatible with the results of functional genomic experiments, suggesting a role for MB-COMT in breast cancer risk. PMID:18632656

  16. 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

  17. GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics

    PubMed Central

    Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C.; Souza, Milena M.; Cirillo, Cintia A.; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S.; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K.

    2014-01-01

    Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88– 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10−13, r2 = 8.9%, β = −0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with—but is statistically distinct from—the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10−37, r2 = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception. PMID:23966204

  18. GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics.

    PubMed

    Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C; Souza, Milena M; Cirillo, Cintia A; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K

    2014-01-01

    Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10(-13), r(2) = 8.9%, β = -0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with-but is statistically distinct from-the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10(-37), r(2) = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.

  19. 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

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

    PubMed Central

    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

  1. 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

  2. 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

  3. Women's interest in genetic testing for breast cancer risk: the influence of sociodemographics and knowledge.

    PubMed

    Bottorff, Joan L; Ratner, Pamela A; Balneaves, Lynda G; Richardson, Chris G; McCullum, Mary; Hack, Tom; Chalmers, Karen; Buxton, Jane

    2002-01-01

    The objective of this study was to assess women's interest in genetic testing for breast cancer risk. Randomly selected samples of 761 women without breast cancer from the general population of British Columbia, Canada, and 260 women with breast cancer from the provincial cancer registry participated in a telephone survey that assessed interest in genetic testing for breast cancer risk, knowledge of hereditary breast cancer and genetic testing, and sociodemographics. Women with breast cancer did not possess superior knowledge of breast cancer genetics compared with women from the general population. Of the women with breast cancer, 30.8% reported interest in testing or had been tested, compared with 28.5% of women without breast cancer. Controlling for differences in age, education, personal history of breast cancer, and knowledge of genetics, women with at least one relative with breast cancer were 2.3 times more likely to express interest in genetic testing for breast cancer risk than those with no family history. There were significant interactions between breast cancer status and education and between age and knowledge of breast cancer genetics. Women without breast cancer and with a positive family history, who were between 20 and 40 years of age, were most likely to be interested in testing. The women with breast cancer who were interested in testing tended to be approximately 50 years of age, had a positive family history, and had more years of education. Women with a family history of breast cancer, well-educated women with breast cancer, and younger women, particularly those with knowledge of genetic testing, are important target audiences for community-based education on genetic testing for breast cancer risk.

  4. [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

  5. [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.

  6. Non-coding RNAs in crop genetic modification: considerations and predictable environmental risk assessments (ERA).

    PubMed

    Ramesh, S V

    2013-09-01

    Of late non-coding RNAs (ncRNAs)-mediated gene silencing is an influential tool deliberately deployed to negatively regulate the expression of targeted genes. In addition to the widely employed small interfering RNA (siRNA)-mediated gene silencing approach, other variants like artificial miRNA (amiRNA), miRNA mimics, and artificial transacting siRNAs (tasiRNAs) are being explored and successfully deployed in developing non-coding RNA-based genetically modified plants. The ncRNA-based gene manipulations are typified with mobile nature of silencing signals, interference from viral genome-derived suppressor proteins, and an obligation for meticulous computational analysis to prevaricate any inadvertent effects. In a broad sense, risk assessment inquiries for genetically modified plants based on the expression of ncRNAs are competently addressed by the environmental risk assessment (ERA) models, currently in vogue, designed for the first generation transgenic plants which are based on the expression of heterologous proteins. Nevertheless, transgenic plants functioning on the foundation of ncRNAs warrant due attention with respect to their unique attributes like off-target or non-target gene silencing effects, small RNAs (sRNAs) persistence, food and feed safety assessments, problems in detection and tracking of sRNAs in food, impact of ncRNAs in plant protection measures, effect of mutations etc. The role of recent developments in sequencing techniques like next generation sequencing (NGS) and the ERA paradigm of the different countries in vogue are also discussed in the context of ncRNA-based gene manipulations.

  7. 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.

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

    PubMed Central

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

    2015-01-01

    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–$2000). 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

  9. Life insurance and breast cancer risk assessment: adverse selection, genetic testing decisions, and discrimination.

    PubMed

    Armstrong, Katrina; Weber, Barbara; FitzGerald, Genevieve; Hershey, John C; Pauly, Mark V; Lemaire, Jean; Subramanian, Krupa; Asch, David A

    2003-07-30

    Life insurance industry access to genetic information is controversial. Consumer groups argue that access will increase discrimination in life insurance premiums and discourage individuals from undergoing genetic testing that may provide health benefits. Conversely, life insurers argue that without access to risk information available to individuals, they face substantial financial risk from adverse selection. Given this controversy, we conducted a retrospective cohort study to evaluate the impact of breast cancer risk information on life insurance purchasing, the impact of concerns about life insurance discrimination on use of BRCA1/2 testing, and the incidence of life insurance discrimination following participation in breast cancer risk assessment and BRCA1/2 testing. Study participants were 636 women who participated in genetic counseling and/or genetic testing at a University based clinic offering breast cancer risk assessment, genetic counseling, and BRCA1/2 testing between January 1995 and May 2000. Twenty-seven women (4%) had increased and six (1%) had decreased their life insurance since participation in breast cancer risk assessment. The decision to increase life insurance coverage was associated with predicted breast cancer risk (adjusted OR 1.03 for each 1% absolute increase in risk, 95% CI 1.01-1.10) and being found to carry a mutation in BRCA1/2 (OR 5.10, 95% CI 1.90-13.66). Concern about life insurance discrimination was inversely associated with the decision to undergo BRCA1/2 testing (RR 0.67, 95% CI 0.52-0.85). No respondent reported having life insurance denied or canceled. In this cohort of women, these results indicate that information about increased breast cancer risk is associated with increase in life insurance purchasing, raising the possibility of adverse selection. Although fear of insurance discrimination is associated with the decision not to undergo BRCA1/2 testing, there was no evidence of actual insurance discrimination from BRCA1

  10. Risk assessment of nitrate and oxytetracycline addition on coastal ecosystem functions.

    PubMed

    Feng-Jiao, Liu; Shun-Xing, Li; Feng-Ying, Zheng; Xu-Guang, Huang; Yue-Gang, Zuo; Teng-Xiu, Tu; Xue-Qing, Wu

    2014-01-01

    Diatoms dominate phytoplankton communities in the well-mixed coastal and upwelling regions. Coastal diatoms are often exposed to both aquaculture pollution and eutrophication. But how these exposures influence on coastal ecosystem functions are unknown. To examine these influences, a coastal centric diatom, Conticribra weissflogii was maintained at different concentrations of nitrate (N) and/or oxytetracycline (OTC). Algal density, cell growth cycle, protein, chlorophyll a, superoxide dismutase (SOD) activity, and malonaldehyde (MDA) were determined for the assessment of algal biomass, lifetime, nutritional value, photosynthesis and respiration, antioxidant capacity, and lipid peroxidation, respectively. When N addition was combined with OTC pollution, the cell growth cycles were shortened by 56-73%; algal density, SOD activities, the concentrations of chlorophyll a, protein, and MDA varied between 73 and 121%, 19 and 397%, 52 and 693%, 19 and 875%, and 66 and 2733% of the values observed in N addition experiments, respectively. According to P-value analysis, the influence of OTC on algal density and SOD activity was not significant, but the effect on cell growth cycle, protein, chlorophyll a, and MDA were significant (P<0.05). The influence of N addition with simultaneous OTC pollution on the above six end points was significant. Algal biomass, lifetime, nutrition, antioxidant capacity, lipid peroxidation, photosynthesis, and respiration were all affected by the addition of OTC and N. Coastal ecosystem functions were severely affected by N and OTC additions, and the influence was increased in the order: Nrisk assessment of aquaculture pollution on coastal ecosystem functions.

  11. Genetic vulnerability to diabetes and obesity: does education offset the risk?

    PubMed

    Liu, S Y; Walter, S; Marden, J; Rehkopf, D H; Kubzansky, L D; Nguyen, T; Glymour, M M

    2015-02-01

    The prevalence of type 2 diabetes (T2D) and obesity has recently increased dramatically. These common diseases are likely to arise from the interaction of multiple genetic, socio-demographic and environmental risk factors. While previous research has found genetic risk and education to be strong predictors of these diseases, few studies to date have examined their joint effects. This study investigates whether education modifies the association between genetic background and risk for type 2 diabetes (T2D) and obesity. Using data from non-Hispanic Whites in the Health and Retirement Study (HRS, n = 8398), we tested whether education modifies genetic risk for obesity and T2D, offsetting genetic effects; whether this effect is larger for individuals who have high risk for other (unobserved) reasons, i.e., at higher quantiles of HbA1c and BMI; and whether effects differ by gender. We measured T2D risk using Hemoglobin A1c (HbA1c) level, and obesity risk using body-mass index (BMI). We constructed separate genetic risk scores (GRS) for obesity and diabetes respectively based on the most current available information on the single nucleotide polymorphism (SNPs) confirmed as genome-wide significant predictors for BMI (29 SNPs) and diabetes risk (39 SNPs). Linear regression models with years of schooling indicate that the effect of genetic risk on HbA1c is smaller among people with more years of schooling and larger among those with less than a high school (HS) degree compared to HS degree-holders. Quantile regression models show that the GRS × education effect systematically increased along the HbA1c outcome distribution; for example the GRS × years of education interaction coefficient was -0.01 (95% CI = -0.03, 0.00) at the 10th percentile compared to -0.03 (95% CI = -0.07, 0.00) at the 90th percentile. These results suggest that education may be an important socioeconomic source of heterogeneity in responses to genetic vulnerability to T2D.

  12. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

    PubMed Central

    Pearce, C L; Near, A M; Van Den Berg, D J; Ramus, S J; Gentry-Maharaj, A; Menon, U; Gayther, S A; Anderson, A R; Edlund, C K; Wu, A H; Chen, X; Beesley, J; Webb, P M; Holt, S K; Chen, C; Doherty, J A; Rossing, M A; Whittemore, A S; McGuire, V; DiCioccio, R A; Goodman, M T; Lurie, G; Carney, M E; Wilkens, L R; Ness, R B; Moysich, K B; Edwards, R; Jennison, E; Kjaer, S K; Hogdall, E; Hogdall, C K; Goode, E L; Sellers, T A; Vierkant, R A; Cunningham, J C; Schildkraut, J M; Berchuck, A; Moorman, P G; Iversen, E S; Cramer, D W; Terry, K L; Vitonis, A F; Titus-Ernstoff, L; Song, H; Pharoah, P D P; Spurdle, A B; Anton-Culver, H; Ziogas, A; Brewster, W; Galitovskiy, V; Chenevix-Trench, G

    2009-01-01

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P⩽0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: ORhomozygous(hom)=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20–6.56, P=0.017, phet across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted. PMID:19127255

  13. Genetic and Epigenetic Changes in Oilseed Rape (Brassica napus L.) Extracted from Intergeneric Allopolyploid and Additions with Orychophragmus

    PubMed Central

    Gautam, Mayank; Dang, Yanwei; Ge, Xianhong; Shao, Yujiao; Li, Zaiyun

    2016-01-01

    Allopolyploidization with the merger of the genomes from different species has been shown to be associated with genetic and epigenetic changes. But the maintenance of such alterations related to one parental species after the genome is extracted from the allopolyploid remains to be detected. In this study, the genome of Brassica napus L. (2n = 38, genomes AACC) was extracted from its intergeneric allohexaploid (2n = 62, genomes AACCOO) with another crucifer Orychophragmus violaceus (2n = 24, genome OO), by backcrossing and development of alien addition lines. B. napus-type plants identified in the self-pollinated progenies of nine monosomic additions were analyzed by the methods of amplified fragment length polymorphism, sequence-specific amplified polymorphism, and methylation-sensitive amplified polymorphism. They showed modifications to certain extents in genomic components (loss and gain of DNA segments and transposons, introgression of alien DNA segments) and DNA methylation, compared with B. napus donor. The significant differences in the changes between the B. napus types extracted from these additions likely resulted from the different effects of individual alien chromosomes. Particularly, the additions which harbored the O. violaceus chromosome carrying dominant rRNA genes over those of B. napus tended to result in the development of plants which showed fewer changes, suggesting a role of the expression levels of alien rRNA genes in genomic stability. These results provided new cues for the genetic alterations in one parental genome that are maintained even after the genome becomes independent. PMID:27148282

  14. Genetic and Epigenetic Changes in Oilseed Rape (Brassica napus L.) Extracted from Intergeneric Allopolyploid and Additions with Orychophragmus.

    PubMed

    Gautam, Mayank; Dang, Yanwei; Ge, Xianhong; Shao, Yujiao; Li, Zaiyun

    2016-01-01

    Allopolyploidization with the merger of the genomes from different species has been shown to be associated with genetic and epigenetic changes. But the maintenance of such alterations related to one parental species after the genome is extracted from the allopolyploid remains to be detected. In this study, the genome of Brassica napus L. (2n = 38, genomes AACC) was extracted from its intergeneric allohexaploid (2n = 62, genomes AACCOO) with another crucifer Orychophragmus violaceus (2n = 24, genome OO), by backcrossing and development of alien addition lines. B. napus-type plants identified in the self-pollinated progenies of nine monosomic additions were analyzed by the methods of amplified fragment length polymorphism, sequence-specific amplified polymorphism, and methylation-sensitive amplified polymorphism. They showed modifications to certain extents in genomic components (loss and gain of DNA segments and transposons, introgression of alien DNA segments) and DNA methylation, compared with B. napus donor. The significant differences in the changes between the B. napus types extracted from these additions likely resulted from the different effects of individual alien chromosomes. Particularly, the additions which harbored the O. violaceus chromosome carrying dominant rRNA genes over those of B. napus tended to result in the development of plants which showed fewer changes, suggesting a role of the expression levels of alien rRNA genes in genomic stability. These results provided new cues for the genetic alterations in one parental genome that are maintained even after the genome becomes independent. PMID:27148282

  15. Additional records of metazoan parasites from Caribbean marine mammals, including genetically identified anisakid nematodes.

    PubMed

    Colón-Llavina, Marlene M; Mignucci-Giannoni, Antonio A; Mattiucci, Simonetta; Paoletti, Michela; Nascetti, Giuseppe; Williams, Ernest H

    2009-10-01

    Studies of marine mammal parasites in the Caribbean are scarce. An assessment for marine mammal endo- and ectoparasites from Puerto Rico and the Virgin Islands, but extending to other areas of the Caribbean, was conducted between 1989 and 1994. The present study complements the latter and enhances identification of anisakid nematodes using molecular markers. Parasites were collected from 59 carcasses of stranded cetaceans and manatees from 1994 to 2006, including Globicephala macrorhynchus, Kogia breviceps, Kogia sima, Lagenodelphis hosei, Mesoplodon densirostris, Peponocephala electra, Stenella longirostris, Steno bredanensis, Trichechus manatus. Tursiops truncatus, and Ziphius cavirostris. Sixteen species of endoparasitic helminthes were morphologically identified, including two species of acanthocephalans (Bolbosoma capitatum, Bolbosoma vasculosum), nine species of nematodes (Anisakis sp., Anisakis brevispiculata, Anisakis paggiae, Anisakis simplex, Anisakis typica, Anisakis ziphidarium, Crassicauda anthonyi, Heterocheilus tunicatus, Pseudoterranova ceticola), two species of cestodes (Monorygma grimaldi, Phyllobothrium delphini), and three species of trematodes (Chiorchis groschafti, Pulmonicola cochleotrema, Monoligerum blairi). The nematodes belonging to the genus Anisakis recovered in some stranded animals were genetically identified to species level based on their sequence analysis of mitochondrial DNA (629 bp of mtDNA cox 2). A total of five new host records and six new geographic records are presented. PMID:19582477

  16. Additional records of metazoan parasites from Caribbean marine mammals, including genetically identified anisakid nematodes.

    PubMed

    Colón-Llavina, Marlene M; Mignucci-Giannoni, Antonio A; Mattiucci, Simonetta; Paoletti, Michela; Nascetti, Giuseppe; Williams, Ernest H

    2009-10-01

    Studies of marine mammal parasites in the Caribbean are scarce. An assessment for marine mammal endo- and ectoparasites from Puerto Rico and the Virgin Islands, but extending to other areas of the Caribbean, was conducted between 1989 and 1994. The present study complements the latter and enhances identification of anisakid nematodes using molecular markers. Parasites were collected from 59 carcasses of stranded cetaceans and manatees from 1994 to 2006, including Globicephala macrorhynchus, Kogia breviceps, Kogia sima, Lagenodelphis hosei, Mesoplodon densirostris, Peponocephala electra, Stenella longirostris, Steno bredanensis, Trichechus manatus. Tursiops truncatus, and Ziphius cavirostris. Sixteen species of endoparasitic helminthes were morphologically identified, including two species of acanthocephalans (Bolbosoma capitatum, Bolbosoma vasculosum), nine species of nematodes (Anisakis sp., Anisakis brevispiculata, Anisakis paggiae, Anisakis simplex, Anisakis typica, Anisakis ziphidarium, Crassicauda anthonyi, Heterocheilus tunicatus, Pseudoterranova ceticola), two species of cestodes (Monorygma grimaldi, Phyllobothrium delphini), and three species of trematodes (Chiorchis groschafti, Pulmonicola cochleotrema, Monoligerum blairi). The nematodes belonging to the genus Anisakis recovered in some stranded animals were genetically identified to species level based on their sequence analysis of mitochondrial DNA (629 bp of mtDNA cox 2). A total of five new host records and six new geographic records are presented.

  17. Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data

    PubMed Central

    2011-01-01

    Background Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. Methods We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. Results In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other

  18. 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.

  19. Measurement and associations of pregnancy risk factors with genetic influences, postnatal environmental influences, and toddler behavior

    PubMed Central

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

    2014-01-01

    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 reported aggregate scores characterizing total obstetric complications, perinatal internalizing symptoms, pregnancy complications, exposure to toxins, substance use, and neonatal complications), and postnatal influences (adoptive parent 18-month internalizing symptoms and over-reactive parenting) and toddler behavior problems (CBCL subscales at 27 months). Findings highlight multiple pathways for toddler’s behavioral development, including genetic, pregnancy, and postnatal main effects. Findings suggest distinct types of pregnancy risk may transmit genetic influences for specific behavior problems rather than broadband problems. PMID:24839336

  20. Measurement and associations of pregnancy risk factors with genetic influences, postnatal environmental influences, and toddler behavior.

    PubMed

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

    2013-07-01

    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 reported aggregate scores characterizing total obstetric complications, perinatal internalizing symptoms, pregnancy complications, exposure to toxins, substance use, and neonatal complications), and postnatal influences (adoptive parent 18-month internalizing symptoms and over-reactive parenting) and toddler behavior problems (CBCL subscales at 27 months). Findings highlight multiple pathways for toddler's behavioral development, including genetic, pregnancy, and postnatal main effects. Findings suggest distinct types of pregnancy risk may transmit genetic influences for specific behavior problems rather than broadband problems.

  1. Addition of restriction fragment length polymorphism markers to the genetic linkage map of Brassica rapa L. (syn. campestris).

    PubMed

    Panigrahi, Jogeswar; Patnaik, Anjana; Kole, Phullara; Koleb, Chitta ranjan

    2009-01-01

    Genetic linkage analysis of 151 restriction fragment length polymorphism (RFLP) loci, that included eight new loci, detected by the six probes in the present study, and four trait loci including seed colour, leaf pubescence, resistance to white rust caused by Albugo candida race-2 (AC-2) and race-7 (AC-7) employing the MAPMAKER/EXP 3.0 programme led to the development of 10 linkage groups (LGs) spanning over 44.4 centiMorgan (cM) to 130.4 cM containing 9 to 22 loci and two short LGs with two or three marker loci in Brassica rapa. The enriched map covers 993.1 cM of B. rapa genome with an average marker interval of 6.41. Eight new RFLP loci occupied new map positions on five linkage groups, LG 2, 3, 6, 8 and 9. Addition of these RFLP loci led to appreciable changes in the corresponding linkage groups and resulted in an increase of the total map length by 102.8 cM and of the marker interval by 0.35 cM. Interval mapping by using the computer programme MAPMAKER/ QTL 1.1 for scanning the genetic map led to the detection of one major quantitative trait locus (QTL) in LG 4 and one minor QTL in LG 8 governing resistance to AC-7. Both QTLs contributed 7.89 to the interaction phenotype (IP) score with 96.3% genetic variation. The multi-locus model suggested additive gene action with 96.8% genetic variation.

  2. Genetic prerequisites for additive or synergistic actions of 5-fluorocytosine and fluconazole in baker's yeast.

    PubMed

    Paluszynski, John P; Klassen, Roland; Meinhardt, Friedhelm

    2008-10-01

    During applications of 5-fluorocytosine (5FC) and fluconazole (FLC), additive or synergistic action may even occur when primary resistance to 5FC is established. Here, we analysed conjoint drug action in Saccharomyces cerevisiae strains deficient in genes known to be essential for 5FC or FLC function. Despite clear primary resistance, residual 5FC activity and additive 5FC+FLC action in cells lacking cytosine permease (Fcy2p) or uracil phosphoribosyl transferase (Fur1p) were detected. In contrast, Deltafcy1 mutants, lacking cytosine deaminase, became entirely resistant to 5FC, concomitantly losing 5FC+FLC additivity. Disruption of the orotate phosphoribosyltransferase gene (URA5) in the wild-type led to low-level 5FC tolerance, while an alternative orotate phosphoribosyltransferase, encoded by URA10, contributed to 5FC toxicity only in the Deltaura5 background. Remarkably, combination of Deltaura5 and Deltafur1 resulted in complete 5FC resistance. Thus, yeast orotate phosphoribosyltransferases are involved in 5FC metabolism. Similarly, disruption of the ergosterol Delta(5,6)-desaturase-encoding gene ERG3 resulted only in partial resistance to FLC, and concomitantly a synergistic effect with 5FC became evident. Full resistance to FLC occurred in Deltaerg3 Deltaerg11 double mutants and, simultaneously, synergism or even an additive effect with FLC and 5FC was no longer discernible. Since the majority of spontaneously occurring resistant yeast clones displayed residual sensitivity to either 5FC or FLC and those strains responded to combined drug treatment in a predictable manner, careful resistance profiling based on the findings reported here may help to address yeast infections by combined application of antimycotic compounds.

  3. AN EXAMINATION OF THE OVERLAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS FOR INTENTIONAL WEIGHT LOSS AND OVEREATING

    PubMed Central

    Wade, Tracey D.; Treloar, Susan A.; Heath, Andrew C.; Martin, Nicholas G

    2009-01-01

    Objective In order to further our understanding of how intentional weight loss (IWL) and overeating are related, we examined the shared genetic and environmental variance between lifetime IWL and overeating. Methods Interview data were available for 1976 female twins (both members of 439 and 264 pairs of monozygotic and dizygotic twins respectively), mean age=40.61, SD=4.72. We used lifetime diagnostic data for eating disorders obtained from a semi-structured psychiatric telephone interview, examined in a bivariate twin analysis. Both lifetime behaviours were measured on a 3-point scale, where absence of IWL or overeating formed one anchor on the scale and lifetime anorexia nervosa (AN) and bulimia nervosa (BN) formed the opposite anchors respectively. Results In line with previous findings, a higher body mass index was significantly associated with the lifetime presence of IWL and/or overeating (odds ratio=1.13, 95% confidence interval (CI): 1.08–1.19). The best fitting twin model contained additive genetic and non-shared environmental influence influencing both IWL and overeating, with correlations between these influences of 0.61 (95% CI: 0.35–0.92) and 0.24 (95% CI: 0.07–0.42) respectively. Conclusion About 37% of genetic risk factors were considered to overlap between IWL and overeating, and with only 6% of overlap between environmental risk factors. Thus considerable independence of risk factors was indicated. PMID:19235851

  4. 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

  5. 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.

  6. Why the preeminent risk factor in sporadic Alzheimer's disease cannot be genetic.

    PubMed

    Foster, H D

    2002-07-01

    If genetic risk factors are preeminent in the etiology of sporadic Alzheimer's disease, three corollaries follow: age-adjusted death rates from it should be fairly spatially uniform, should not vary significantly over time and should not alter markedly with migration. Globally, none of these corollaries hold true. The APO E(4) allele and other genetic aberrations that promote sporadic Alzheimer's disease do so most effectively in low alkalinity-high aluminum environments, especially if these are experiencing acid rain.

  7. 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

  8. Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders.

    PubMed

    Roussotte, Florence F; Daianu, Madelaine; Jahanshad, Neda; Leonardo, Cassandra D; Thompson, Paul M

    2014-06-01

    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 multi-modal 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.

  9. Predictive value of breast cancer cognitions and attitudes toward genetic testing on women’s interest in genetic testing for breast cancer risk

    PubMed Central

    Reitz, Frauke; Barth, Jürgen; Bengel, Jürgen

    2004-01-01

    In the past years advances in genetic technologies have led to an increased interest in predictive genetic testing for breast cancer risk. Studies in the US and UK reported an increasing interest among women of the general public in genetic testing for breast cancer risk, although the benefit of such a test is questionable for low risk women. The aim of the present study was to identify factors that predict interest in genetic testing of German women in the general public. Women with neither a family history of breast cancer nor breast cancer themselves received an information letter by mail, were interviewed by telephone, and completed a self-administered questionnaire (N=377). Structural equation modeling was used to determine the predictive value of attitudinal and cognitive variables on interest in genetic testing for breast cancer risk. The resulting model achieved good fit indices, and 42% of variance could be explained. Women with more expectations concerning the test, more positive attitudes concerning genetic testing in general, an increased breast cancer risk perception, and increased breast cancer worries showed more interest in testing. These findings suggest the need for information and counseling strategies for low risk women which should focus in particular on decreasing unrealistic expectations concerning genetic testing for breast cancer risk but also on decreasing perceived breast cancer risk and breast cancer worries. PMID:19742051

  10. 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.

  11. 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

  12. 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

  13. Fatalistic responses to different types of genetic risk information: exploring the role of self-malleability.

    PubMed

    Claassen, Liesbeth; Henneman, Lidewij; De Vet, Riekie; Knol, Dirk; Marteau, Theresa; Timmermans, Danielle

    2010-02-01

    Providing people with genetic risk information may induce a sense of fatalism, the belief that little can be done to reduce the risk. We postulated that fatalism is a function of health risk information and individual differences in self-perception. DNA-based risk information was hypothesised to generate more fatalism than risk information based on family history or non-genetic risk information. Moreover, people who view themselves as more rather than less able to change self-attributes were hypothesised to respond least fatalistically. Factor analyses in separate samples were used to construct a five-item 'Malleability of self' measure. Predictive validity of the measure was tested using a within-subjects analogue design. Participants responded to three scenario vignettes in which they were informed of an increased risk of cardiovascular disease (CVD). In Scenario 1, risk was ascertained by DNA testing, family history and cholesterol testing; in Scenario 2, it was ascertained by family history and cholesterol testing; in Scenario 3, risk was ascertained by cholesterol testing alone. Scenario 1 was associated with least perceived control over cholesterol level and CVD risk. People who viewed themselves as more able to change self-attributes experienced more control in all three scenarios.

  14. 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

  15. A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses

    PubMed Central

    2014-01-01

    Background Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse. Results Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb – 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042). Conclusions Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods

  16. Shared Genetic Factors Influence Risk for Bipolar Disorder and Alcohol Use Disorders

    PubMed Central

    Carmiol, Nasdia; Peralta, Juan M; Almasy, Laura; Contreras, Javier; Pacheco, Adriana; Escamilla, Michael A; Knowles, Emma E; Raventós, Henriette; Glahn, David C

    2014-01-01

    Bipolar disorder and alcohol use disorder (AUD) have a high rate of comorbidity, more than 50% of individuals with bipolar disorder also receive a diagnosis of AUD in their lifetimes. Although both disorders are heritable, it is unclear if the same genetic factors mediate risk for bipolar disorder and AUD. We examined 733 Costa Rican individuals from 61 bipolar pedigrees. Based on a best-estimate process, 32% of the sample met criteria for bipolar disorder, 17% had a lifetime AUD diagnosis, 32% met criteria for lifetime nicotine dependence, and 21% had an anxiety disorder. AUD, nicotine dependence and anxiety disorders were relatively more common among individuals with bipolar disorder than in their non-bipolar relatives. All illnesses were shown to be heritable and bipolar disorder was genetically correlated with AUD, nicotine dependence and anxiety disorders. The genetic correlation between bipolar and AUD remained when controlling for anxiety, suggesting that unique genetic factors influence risk for comorbid bipolar and AUD independent of anxiety. Our findings provide evidence for shared genetic effects on bipolar disorder and AUD risk. Demonstrating that common genetic factors influence these independent diagnostic constructs could help to refine our diagnostic nosology. PMID:24321773

  17. Genetic association studies in complex disease: disentangling additional predisposing loci from associated neutral loci using a constrained - permutation approach.

    PubMed

    Spijker, G T; Nolte, I M; Jansen, R C; Te Meerman, G J

    2005-01-01

    In the process of genetically mapping a complex disease, the question may arise whether a certain polymorphism is the only causal variant in a region. A number of methods can answer this question, but unfortunately these methods are optimal for bi-allelic loci only. We wanted to develop a method that is more suited for multi-allelic loci, such as microsatellite markers. We propose the Additional Disease Loci Test (ADLT): the alleles at an additional locus are permuted within the subsample of haplotypes that have identical alleles at the predisposing locus. The hypothesis being tested is, whether the predisposing locus is the sole factor predisposing to the trait that is in LD with the additional locus under study. We applied ADLT to simulated datasets and a published dataset on Type 1 Diabetes, genotyped for microsatellite markers in the HLA-region. The method showed the expected number of false-positive results in the absence of additional loci, but proved to be more powerful than existing methods in the presence of additional disease loci. ADLT was especially superior in datasets with less LD or with multiple predisposing alleles. We conclude that the ADLT can be useful in identifying additional disease loci.

  18. Variance in disease risk: rural populations and genetic diversity.

    PubMed

    Jenkins, W D; Lipka, A E; Fogleman, A J; Delfino, K R; Malhi, R S; Hendricks, B

    2016-07-01

    Over 19% of the US population resides in rural areas, where studies of disease risk and disease outcomes are difficult to assess due to smaller populations and lower incidence. While some studies suggest rural disparities for different chronic diseases, the data are inconsistent across geography and definitions of rurality. We reviewed the literature to examine if local variations in population genomic diversity may plausibly explain inconsistencies in estimating disease risk. Many rural communities were founded over 150 years ago by small groups of ethnically and ancestrally similar families. These have since endured relative geographical isolation, similar to groups in other industrialized nations, perhaps resulting in founder effects impacting local disease susceptibility. Studies in Europe and Asia have found that observably different phenotypes may appear in isolated communities within 100 years, and that genomic variation can significantly vary over small geographical scales. Epidemiological studies utilizing common "rural" definitions may miss significant disease differences due to assumptions of risk homogeneity and misinterpretation of administrative definitions of rurality. Local genomic heterogeneity should be an important aspect of chronic disease epidemiology in rural areas, and it is important to consider for designing studies and interpreting results, enabling a better understanding of the heritable components of complex diseases. PMID:27334395

  19. Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication.

    PubMed

    Park, Byung Lae; Kim, Jee Wook; Cheong, Hyun Sub; Kim, Lyoung Hyo; Lee, Boung Chul; Seo, Cheong Hoon; Kang, Tae-Cheon; Nam, Young-Woo; Kim, Goon-Bo; Shin, Hyoung Doo; Choi, Ihn-Geun

    2013-06-01

    Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case-control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10(-21), OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.

  20. 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 ...

  1. [Health risks of genetically modified foods: a literature review].

    PubMed

    Domingo Roig, J L; Gómez Arnáiz, M

    2000-01-01

    In 1999, there has been much concern on the safety of genetically modified (GM) foods, an important and complex area of safety research, which demands rigorous standards. Various groups, including consumers and environmental Non Governmental Organizations (NGO) have suggested that all GM foods should be subjected to long-term animal feeding studies before approval for human consumption. The main goal of this review has been to know which is the state-of-the art regarding to the potential adverse effects of GM foods. Two databases, MEDLINE and TOXLINE, as well as a number of URL from INTERNET were used for references. Although commentaries, general news and letters to the Editor have been frequently published in reputable journals, papers about experimental studies on the safety of GM foods are surprisingly very scant. If data on toxicological assessment of GM foods have been obtained, these have not been reported in scientific journals and subjected to the scientific judgement.

  2. 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

  3. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

    PubMed

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M; McLaughlin, Russell L; Diekstra, Frank P; Pulit, Sara L; van der Spek, Rick A A; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R; Yang, Jian; Fogh, Isabella; van Doormaal, Perry Tc; Tazelaar, Gijs H P; Koppers, Max; Blokhuis, Anna M; Sproviero, William; Jones, Ashley R; Kenna, Kevin P; van Eijk, Kristel R; Harschnitz, Oliver; Schellevis, Raymond D; Brands, William J; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E; Shaw, Pamela J; Hardy, John; Orrell, Richard W; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A; Staats, Kim A; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Basak, A Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A M; Saker-Delye, Safaa; Dürr, Alexandra; Wood, Nicholas W; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M; van der Kooi, Anneke J; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E; Smith, Bradley N; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P; Fifita, Jennifer A; Nicholson, Garth A; Rowe, Dominic B; Pamphlett, Roger; Kiernan, Matthew C; Grosskreutz, Julian; Witte, Otto W; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Hübner, Christian A; Leigh, P Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C; Weishaupt, Jochen H; Robberecht, Wim; Van Damme, Philip; Franke, Lude; Pers, Tune H; Brown, Robert H; Glass, Jonathan D; Landers, John E; Hardiman, Orla; Andersen, Peter M; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R; Visscher, Peter M; de Bakker, Paul I W; van Es, Michael A; Pasterkamp, R Jeroen; Lewis, Cathryn M; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan H

    2016-09-01

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk. PMID:27455348

  4. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

    PubMed

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M; McLaughlin, Russell L; Diekstra, Frank P; Pulit, Sara L; van der Spek, Rick A A; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R; Yang, Jian; Fogh, Isabella; van Doormaal, Perry Tc; Tazelaar, Gijs H P; Koppers, Max; Blokhuis, Anna M; Sproviero, William; Jones, Ashley R; Kenna, Kevin P; van Eijk, Kristel R; Harschnitz, Oliver; Schellevis, Raymond D; Brands, William J; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E; Shaw, Pamela J; Hardy, John; Orrell, Richard W; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A; Staats, Kim A; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Basak, A Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A M; Saker-Delye, Safaa; Dürr, Alexandra; Wood, Nicholas W; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M; van der Kooi, Anneke J; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E; Smith, Bradley N; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P; Fifita, Jennifer A; Nicholson, Garth A; Rowe, Dominic B; Pamphlett, Roger; Kiernan, Matthew C; Grosskreutz, Julian; Witte, Otto W; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Hübner, Christian A; Leigh, P Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C; Weishaupt, Jochen H; Robberecht, Wim; Van Damme, Philip; Franke, Lude; Pers, Tune H; Brown, Robert H; Glass, Jonathan D; Landers, John E; Hardiman, Orla; Andersen, Peter M; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R; Visscher, Peter M; de Bakker, Paul I W; van Es, Michael A; Pasterkamp, R Jeroen; Lewis, Cathryn M; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan H

    2016-09-01

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

  5. Additive genetic and heterosis effects in crosses among cattle breeds of British, European and Zebu origin.

    PubMed

    Peacock, F M; Koger, M; Olson, T A; Crockett, J R

    1981-05-01

    Breed and heterosis effects for maternal and calf components for weaning traits were measured in the progeny of Angus (A), Brahman (B) and Charolais (C) sires mated to A, B, C and reciprocal AB, AC and BC dams. Additive breed effects for the calf component for weaning weight were -3.0 +/- 3.2, -26.6 +/- 3.1 and 29.6 +/- 3.3 kg for A, B and C, respectively. Corresponding maternal breed effects were -1.7 +/- 2.4, 7.8 +/- 2.3 and -6.1 +/- 2.6 kilograms. Heterosis effects on weaning weight for the calf component were 21.2 +/- 3.6 for AB, 1.4 +/- 3.7 for AC and 16.5 +/- 3.4 for BC crosses, while heterosis levels for the maternal component were 28.9 +/- 2.7 for AB, 16.5 +/- 3.2 for AC and 18.7 +/- 2.9 kg for BC dams. The corresponding estimates for condition scores tended to parallel those for weaning weight. Approximate relative production efficiency rates were computed for the different mating groups as (calf weight divided by cow weight) x weaning rate. These values were .34 for purebred matings, .36 for purebred dams raising F1 calves, .40 for F1 cows raising backcross calves and .43 for F1 dams raising three breed crossbred calves.

  6. 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

  7. The addition of whole soy flour to cafeteria diet reduces metabolic risk markers in wistar rats

    PubMed Central

    2013-01-01

    Background Soybean is termed a functional food because it contains bioactive compounds. However, its effects are not well known under unbalanced diet conditions. This work is aimed at evaluating the effect of adding whole soy flour to a cafeteria diet on intestinal histomorphometry, metabolic risk and toxicity markers in rats. Methods In this study, 30 male adult Wistar rats were used, distributed among three groups (n = 10): AIN-93 M diet, cafeteria diet (CAF) and cafeteria diet with soy flour (CAFS), for 56 days. The following parameters were measured: food intake; weight gain; serum concentrations of triglycerides, total cholesterol, HDL-c, glycated hemoglobin (HbA1c), aspartate (AST) and alanine (ALT) aminotransferases and Thiobarbituric Acid Reactive Substances (TBARS); humidity and lipid fecal content; weight and fat of the liver. The villous height, the crypt depth and the thickness of the duodenal and ileal circular and longitudinal muscle layers of the animals were also measured. Results There was a significant reduction in the food intake in the CAF group. The CAFS showed lower serum concentrations of triglycerides and serum TBARS and a lower percentage of hepatic fat, with a corresponding increase in thickness of the intestinal muscle layers. In the CAF group, an increase in the HbA1c, ALT, lipid excretion, liver TBARS and crypt depth, was observed associated with lower HDL-c and villous height. The addition of soy did not promote any change in these parameters. Conclusions The inclusion of whole soy flour in a high-fat diet may be helpful in reducing some markers of metabolic risk; however, more studies are required to clarify its effects on unbalanced diets. PMID:24119309

  8. Bringing policy relevance and scientific discipline to environmental risk assessment for genetically modified crops.

    PubMed

    Herman, Rod A; Garcia-Alonso, Monica; Layton, Raymond; Raybould, Alan

    2013-09-01

    Although public opinion is important in deciding what is valued by society, governments have determined that scientific expertise is required to evaluate potential environmental effects of genetically modified (GM) crops. We suggest how to evaluate rigorously the environmental effects of GM crops in the context of a scientific investigation. Following a disciplined scientific approach to environmental risk assessment (ERA) for GM crops should help resolve controversy in identifying and addressing risk.

  9. Safety risks for animals fed genetic modified (GM) plants.

    PubMed

    Bertoni, G; Marsan, P Ajmone

    2005-08-01

    GM plants are widely grown all over the world, but many constraints still tend to discourage their use in Europe. Potential risks suggested to be associated with the use of GM are unexpected gene effects, allergenic potential, antibiotic resistance, gene flow. GM feed safety is presently evaluated by adopting the concept of GM substantial equivalence, by comparison with non-GM isogenic crops. Comparison is based on a wide spectrum of chemical components and on livestock performance. From the available experimental data, currently utilized GM plants appear safe and show no effects on animals or animal products. Hence, although they potentially exist, safety risks caused by the use of GM plants appear to be so low as be negligible in comparison with their potential benefits, if appropriately designed. GM plants represent a valuable option for future breeding, to increase yield while reducing the use of pesticides, improve plant adaptation to unfavourable environments, and produce better quality crops, also from a nutritional point of view. Nonetheless, GM crops are novel foods and the assessment of their safety using a scientific sound approach seems essential to protect the environment, as well as the health of humans and livestock.

  10. Goodness-of-fit tests for the additive risk model with (p > 2)-dimensional time-invariant covariates.

    PubMed

    Kim, J; Song, M S; Lee, S

    1998-01-01

    This paper presents methods for checking the goodness-of-fit of the additive risk model with p(> 2)-dimensional time-invariant covariates. The procedures are an extension of Kim and Lee (1996) who developed a test to assess the additive risk assumption for two-sample censored data. We apply the proposed tests to survival data from South Wales nikel refinery workers. Simulation studies are carried out to investigate the performance of the proposed tests for practical sample sizes. PMID:9880997

  11. 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

  12. VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis

    PubMed Central

    Avidan, Nili; Le Panse, Rozen; Harbo, Hanne F; Bernasconi, Pia; Poulas, Konstantinos; Ginzburg, Elizabeta; Cavalcante, Paola; Colleoni, Lara; Baggi, Fulvio; Antozzi, Carlo; Truffault, Frédérique; Horn-Saban, Shirley; Pöschel, Simone; Zagoriti, Zoi; Maniaol, Angelina; Lie, Benedicte A; Bernard, Isabelle; Saoudi, Abdelhadi; Illes, Zsolt; Casasnovas Pons, Carlos; Melms, Arthur; Tzartos, Socrates; Willcox, Nicholas; Kostera-Pruszczyk, Anna; Tallaksen, Chantal; Mantegazza, Renato; Berrih-Aknin, Sonia; Miller, Ariel

    2014-01-01

    Objective To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy. Methods Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA-DRA and TNF-α loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG. PMID:25356403

  13. Additive Effects of the Risk Alleles of PNPLA3 and TM6SF2 on Non-alcoholic Fatty Liver Disease (NAFLD) in a Chinese Population

    PubMed Central

    Wang, Xiaoliang; Liu, Zhipeng; Wang, Kai; Wang, Zhaowen; Sun, Xing; Zhong, Lin; Deng, Guilong; Song, Guohe; Sun, Baining; Peng, Zhihai; Liu, Wanqing

    2016-01-01

    Recent genome-wide association studies have identified that variants in or near PNPLA3, NCAN, GCKR, LYPLAL1, and TM6SF2 are significantly associated with non-alcoholic fatty liver disease (NAFLD) in multiple ethnic groups. Studies on their impact on NAFLD in Han Chinese are still limited. In this study, we examined the relevance of these variants to NAFLD in a community-based Han Chinese population and further explored their potential joint effect on NAFLD. Six single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, rs2294918, NCAN rs2228603, GCKR rs780094, LYPLAL1 rs12137855, and TM6SF2 rs58542926) previously identified in genome-wide analyses, to be associated with NAFLD were genotyped in 384 NAFLD patients and 384 age- and gender-matched healthy controls. We found two out of the six polymorphisms, PNPLA3 rs738409 (OR = 1.52, 95%CI: 1.19–1.96; P = 0.00087) and TM6SF2 rs58542926 (OR = 2.11, 95%CI: 1.34–3.39; P = 0.0016) are independently associated with NAFLD after adjustment for the effects of age, gender, and BMI. Our analysis further demonstrated the strong additive effects of the risk alleles of PNPLA3 and TM6SF2 with an overall significance between the number of risk alleles and NAFLD (OR = 1.64, 95%CI: 1.34–2.01; P = 1.4 × 10-6). The OR for NAFLD increased in an additive manner, with an average increase in OR of 1.52 per additional risk allele. Our results confirmed that the PNPLA3 and TM6SF2 variants were the most significant risk alleles for NAFLD in Chinese population. Therefore, genotyping these two genetic risk factors may help identify individuals with the highest risk of NAFLD. PMID:27532011

  14. Genetic variations in the transforming growth factor beta pathway as predictors of bladder cancer risk.

    PubMed

    Wei, Hua; Kamat, Ashish M; Aldousari, Saad; Ye, Yuanqing; Huang, Maosheng; Dinney, Colin P; Wu, Xifeng

    2012-01-01

    Bladder cancer is the fifth most common cancer in the United States, and identifying genetic markers that may predict susceptibility in high-risk population is always needed. The purpose of our study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with bladder cancer risk. We identified 356 single-nucleotide polymorphisms (SNPs) in 37 key genes from this pathway and evaluated their association with cancer risk in 801 cases and 801 controls. Forty-one SNPs were significantly associated with cancer risk, and after adjusting for multiple comparisons, 9 remained significant (Q-value ≤0.1). Haplotype analysis further revealed three haplotypes within VEGFC and two haplotypes in EGFR were significantly associated with increased bladder cancer risk compared to the most common haplotype. Classification and regression tree analysis further revealed potential high-order gene-gene interactions, with VEGFC: rs3775194 being the initial split, which suggests that this variant is responsible for the most variation in risk. Individuals carrying the common genotype for VEGFC: rs3775194 and EGFR: rs7799627 and the variant genotype for VEGFR: rs4557213 had a 4.22-fold increase in risk, a much larger effect magnitude than that conferred by common genotype for VEGFR: rs4557213. Our study provides the first epidemiological evidence supporting a connection between TGF-β pathway variants and bladder cancer risk.

  15. Skin Cancer Concerns and Genetic Risk Information-Seeking in Primary Care

    PubMed Central

    Hay, J.; Kaphingst, K.A.; Baser, R.; Li, Y.; Hensley-Alford, S.; McBride, C.M.

    2012-01-01

    Background Genomic testing for common genetic variants associated with skin cancer risk could enable personalized risk feedback to motivate skin cancer screening and sun protection. Methods In a cross-sectional study, we investigated whether skin cancer cognitions and behavioral factors, sociodemographics, family factors, and health information-seeking were related to perceived importance of learning about how (a) genes and (b) health habits affect personal health risks using classification and regression trees (CART). Results The sample (n = 1,772) was collected in a large health maintenance organization as part of the Multiplex Initiative, ranged in age from 25–40, was 53% female, 41% Caucasian, and 59% African-American. Most reported that they placed somewhat to very high importance on learning about how genes (79%) and health habits (88%) affect their health risks. Social influence actors were associated with information-seeking about genes and health habits. Awareness of family history was associated with importance of health habit, but not genetic, information-seeking. Conclusions The investment of family and friends in health promotion may be a primary motivator for prioritizing information-seeking about how genes and health habits affect personal health risks and may contribute to the personal value, or personal utility, of risk information. Individuals who seek such risk information may be receptive to interventions aimed to maximize the social implications of healthy lifestyle change to reduce their health risks. PMID:21921576

  16. The influence of question wording on assessments of interest in genetic testing for breast cancer risk.

    PubMed

    Bottorff, Joan L; Ratner, Pamela A; Richardson, Chris; Balneaves, Lynda G; McCullum, Mary; Hack, Tom; Chalmers, Karen; Buxton, Jane

    2003-01-01

    The purpose of this study was to compare the results of different measures of interest in genetic testing for breast cancer risk. A telephone survey of a random sample of women without breast cancer was conducted in British Columbia, Canada. Interest in genetic testing for breast cancer risk was measured in three ways: (1) an unprompted assessment of interest, (2) assessment of interest when prompted with a hypothetical offer of testing, and (3) assessment of interest when provided with supplementary information. Substantial differences in reported levels of interest in genetic testing were observed across the different assessment approaches, with the unprompted assessment of interest resulting in lowest levels of interest. The highest levels of interest were observed when the assessment of interest was prompted with a hypothetical offer of testing. Factors predicting interest in genetic testing varied depending on the assessment measure used. These findings suggest that more attention must be given to measurement issues, including complete reporting of measures used in research, development of standardized approaches to assessing interest in genetic testing, and more rigorous psychometric evaluations of measures of interest in genetic testing.

  17. "In sickness and in health"? Disclosures of genetic risks in dating.

    PubMed

    Klitzman, Robert L; Sweeney, Meghan M

    2011-02-01

    Individuals who have, or are at risk for, various genetic disorders face many challenges concerning disclosures of genetic information in dating situations. We conducted a qualitative interview study of 64 individuals confronting Huntington's disease, breast cancer, or Alpha-1 antitrypsin deficiency, examining what issues these individuals encountered, and how they viewed and addressed these--including issues of understandings, privacy, and disclosures of genetic information to various groups (e.g., family members). Incidental to the primary research questions addressed, participants also often described a series of dilemmas in dating situations that they and/or family members, friends, and fellow patients faced of whether to date, and if so, whether, what, how, why, and when to disclose their genetic risk or illness. At times, these individuals feared and experienced rejection, and hence delayed, avoided, or opposed disclosure, or disclosed indirectly or inadvertently. These data are reported in this paper and highlight the importance of patients, their loved ones, genetic counselors, and other health care providers being aware of these issues, and appreciating the complex factors involved, which can affect patients' coping and social support. This paper, the first to explore several key aspects of disclosures of genetic information in dating, thus suggests needs for public and professional education, and future research in this area.

  18. 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

  19. 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...

  20. 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...

  1. 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…

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

    PubMed

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

    2012-03-01

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

  3. Risk Terminology in Biobanking and Genetic Research: What’s in a name?

    PubMed Central

    Quinn, Gwendolyn P.; Castañeda, Heide; Pal, Tuya; Rice, Janique L.; Meade, Cathy D.; Gwede, Clement K.

    2013-01-01

    It is well established that the general public has varying interpretations of the term “risk” and the qualifiers associated with it, such as low, moderate, or high. What is less well known is how definition and application of this term impacts recruitment of individuals, particularly for biomedical and behavioral research designed to improve knowledge of and access to innovations in cancer genetics. This Commentary discusses the nomenclature used in bio-behavioral research and the potential for confusion due to divergent meanings of risk and its associated categorizations. We discuss both our experience with recruitment of familial cancer families for a study on perceptions of biobanking as well as lessons learned from published examples where divergent understanding of risk levels, genetic research processes, and interpretation of results between community members and researchers result in misunderstandings for both parties. Ultimately, a critical challenge remains to ensure that accurate and mutually relevant risk terms are used in recruiting research participants and providing genetic results. Achieving this goal requires that regulations, policy, education and practice change in step with rapid discoveries in genetic research to reduce misinterpretations resulting from lack of common understanding and specificity in risk terminology. PMID:23824712

  4. A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease.

    PubMed

    Andersson, Carl-Henrik; Hansson, Oskar; Minthon, Lennart; Andreasen, Niels; Blennow, Kaj; Zetterberg, Henrik; Skoog, Ingmar; Wallin, Anders; Nilsson, Staffan; Kettunen, Petronella

    2016-07-01

    Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD. PMID:27392867

  5. Genetic polymorphisms of CASR and cancer risk: evidence from meta-analysis and HuGE review

    PubMed Central

    Jeong, Sohyun; Kim, Jae Hyun; Kim, Myeong Gyu; Han, Nayoung; Kim, In-Wha; Kim, Therasa; Oh, Jung Mi

    2016-01-01

    Background CASR gene appears to be involved in cancer biology and physiology. However, a number of studies investigating CASR polymorphisms and cancer risks have presented inconclusive results. Thus, a systematic review and a meta-analysis of the effect of CASR polymorphisms on several cancer risks were performed to suggest a statistical evidence for the association of CASR polymorphisms with cancer risks. Methods MEDLINE, EMBASE, Web of Science, Scopus, and the HuGE databases were searched. Nineteen articles of case–control and cohort studies were included for the final analysis. Results The colorectal cancer risk was reduced in proximal (odds ratio [OR] =0.679, P=0.001) and distal (OR =0.753, P=0.026) colon sites with GG genotype of CASR rs1042636 and increased in distal colon site (OR =1.418, P=0.039) with GG genotype of rs1801726 by additive genetic model. The rs17251221 demonstrated noticeable associations that carrying a homozygote variant increases breast and prostate cancer risk considerably. Conclusion The significant association of CASR polymorphisms with several cancer risks was observed in this review. In particular, the act of CASR polymorphisms as a tumor suppressor or an oncogene differs by cancer site and can be the research target for tumorigenesis. PMID:26929638

  6. 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

  7. Risky business: risk perception and the use of medical services among customers of DTC personal genetic testing.

    PubMed

    Kaufman, David J; Bollinger, Juli M; Dvoskin, Rachel L; Scott, Joan A

    2012-06-01

    Direct-to-consumer genetic testing has generated speculation about how customers will interpret results and how these interpretations will influence healthcare use and behavior; however, few empirical data on these topics exist. We conducted an online survey of DTC customers of 23andMe, deCODEme, and Navigenics to begin to address these questions. Random samples of U.S. DTC customers were invited to participate. Survey topics included demographics, perceptions of two sample DTC results, and health behaviors following DTC testing. Of 3,167 DTC customers invited, 33% (n = 1,048) completed the survey. Forty-three percent of respondents had sought additional information about a health condition tested; 28% had discussed their results with a healthcare professional; and 9% had followed up with additional lab tests. Sixteen percent of respondents had changed a medication or supplement regimen, and one-third said they were being more careful about their diet. Many of these health-related behaviors were significantly associated with responses to a question that asked how participants would perceive their colon cancer risk (as low, moderate, or high) if they received a test result showing an 11% lifetime risk, as compared to 5% risk in the general population. Respondents who would consider themselves to be at high risk for colon cancer were significantly more likely to have sought information about a disease (p = 0.03), discussed results with a physician (p = 0.05), changed their diet (p = 0.02), and started exercising more (p = 0.01). Participants' personal health contexts--including personal and family history of disease and quality of self-perceived health--were also associated with health-related behaviors after testing. Subjective interpretations of genetic risk data and personal context appear to be related to health behaviors among DTC customers. Sharing DTC test results with healthcare professionals may add perceived utility to the tests.

  8. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

    PubMed Central

    Newcomb, Polly A.; Campbell, Peter T.; Baron, John A.; Berndt, Sonja I.; Bezieau, Stephane; Brenner, Hermann; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Du, Mengmeng; Figueiredo, Jane C.; Gallinger, Steven; Giovannucci, Edward L.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jeon, Jihyoun; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Lin, Yi; Lindor, Noralane M.; Nishihara, Reiko; Ogino, Shuji; Potter, John D.; Rudolph, Anja; Schoen, Robert E.; Seminara, Daniela; Slattery, Martha L.; Thibodeau, Stephen N.; Thornquist, Mark; Toth, Reka; Wallace, Robert; White, Emily; Jiao, Shuo; Lemire, Mathieu; Hsu, Li; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10−8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74–0.91]; P = 2.1×10−4) and TT genotypes (OR,0.62 [95% CI, 0.51–0.75]; P = 1.3×10−6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk. PMID:27723779

  9. Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects.

    PubMed

    Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A

    2016-03-01

    The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates' offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of "half-sibling" in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure.

  10. Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects

    PubMed Central

    Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A.

    2016-01-01

    The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates’ offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of “half-sibling” in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure. PMID:26801647

  11. Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects.

    PubMed

    Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A

    2016-03-01

    The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates' offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of "half-sibling" in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure. PMID:26801647

  12. 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…

  13. Familial and Genetic Risk of Transitional Cell Carcinoma of the Urinary Tract

    PubMed Central

    Mueller, Christine M.; Caporaso, Neil; Greene, Mark H.

    2008-01-01

    Environmental exposures, including tobacco smoke and occupational exposure to aromatic amines, have been implicated in bladder cancer etiology. However, the pathogenesis of urinary bladder transitional cell carcinoma remains incompletely defined. In epidemiologic studies, family history confers a two-fold increase in bladder cancer risk, but it is uncertain whether this represents evidence of a genetic and/or a shared environmental basis for familial aggregation. Polymorphisms in genes involved in the metabolism of environmental toxins (e.g., NAT2) clearly modify individual susceptibility to bladder cancer. A genetic predisposition has also been suggested by case reports describing multiple-case families, and the development of bladder cancer in association with several well-described Mendelian disorders (e.g., HNPCC, retinoblastoma). Here we update a previously-reported family, report a new multiple-case kindred, critically review previously-reported bladder cancer families and the epidemiologic literature related to family history of transitional cell carcinoma of the urinary tract (TCCUT) as a risk factor, as well as provide a brief summary of genetic factors that have been implicated in TCCUT risk. We conclude that familial TCCUT is either very uncommon or significantly under-reported, perhaps on the assumption that this is an environmental rather than a genetic disorder. The interaction between multiple genetic and environmental factors has made it challenging to identify genetic components responsible for many common diseases; therefore, a proposed genome-wide association study (GWAS) for urinary bladder cancer may help to clarify the etiologic role of the candidate genetic pathways reviewed here, as well as characterize gene/environment interactions that contribute to TCCUT carcinogenesis. PMID:18562223

  14. 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

  15. Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

    PubMed Central

    Koller, Daniel L.; Edenberg, Howard J.; Foroud, Tatiana; Liu, Hai; Glowinski, Anne L.; McInnis, Melvin G.; Wilcox, Holly C.; Frankland, Andrew; Roberts, Gloria; Schofield, Peter R.; Mitchell, Philip B.; Nurnberger, John I.

    2015-01-01

    Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10−5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ2 = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID

  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. The risk of stillbirth and infant death by each additional week of expectant management stratified by maternal age

    PubMed Central

    Page, Jessica M.; Snowden, Jonathan M.; Cheng, Yvonne W.; Doss, Amy; Rosenstein, Melissa G.; Caughey, Aaron B.

    2016-01-01

    OBJECTIVE The objective of the study was to examine fetal/infant mortality by gestational age at term stratified by maternal age. STUDY DESIGN A retrospective cohort study was conducted using 2005 US national birth certificate data. For each week of term gestation, the risk of mortality associated with delivery was compared with composite mortality risk of expectant management. The expectant management measure included stillbirth and infant death. This expectant management risk was calculated to estimate the composite mortality risk with remaining pregnant an additional week by combining the risk of stillbirth during the additional week of pregnancy and infant death risk following delivery at the next week. Maternal age was stratified by 35 years or more compared with women younger than 35 years as well as subgroup analyses of younger than 20, 20–34, 35–39, or 40 years old or older. RESULTS The fetal/infant mortality risk of expectant management is greater than the risk of infant death at 39 weeks’ gestation in women 35 years old or older (15.2 vs 10.9 of 10,000, P < .05). In women younger than 35 years old, the risk of expectant management also exceeded that of infant death at 39 weeks (21.3 vs 18.8 of 10,000, P < .05). For women younger than 35 years old, the overall expectant management risk is influenced by higher infant death risk and does not rise significantly until 41 weeks compared with women 35 years old or older in which it increased at 40 weeks. CONCLUSION Risk varies by maternal age, and delivery at 39 weeks minimizes fetal/infant mortality for both groups, although the magnitude of the risk reduction is greater in older women. PMID:23707677

  18. A risk-based classification scheme for genetically modified foods. II: Graded testing.

    PubMed

    Chao, Eunice; Krewski, Daniel

    2008-12-01

    This paper presents a graded approach to the testing of crop-derived genetically modified (GM) foods based on concern levels in a proposed risk-based classification scheme (RBCS) and currently available testing methods. A graded approach offers the potential for more efficient use of testing resources by focusing less on lower concern GM foods, and more on higher concern foods. In this proposed approach to graded testing, products that are classified as Level I would have met baseline testing requirements that are comparable to what is widely applied to premarket assessment of GM foods at present. In most cases, Level I products would require no further testing, or very limited confirmatory analyses. For products classified as Level II or higher, additional testing would be required, depending on the type of the substance, prior dietary history, estimated exposure level, prior knowledge of toxicity of the substance, and the nature of the concern related to unintended changes in the modified food. Level III testing applies only to the assessment of toxic and antinutritional effects from intended changes and is tailored to the nature of the substance in question. Since appropriate test methods are not currently available for all effects of concern, future research to strengthen the testing of GM foods is discussed.

  19. PTPN22 R620W minor allele is a genetic risk factor for giant cell arteritis

    PubMed Central

    Lester, Susan; Hewitt, Alex W; Ruediger, Carlee D; Bradbury, Linda; De Smit, Elisabeth; Wiese, Michael D; Black, Rachel; Harrison, Andrew; Jones, Graeme; Littlejohn, Geoffrey O; Merriman, Tony R; Shenstone, Bain; Smith, Malcolm D; Rischmueller, Maureen; Brown, Matthew A; Hill, Catherine L

    2016-01-01

    Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although environmental, infectious and genetic risk factors are implicated. One gene of interest is PTPN22, encoding lymphoid protein tyrosine phosphatase (Lyp), expressed exclusively in immune cells, which is proposed to be an ‘archetypal non-HLA autoimmunity gene’. The minor allele of a functional PTPN22 single nucleotide polymorphism (rs2476601, R620W), which disrupts an interaction motif in the protein, was originally reported to be associated with biopsy-proven GCA in Spanish patients, with supporting data from three replicate Northern European studies. Recently, this observation was extended with additional patients and controls, and studies encompassing European, Scandinavian, UK and American patients. The aim of our study was to determine the association between PTPN22 rs2476601 (R620W) and biopsy-proven GCA in an Australian case cohort. PMID:27110387

  20. The structure of genetic and environmental risk factors for fears and phobias

    PubMed Central

    Loken, E. K.; Hettema, J.M.; Aggen, S.H.; Kendler, K. S.

    2014-01-01

    Background Although prior genetic studies of interview-assessed fears and phobias have shown that genetic factors predispose individuals to fears and phobias, they have been restricted to the DSM-III to DSM-IV aggregated subtypes of phobias rather than to individual fearful and phobic stimuli. Method We examined the lifetime history of fears and/or phobias in response to 21 individual phobic stimuli in 4067 personally interviewed twins from same-sex pairs from the Virginia Adult Twin Study of Psychiatric and Substance Abuse Disorders (VATSPSUD). We performed multivariate statistical analyses using Mx and Mplus. Results The best-fitting model for the 21 phobic stimuli included four genetic factors (agora-social-acrophobia, animal phobia, blood-injection-illness phobia and claustrophobia) and three environmental factors (agora-social-hospital phobia, animal phobia, and situational phobia). Conclusions This study provides the first view of the architecture of genetic and environmental risk factors for phobic disorders and their subtypes. The genetic factors of the phobias support the DSM-IV and DSM-5 constructs of animal and blood-injection-injury phobias but do not support the separation of agoraphobia from social phobia. The results also do not show a coherent genetic factor for the DSM-IV and DSM-5 situational phobia. Finally, the patterns of co-morbidity across individual fears and phobias produced by genetic and environmental influences differ appreciably. PMID:24384457

  1. 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.

  2. 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

  3. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

    PubMed Central

    Timofeeva, Maria N.; Hung, Rayjean J.; Rafnar, Thorunn; Christiani, David C.; Field, John K.; Bickeböller, Heike; Risch, Angela; McKay, James D.; Wang, Yufei; Dai, Juncheng; Gaborieau, Valerie; McLaughlin, John; Brenner, Darren; Narod, Steven A.; Caporaso, Neil E.; Albanes, Demetrius; Thun, Michael; Eisen, Timothy; Wichmann, H.-Erich; Rosenberger, Albert; Han, Younghun; Chen, Wei; Zhu, Dakai; Spitz, Margaret; Wu, Xifeng; Pande, Mala; Zhao, Yang; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Krokan, Hans E.; Gabrielsen, Maiken Elvestad; Skorpen, Frank; Vatten, Lars; Njølstad, Inger; Chen, Chu; Goodman, Gary; Lathrop, Mark; Benhamou, Simone; Vooder, Tõnu; Välk, Kristjan; Nelis, Mari; Metspalu, Andres; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Muley, Thomas; Dienemann, Hendrik; Thorleifsson, Gudmar; Shen, Hongbing; Stefansson, Kari; Brennan, Paul; Amos, Christopher I.; Houlston, Richard; Landi, Maria Teresa

    2012-01-01

    Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21–6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10−16), 6p21 (P = 2.3 × 10−14) and 15q25 (P = 2.2 × 10−63). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16INK4A/p14ARF/CDKN2B/p15INK4B/ANRIL; rs1333040, P = 3.0 × 10−7) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10−8). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer. PMID:22899653

  4. DIAGNOSIS-GUIDED METHOD FOR IDENTIFYING MULTI-MODALITY NEUROIMAGING BIOMARKERS ASSOCIATED WITH GENETIC RISK FACTORS IN ALZHEIMER'S DISEASE.

    PubMed

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

    2016-01-01

    Many recent imaging genetic studies focus on detecting the associations between genetic markers such as single nucleotide polymorphisms (SNPs) and quantitative traits (QTs). Although there exist a large number of generalized multivariate regression analysis methods, few of them have used diagnosis information in subjects to enhance the analysis performance. In addition, few of models have investigated the identification of multi-modality phenotypic patterns associated with interesting genotype groups in traditional methods. To reveal disease-relevant imaging genetic associations, we propose a novel diagnosis-guided multi-modality (DGMM) framework to discover multi-modality imaging QTs that are associated with both Alzheimer's disease (AD) and its top genetic risk factor (i.e., APOE SNP rs429358). The strength of our proposed method is that it explicitly models the priori diagnosis information among subjects in the objective function for selecting the disease-relevant and robust multi-modality QTs associated with the SNP. We evaluate our method on two modalities of imaging phenotypes, i.e., those extracted from structural magnetic resonance imaging (MRI) data and fluorodeoxyglucose positron emission tomography (FDG-PET) data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The experimental results demonstrate that our proposed method not only achieves better performances under the metrics of root mean squared error and correlation coefficient but also can identify common informative regions of interests (ROIs) across multiple modalities to guide the disease-induced biological interpretation, compared with other reference methods.

  5. The Geographic Distribution of Genetic Risk as Compared to Social Risk for Chronic Diseases in the United States.

    PubMed

    Rehkopf, David H; Domingue, Benjamin W; Cullen, Mark R

    2016-01-01

    There is an association between chronic disease and geography, and there is evidence that the environment plays a critical role in this relationship. Yet at the same time, there is known to be substantial geographic variation by ancestry across the United States. Resulting geographic genetic variation-that is, the extent to which single nucleotide polymorphisms (SNPs) related to chronic disease vary spatially-could thus drive some part of the association between geography and disease. We describe the variation in chronic disease genetic risk by state of birth by taking risk SNPs from genome-wide association study meta-analyses for coronary artery disease, diabetes, and ischemic stroke and creating polygenic risk scores. We compare the amount of variability across state of birth in these polygenic scores to the variability in parental education, own education, earnings, and wealth. Our primary finding is that the polygenic risk scores are only weakly differentially distributed across U.S. states. The magnitude of the differences in geographic distribution is very small in comparison to the distribution of social and economic factors and thus is not likely sufficient to have a meaningful effect on geographic disease differences by U.S. state. PMID:27050037

  6. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

    PubMed

    Campbell, Ian M; Stewart, Jonathan R; James, Regis A; Lupski, James R; Stankiewicz, Paweł; Olofsson, Peter; Shaw, Chad A

    2014-10-01

    Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

  7. Communicating Genetic Risk Information for Common Disorders in the Era of Genomic Medicine

    PubMed Central

    Lautenbach, Denise M.; Christensen, Kurt D.; Sparks, Jeffrey A.; Green, Robert C.

    2013-01-01

    Communicating genetic risk information in ways that maximize understanding and promote health is increasingly important given the rapidly expanding availability and capabilities of genomic technologies. A well-developed literature on risk communication in general provides guidance for best practices, including presentation of information in multiple formats, attention to framing effects, use of graphics, sensitivity to the way numbers are presented, parsimony of information, attentiveness to emotions, and interactivity as part of the communication process. Challenges to communicating genetic risk information include deciding how best to tailor it, streamlining the process, deciding what information to disclose, accepting that communications may have limited influence, and understanding the impact of context. Meeting these challenges has great potential for empowering individuals to adopt healthier lifestyles and improve public health, but will require multidisciplinary approaches and collaboration. PMID:24003856

  8. Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease

    PubMed Central

    Baumgaertel, Johanna; Haussmann, Robert; Gruschwitz, Antonia; Werner, Annett; Osterrath, Antje; Lange, Jan; Donix, Katharina L.; Linn, Jennifer; Donix, Markus

    2016-01-01

    Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients. PMID:27699079

  9. Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease

    PubMed Central

    Baumgaertel, Johanna; Haussmann, Robert; Gruschwitz, Antonia; Werner, Annett; Osterrath, Antje; Lange, Jan; Donix, Katharina L.; Linn, Jennifer; Donix, Markus

    2016-01-01

    Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients.

  10. Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh.

    PubMed

    Ahsan, Habibul; Chen, Yu; Kibriya, Muhammad G; Slavkovich, Vesna; Parvez, Faruque; Jasmine, Farzana; Gamble, Mary V; Graziano, Joseph H

    2007-06-01

    We conducted a case-control study to investigate interindividual variability in susceptibility to health effects of inorganic arsenic due to arsenic metabolism efficiency, genetic factors, and their interaction. A total of 594 cases of arsenic-induced skin lesions and 1,041 controls was selected from baseline participants in a large prospective cohort study in Bangladesh. Adjusted odds ratios (OR) for skin lesions were estimated in relation to the polymorphisms in the glutathione S-transferase omega1 and methylenetetrahydrofolate reductase genes, the percentage of monomethylarsonous acid (%MMA) and dimethylarsinic acid (%DMA) in urine, and the ratios of MMA to inorganic arsenic and DMA to MMA. Water arsenic concentration was positively associated with %MMA and inversely associated with %DMA. The dose-response relationship of risk of skin lesion with %MMA was more apparent than those with other methylation indices; the ORs for skin lesions in relation to increasing %MMA quartiles were 1.00 (reference), 1.33 [95% confidence interval (95% CI), 0.92-1.93], 1.68 (95% CI, 1.17-2.42), and 1.57 (95% CI, 1.10-2.26; P for trend = 0.01). The ORs for skin lesions in relation to the methylenetetrahydrofolate reductase 677TT/1298AA and 677CT/1298AA diplotypes (compared with 677CC/1298CC diplotype) were 1.66 (95% CI, 1.00-2.77) and 1.77 (95% CI, 0.61-5.14), respectively. The OR for skin lesions in relation to the glutathione S-transferase omega1 diplotype containing all at-risk alleles was 3.91 (95% CI, 1.03-14.79). Analysis of joint effects of genotypes/diplotypes with water arsenic concentration and urinary %MMA suggests additivity of these factors. The findings suggest that arsenic metabolism, particularly the conversion of MMA to DMA, may be saturable and that differences in urinary arsenic metabolites, genetic factors related to arsenic metabolism, and their joint distributions modulate arsenic toxicity.

  11. Evolution of the additive genetic variance-covariance matrix under continuous directional selection on a complex behavioural phenotype.

    PubMed

    Careau, Vincent; Wolak, Matthew E; Carter, Patrick A; Garland, Theodore

    2015-11-22

    Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance-covariance matrix ( G: ). Yet knowledge of G: in a population experiencing new or altered selection is not sufficient to predict selection response because G: itself evolves in ways that are poorly understood. We experimentally evaluated changes in G: when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G: induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G: induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G: and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change.

  12. Evolution of the additive genetic variance-covariance matrix under continuous directional selection on a complex behavioural phenotype.

    PubMed

    Careau, Vincent; Wolak, Matthew E; Carter, Patrick A; Garland, Theodore

    2015-11-22

    Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance-covariance matrix ( G: ). Yet knowledge of G: in a population experiencing new or altered selection is not sufficient to predict selection response because G: itself evolves in ways that are poorly understood. We experimentally evaluated changes in G: when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G: induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G: induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G: and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change. PMID:26582016

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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

  18. Increased Risk of Additional Cancers Among Patients with Gastrointestinal Stromal Tumors: A Population-Based Study

    PubMed Central

    Murphy, James D.; Ma, Grace L.; Baumgartner, Joel M.; Madlensky, Lisa; Burgoyne, Adam M.; Tang, Chih-Min; Martinez, Maria Elena; Sicklick, Jason K.

    2015-01-01

    Purpose Most gastrointestinal stromal tumors (GIST) are considered non-hereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies with increased frequencies. We hypothesized that we could gain greater insight into possible associations between GIST and other malignancies using a national cancer database inquiry. Methods Patients diagnosed with GIST (2001–2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, when compared with the general U.S. population. Results Of 6,112 GIST patients, 1,047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR=1.44) before diagnosis and 66% (SIR=1.66) after GIST diagnoses. Malignancies with significantly increased occurrence both before/after diagnoses included other sarcomas (SPR=5.24/SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56/SIR=4.79), non-Hodgkin’s lymphoma (SPR=1.69/SIR=1.76), and colorectal adenocarcinoma (SPR=1.51/SIR=2.16). Esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20) were significantly more common only before GIST. Ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinomas (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65) were significantly more common only after GIST. Conclusion This is the first population-based study to characterize the associations and temporal relationships between GIST and other cancers, both by site and

  19. 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

  20. 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.

  1. Association of BCL2-938C>A genetic polymorphism with glioma risk in Chinese Han population.

    PubMed

    Li, Wei; Qian, Chunfa; Wang, Linxiong; Teng, Hong; Zhang, Li

    2014-03-01

    Glioma is the most common type of primary brain malignancy in adults. The anti-apoptotic protein B-cell lymphoma 2 (BCL2) has been implicated in the pathogenesis of glioma. This study aimed to evaluate the potential association between BCL2-938C>A genetic polymorphism and glioma susceptibility. This case-control study was conducted in Chinese Han populations consisting of 248 glioma cases and 252 cancer-free controls. The BCL2-938C>A genetic polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and verified using DNA sequencing methods. Our data suggested that the genotype/allele of BCL2-938C>A polymorphism were statistically associated with the increased risk of glioma where the risk of glioma for genotype AA or allele A is significantly higher than wild genotype CC (odds ratio (OR) = 2.23, 95% confidence interval (CI) 1.21-4.10, p = 0.009) or allele C (OR = 1.39, 95% CI 1.06-1.82, p = 0.016), respectively. In addition, the BCL2-938AA genotype was significantly more common in patients with glioblastoma and in patients with grade IV glioma. Our findings indicate that the BCL2-938C>A polymorphism is associated with the susceptibility to glioma in Chinese Han populations and might be used as molecular markers for evaluating glioma risk.

  2. Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population