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Sample records for strong genetic risk

  1. Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score

    Directory of Open Access Journals (Sweden)

    Weigl K

    2018-01-01

    Full Text Available Korbinian Weigl,1,2 Jenny Chang-Claude,3,4 Phillip Knebel,5 Li Hsu,6 Michael Hoffmeister,1 Hermann Brenner1,2,7 1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ, Heidelberg, 2German Cancer Consortium (DKTK, German Cancer Research Center (DKFZ, Heidelberg, 3Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ, Heidelberg, 4University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, 5Department for General, Visceral and Transplantation Surgery, University Heidelberg, Heidelberg, Germany; 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 7Division of Preventive Oncology, German Cancer Research Center (DKFZ and National Center for Tumor Diseases (NCT, Heidelberg, Germany Background and aim: Family history (FH and genetic risk scores (GRSs are increasingly used for risk stratification for colorectal cancer (CRC screening. However, they were mostly considered alternatively rather than jointly. The aim of this study was to assess the potential of individual and joint risk stratification for CRC by FH and GRS.Patients and methods: A GRS was built based on the number of risk alleles in 53 previously identified single-nucleotide polymorphisms among 2,363 patients with a first diagnosis of CRC and 2,198 controls in DACHS [colorectal cancer: chances for prevention through screening], a population-based case-control study in Germany. Associations between GRS and FH with CRC risk were quantified by multiple logistic regression.Results: A total of 316 cases (13.4% and 214 controls (9.7% had a first-degree relative (FDR with CRC (adjusted odds ratio [aOR] 1.86, 95% CI 1.52–2.29. A GRS in the highest decile was associated with a 3.0-fold increased risk of CRC (aOR 3.00, 95% CI 2.24–4.02 compared with the lowest decile. This association was tentatively more pronounced in older age groups. FH and GRS were essentially unrelated, and their

  2. Genetic risk

    OpenAIRE

    ten Kate, Leo P.

    2012-01-01

    In this paper I will review different aspects of genetic risk in the context of preconception care. I restrict myself to the knowledge of risk which is relevant for care and/or enables reproductive choice. The paper deals with chromosomes, genes and the genetic classification of diseases, and it explains why Mendelian disorders frequently do not show the expected pattern of occurrence in families. Factors that amplify genetic risk are also discussed. Of the two methods of genetic risk assessm...

  3. Genetic risk

    NARCIS (Netherlands)

    ten Kate, L.P.

    2012-01-01

    In this paper I will review different aspects of genetic risk in the context of preconception care. I restrict myself to the knowledge of risk which is relevant for care and/or enables reproductive choice. The paper deals with chromosomes, genes and the genetic classification of diseases, and it

  4. Genetic risks from radiation

    International Nuclear Information System (INIS)

    Selby, P.B.

    Two widely-recognized committees, UNSCEAR and BEIR, have reevaluated their estimates of genetic risks from radiation. Their estimates for gene mutations are based on two different approaches, one being the doubling-dose approach and the other being a new direct approach based on an empirical determination of the amount of dominant induced damage in the skeletons of mice in the first generation following irradiation. The estimates made by these committees are in reasonably good agreement and suggest that the genetic risks from present exposures resultng from nuclear power production are small. There is room for much improvement in the reliability of the risk estimates. The relatively new approach of measuring the amount of induced damage to the mouse skeleton shows great promise of improving knowledge about how changes in the mutation frequency affect the incidence of genetic disorders. Such findings may have considerable influence on genetic risk estimates for radiation and on the development of risk estimates for other less-well-understood environmental mutagens. (author)

  5. Strong genetic overlap between executive functions and intelligence.

    Science.gov (United States)

    Engelhardt, Laura E; Mann, Frank D; Briley, Daniel A; Church, Jessica A; Harden, K Paige; Tucker-Drob, Elliot M

    2016-09-01

    Executive functions (EFs) are cognitive processes that control, monitor, and coordinate more basic cognitive processes. EFs play instrumental roles in models of complex reasoning, learning, and decision making, and individual differences in EFs have been consistently linked with individual differences in intelligence. By middle childhood, genetic factors account for a moderate proportion of the variance in intelligence, and these effects increase in magnitude through adolescence. Genetic influences on EFs are very high, even in middle childhood, but the extent to which these genetic influences overlap with those on intelligence is unclear. We examined genetic and environmental overlap between EFs and intelligence in a racially and socioeconomically diverse sample of 811 twins ages 7 to 15 years (M = 10.91, SD = 1.74) from the Texas Twin Project. A general EF factor representing variance common to inhibition, switching, working memory, and updating domains accounted for substantial proportions of variance in intelligence, primarily via a genetic pathway. General EF continued to have a strong, genetically mediated association with intelligence even after controlling for processing speed. Residual variation in general intelligence was influenced only by shared and nonshared environmental factors, and there remained no genetic variance in general intelligence that was unique of EF. Genetic variance independent of EF did remain, however, in a more specific perceptual reasoning ability. These results provide evidence that genetic influences on general intelligence are highly overlapping with those on EF. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  6. Strong Genetic Overlap Between Executive Functions and Intelligence

    Science.gov (United States)

    Engelhardt, Laura E.; Mann, Frank D.; Briley, Daniel A.; Church, Jessica A.; Harden, K. Paige; Tucker-Drob, Elliot M.

    2016-01-01

    Executive functions (EFs) are cognitive processes that control, monitor, and coordinate more basic cognitive processes. EFs play instrumental roles in models of complex reasoning, learning, and decision-making, and individual differences in EFs have been consistently linked with individual differences in intelligence. By middle childhood, genetic factors account for a moderate proportion of the variance in intelligence, and these effects increase in magnitude through adolescence. Genetic influences on EFs are very high, even in middle childhood, but the extent to which these genetic influences overlap with those on intelligence is unclear. We examined genetic and environmental overlap between EFs and intelligence in a racially and socioeconomically diverse sample of 811 twins ages 7-15 years (M = 10.91, SD = 1.74) from the Texas Twin Project. A general EF factor representing variance common to inhibition, switching, working memory, and updating domains accounted for substantial proportions of variance in intelligence, primarily via a genetic pathway. General EF continued to have a strong, genetically-mediated association with intelligence even after controlling for processing speed. Residual variation in general intelligence was influenced only by shared and nonshared environmental factors, and there remained no genetic variance in general intelligence that was unique of EF. Genetic variance independent of EF did remain, however, in a more specific perceptual reasoning ability. These results provide evidence that genetic influences on general intelligence are highly overlapping with those on EF. PMID:27359131

  7. Genetic risks of ionizing radiation

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1990-01-01

    Quantitative genetic risk estimation is made using two methods: the direct method, and the doubling dose (DD) method. The doubling dose currently used is 1 Gy for low LET, low dose, low dose rate irradiation, and is based on mouse data. Tables present the 1988 UNSCEAR estimates of genetic risk using both methods. (L.L.) (Tab.)

  8. Trapped in the extinction vortex? Strong genetic effects in a declining vertebrate population

    Directory of Open Access Journals (Sweden)

    Larsson Mikael

    2010-02-01

    Full Text Available Abstract Background Inbreeding and loss of genetic diversity are expected to increase the extinction risk of small populations, but detailed tests in natural populations are scarce. We combine long-term population and fitness data with those from two types of molecular markers to examine the role of genetic effects in a declining metapopulation of southern dunlins Calidris alpina schinzii, an endangered shorebird. Results The decline is associated with increased pairings between related individuals, including close inbreeding (as revealed by both field observations of parentage and molecular markers. Furthermore, reduced genetic diversity seems to affect individual fitness at several life stages. Higher genetic similarity between mates correlates negatively with the pair's hatching success. Moreover, offspring produced by related parents are more homozygous and suffer from increased mortality during embryonic development and possibly also after hatching. Conclusions Our results demonstrate strong genetic effects in a rapidly declining population, emphasizing the importance of genetic factors for the persistence of small populations.

  9. Genetic resources of teak (Tectona grandis Linn. f.)—strong genetic structure among natural populations

    DEFF Research Database (Denmark)

    Hansen, Ole Kim; Changtragoon, Suchitra; Ponoy, Bundit

    2015-01-01

    Twenty-nine provenances of teak (Tectona grandis Linn. f.) representing the full natural distribution range of the species were genotyped with microsatellite DNA markers to analyse genetic diversity and population genetic structure. Provenances originating from the semi-moist east coast of India...... of genetic diversity supports the hypothesis that teak has its centre of origin in India, from where it spread eastwards. The analysis of molecular variance (AMOVA) gave an overall highly significant F st value of 0.227—population pairwise F st values were in the range 0.01–0.48. Applying the G......″st differentiation parameter, the estimated overall differentiation was 0.632, implying a strong genetic structure among populations. A neighbour-joining (NJ) tree, using the pairwise population matrix of G″st values as input, contained three distinct groups: (1) the eight provenances from Thailand and Laos, (2...

  10. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies

    DEFF Research Database (Denmark)

    Lal, Dennis; Ruppert, Ann-Kathrin; Trucks, Holger

    2015-01-01

    Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (...%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative...... a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes....

  11. A Strong Case for Viral Genetic Factors in HIV Virulence

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    Joshua T. Herbeck

    2011-03-01

    Full Text Available HIV infections show great variation in the rate of progression to disease, and the role of viral genetic factors in this variation had remained poorly characterized until recently. Now a series of four studies [1–4] published within a year has filled this important gap and has demonstrated a robust effect of the viral genotype on HIV virulence.

  12. Ionizing radiation and genetic risks

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.; Wassom, J.S.

    2005-01-01

    Recent estimates of genetic risks from exposure of human populations to ionizing radiation are those presented in the 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). These estimates incorporate two important concepts, namely, the following: (1) most radiation-induced mutations are DNA deletions, often encompassing multiple genes, but only a small proportion of the induced deletions is compatible with offspring viability; and (2) the viability-compatible deletions induced in germ cells are more likely to manifest themselves as multi-system developmental anomalies rather than as single gene disorders. This paper: (a) pursues these concepts further in the light of knowledge of mechanisms of origin of deletions and other rearrangements from two fields of contemporary research: repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and human molecular genetics; and (b) extends them to deletions induced in the germ cell stages of importance for radiation risk estimation, namely, stem cell spermatogonia in males and oocytes in females. DSB repair studies in somatic cells have elucidated the roles of two mechanistically distinct pathways, namely, homologous recombination repair (HRR) that utilizes extensive sequence homology and non-homologous end-joining (NHEJ) that requires little or no homology at the junctions. A third process, single-strand annealing (SSA), which utilizes short direct repeat sequences, is considered a variant of HRR. HRR is most efficient in late S and G 2 phases of the cell cycle and is a high fidelity mechanism. NHEJ operates in all cell cycle phases, but is especially important in G 1 . In the context of radiation-induced DSBs, NHEJ is error-prone. SSA is also an error-prone mechanism and its role is presumably similar to that of HRR. Studies in human molecular genetics have demonstrated that the occurrence of large deletions, duplications or other rearrangements

  13. Deposit Insurance and Risk Shifting in a Strong Regulatory Environment

    DEFF Research Database (Denmark)

    Bartholdy, Jan; Justesen, Lene Gilje

    This study provides empirical evidence on the moral hazard implications of introducing deposit insurance into a strong regulatory environment. Denmark offers a unique setting because commercial banks and savings banks have different ownership structures, but are subject to the same set of regulat......This study provides empirical evidence on the moral hazard implications of introducing deposit insurance into a strong regulatory environment. Denmark offers a unique setting because commercial banks and savings banks have different ownership structures, but are subject to the same set...... of regulations. The ownership structure in savings banks implies that they have no incentive to increase risk after the implementation of a deposit insurance scheme whereas commercial banks have. Also, at the time of introduction, Denmark had high capital requirements and a strict closure policy. Using...... a difference-in-difference framework we show that commercial banks did not increase their risk compared to savings banks when deposit insurance was introduced. The results also hold for large commercial banks, indicating that the systemic risk did not increase either. Thus for a system with high capital...

  14. Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition.

    Science.gov (United States)

    Husted, Janice A; Ahmed, Rashid; Chow, Eva W C; Brzustowicz, Linda M; Bassett, Anne S

    2012-05-01

    There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood trauma, covariates and familial clustering (adjusted odds ratio (95% confidence interval)=1.55 (1.01, 2.38)). The results provide further support that early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Uniform risk spectra of strong earthquake ground motion: NEQRISK

    International Nuclear Information System (INIS)

    Lee, V.W.; Trifunac, M.D.

    1987-01-01

    The concept of uniform risk spectra of Anderson and Trifunac (1977) has been generalized to include (1) more refined description of earthquake source zones, (2) the uncertainties in estimating seismicity parameters a and b in log 10 N = a - bM, (3) to consider uncertainties in estimation of maximum earthquake size in each source zone, and to (4) include the most recent results on empirical scaling of strong motion amplitudes at a site. Examples of using to new NEQRISK program are presented and compared with the corresponding case studies of Anderson and Trifunac (1977). The organization of the computer program NEQRISK is also briefly described

  16. Debunking vaccination myths: strong risk negations can increase perceived vaccination risks.

    Science.gov (United States)

    Betsch, Cornelia; Sachse, Katharina

    2013-02-01

    Information about risks is often contradictory, especially in the health domain. A vast amount of bizarre information on vaccine-adverse events (VAE) can be found on the Internet; most are posted by antivaccination activists. Several actors in the health sector struggle against these statements by negating claimed risks with scientific explanations. The goal of the present work is to find optimal ways of negating risk to decrease risk perceptions. In two online experiments, we varied the extremity of risk negations and their source. Perception of the probability of VAE, their expected severity (both variables serve as indicators of perceived risk), and vaccination intentions. Paradoxically, messages strongly indicating that there is "no risk" led to a higher perceived vaccination risk than weak negations. This finding extends previous work on the negativity bias, which has shown that information stating the presence of risk decreases risk perceptions, while information negating the existence of risk increases such perceptions. Several moderators were also tested; however, the effect occurred independently of the number of negations, recipient involvement, and attitude. Solely the credibility of the information source interacted with the extremity of risk negation: For credible sources (governmental institutions), strong and weak risk negations lead to similar perceived risk, while for less credible sources (pharmaceutical industries) weak negations lead to less perceived risk than strong negations. Optimal risk negation may profit from moderate rather than extreme formulations as a source's trustworthiness can vary.

  17. Genetic cancer risk assessment in practice

    International Nuclear Information System (INIS)

    Gruber, S.

    2004-01-01

    The advent of genetic testing has made a dramatic impact on the management of individuals with inherited susceptibility to cancer and their relatives. Genetic counsel ing, with or without testing, is warranted when clues to familial cancer are recognized. Today, genetic testing for classic cancer genetic syndromes is now the standard of care, and has been complemented by genetic testing for other situations commonly encountered in clinical practice. Genetic testing for colorectal cancer, breast cancer, kidney cancer, thyroid cancer, melanoma, and pancreatic cancer raise important issues about the parameters for testing. Genetic cancer risk assessment can lead to measurable reductions in morbidity and mortality through strategies that rely on surveillance, chemo prevention, and risk-reducing surgery

  18. Integrating Genetics and Social Science: Genetic Risk Scores

    Science.gov (United States)

    Belsky, Daniel W.; Israel, Salomon

    2014-01-01

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

  19. Genetic variants and multiple myeloma risk

    DEFF Research Database (Denmark)

    Martino, Alessandro; Campa, Daniele; Jurczyszyn, Artur

    2014-01-01

    BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. METHODS...... with multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. IMPACT: Independent validation studies are crucial to identify true genetic risk...

  20. Hydrochlorothiazide use is strongly associated with risk of lip cancer.

    Science.gov (United States)

    Pottegård, A; Hallas, J; Olesen, M; Svendsen, M T; Habel, L A; Friedman, G D; Friis, S

    2017-10-01

    The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer. © 2017 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

  1. Genetic variation associated with cardiovascular risk in autoimmune diseases.

    Science.gov (United States)

    Perrotti, Pedro P; Aterido, Adrià; Fernández-Nebro, Antonio; Cañete, Juan D; Ferrándiz, Carlos; Tornero, Jesús; Gisbert, Javier P; Domènech, Eugeni; Fernández-Gutiérrez, Benjamín; Gomollón, Fernando; García-Planella, Esther; Fernández, Emilia; Sanmartí, Raimon; Gratacós, Jordi; Martínez-Taboada, Víctor Manuel; Rodríguez-Rodríguez, Luís; Palau, Núria; Tortosa, Raül; Corbeto, Mireia L; Lasanta, María L; Marsal, Sara; Julià, Antonio

    2017-01-01

    Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.

  2. Genetic variation associated with cardiovascular risk in autoimmune diseases.

    Directory of Open Access Journals (Sweden)

    Pedro P Perrotti

    Full Text Available Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways. The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.

  3. Stroke Risk Factors, Genetics, and Prevention.

    Science.gov (United States)

    Boehme, Amelia K; Esenwa, Charles; Elkind, Mitchell S V

    2017-02-03

    Stroke is a heterogeneous syndrome, and determining risk factors and treatment depends on the specific pathogenesis of stroke. Risk factors for stroke can be categorized as modifiable and nonmodifiable. Age, sex, and race/ethnicity are nonmodifiable risk factors for both ischemic and hemorrhagic stroke, while hypertension, smoking, diet, and physical inactivity are among some of the more commonly reported modifiable risk factors. More recently described risk factors and triggers of stroke include inflammatory disorders, infection, pollution, and cardiac atrial disorders independent of atrial fibrillation. Single-gene disorders may cause rare, hereditary disorders for which stroke is a primary manifestation. Recent research also suggests that common and rare genetic polymorphisms can influence risk of more common causes of stroke, due to both other risk factors and specific stroke mechanisms, such as atrial fibrillation. Genetic factors, particularly those with environmental interactions, may be more modifiable than previously recognized. Stroke prevention has generally focused on modifiable risk factors. Lifestyle and behavioral modification, such as dietary changes or smoking cessation, not only reduces stroke risk, but also reduces the risk of other cardiovascular diseases. Other prevention strategies include identifying and treating medical conditions, such as hypertension and diabetes, that increase stroke risk. Recent research into risk factors and genetics of stroke has not only identified those at risk for stroke but also identified ways to target at-risk populations for stroke prevention. © 2017 American Heart Association, Inc.

  4. Computing strong metric dimension of some special classes of graphs by genetic algorithms

    Directory of Open Access Journals (Sweden)

    Kratica Jozef

    2008-01-01

    Full Text Available In this paper we consider the NP-hard problem of determining the strong metric dimension of graphs. The problem is solved by a genetic algorithm that uses binary encoding and standard genetic operators adapted to the problem. This represents the first attempt to solve this problem heuristically. We report experimental results for the two special classes of ORLIB test instances: crew scheduling and graph coloring.

  5. A strong genetic footprint of the re-introduction history of Alpine ibex (Capra ibex ibex).

    Science.gov (United States)

    Biebach, Iris; Keller, Lukas F

    2009-12-01

    A population's neutral genetic variation is a composite of its size, degree of isolation and demographic history. Bottlenecks and founder events increase genetic drift, leading to the loss of genetic variation and increased genetic differentiation among populations. Gene flow has the opposite effects. Thus, gene flow can override the genetic patterns caused by founder events. Using 37 microsatellite loci, we investigated the effects of serial bottlenecks on genetic variation and differentiation among 42 Alpine ibex populations in Switzerland with known re-introduction histories. We detected a strong footprint of re-introduction events on contemporary genetic structure, with re-introduction history explaining a substantial part of the genetic differentiation among populations. As a result of the translocation of a considerable number of individuals from the sole formerly surviving population in northern Italy, most of the genetic variation of the ancestral population is now present in the combined re-introduced Swiss populations. However, re-introductions split up the genetic variation among populations, such that each contemporary Swiss population showed lower genetic variation than the ancestral population. As expected, serial bottlenecks had different effects on the expected heterozygosity (He) and standardized number of alleles (sNa). While loss of sNa was higher in the first bottlenecks than in subsequent ones, He declined to a similar degree with each bottleneck. Thus, genetic drift was detected with each bottleneck, even when no loss of sNa was observed. Overall, more than a hundred years after the beginning of this successful re-introduction programme, re-introduction history was the main determinant of today's genetic structure.

  6. Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

    Directory of Open Access Journals (Sweden)

    John S K Kauwe

    Full Text Available Alzheimer's disease (AD is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date.We assessed the familiality of AD in The Utah Population Database (UPDB, a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF between AD individuals and randomly selected controls and estimated the Relative Risk (RR for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

  7. Genetic Predisposition to Ischemic Stroke: A Polygenic Risk Score.

    Science.gov (United States)

    Hachiya, Tsuyoshi; Kamatani, Yoichiro; Takahashi, Atsushi; Hata, Jun; Furukawa, Ryohei; Shiwa, Yuh; Yamaji, Taiki; Hara, Megumi; Tanno, Kozo; Ohmomo, Hideki; Ono, Kanako; Takashima, Naoyuki; Matsuda, Koichi; Wakai, Kenji; Sawada, Norie; Iwasaki, Motoki; Yamagishi, Kazumasa; Ago, Tetsuro; Ninomiya, Toshiharu; Fukushima, Akimune; Hozawa, Atsushi; Minegishi, Naoko; Satoh, Mamoru; Endo, Ryujin; Sasaki, Makoto; Sakata, Kiyomi; Kobayashi, Seiichiro; Ogasawara, Kuniaki; Nakamura, Motoyuki; Hitomi, Jiro; Kita, Yoshikuni; Tanaka, Keitaro; Iso, Hiroyasu; Kitazono, Takanari; Kubo, Michiaki; Tanaka, Hideo; Tsugane, Shoichiro; Kiyohara, Yutaka; Yamamoto, Masayuki; Sobue, Kenji; Shimizu, Atsushi

    2017-02-01

    The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk. We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets). In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33-2.31) and 1.99 (95% confidence interval, 1.19-3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001). The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors. © 2016 The Authors.

  8. Quantifying introgression risk with realistic population genetics.

    Science.gov (United States)

    Ghosh, Atiyo; Meirmans, Patrick G; Haccou, Patsy

    2012-12-07

    Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: realistic genetical mechanisms, repeated invasions and stochasticity. In addition, the use of linkage as a risk mitigation strategy has not been studied properly yet with genetic introgression models. Current genetic introgression studies fail to take repeated invasions and demographic stochasticity into account properly, and use incorrect measures of introgression risk that can be manipulated by arbitrary choices. In this study, we present proper methods for risk quantification that overcome these difficulties. We generalize a probabilistic risk measure, the so-called hazard rate of introgression, for application to introgression models with complex genetics and small natural population sizes. We illustrate the method by studying the effects of linkage and recombination on transgene introgression risk at different population sizes.

  9. Methods to estimate the genetic risk

    International Nuclear Information System (INIS)

    Ehling, U.H.

    1989-01-01

    The estimation of the radiation-induced genetic risk to human populations is based on the extrapolation of results from animal experiments. Radiation-induced mutations are stochastic events. The probability of the event depends on the dose; the degree of the damage dose not. There are two main approaches in making genetic risk estimates. One of these, termed the direct method, expresses risk in terms of expected frequencies of genetic changes induced per unit dose. 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 advantage of the indirect method is that not only can Mendelian mutations be quantified, but also other types of genetic disorders. The disadvantages of the method are the uncertainties in determining the current incidence of genetic disorders in human and, in addition, the estimasion of the genetic component of congenital anomalies, anomalies expressed later and constitutional and degenerative diseases. Using the direct method we estimated that 20-50 dominant radiation-induced mutations would be expected in 19 000 offspring born to parents exposed in Hiroshima and Nagasaki, but only a small proportion of these mutants would have been detected with the techniques used for the population study. These methods were used to predict the genetic damage from the fallout of the reactor accident at Chernobyl in the vicinity of Southern Germany. The lack of knowledge for the interaction of chemicals with ionizing radiation and the discrepancy between the high safety standards for radiation protection and the low level of knowledge for the toxicological evaluation of chemical mutagens will be emphasized. (author)

  10. Risk Assessment of Genetically Modified Microorganisms

    DEFF Research Database (Denmark)

    Jacobsen, B. L.; Wilcks, Andrea

    2001-01-01

    the industry, national administration and research institutions were gathered to discuss which elements should be considered in a risk assessment of genetically modified microorganisms used as food or food ingredients. The existing EU and national regulations were presented, together with the experiences...

  11. Quantifying introgression risk with realistic population genetics

    NARCIS (Netherlands)

    Ghosh, A.; Meirmans, P.G.; Haccou, P.

    2012-01-01

    Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified

  12. Population-based, risk-stratified genetic testing for ovarian cancer risk: a focus group study.

    Science.gov (United States)

    Meisel, S F; Side, L; Fraser, L; Gessler, S; Wardle, J; Lanceley, A

    2013-01-01

    A population-based risk stratification programme for ovarian cancer (OC) may improve OC survival by identifying women at increased risk and implementing an appropriate risk management strategy. The present study explored attitudes towards an OC risk stratification programme incorporating predictive genetic testing and risk-stratified screening as part of a larger study investigating OC screening. Focus groups consisting of 56 members of the general public (mean age 45 years; 34% non-white) were conducted using a hypothetical scenario. The group sessions were recorded, transcribed verbatim and analysed using Framework Analysis. There was strong support for the proposed programme. Genetic testing and risk-stratified screening was thought to raise awareness, offer reassurance and offer opportunities for early intervention. Anxiety was only mentioned in relation to receiving a diagnosis of OC and not with screening per se. Perhaps because lay models of cancer already embrace both environmental and genetic factors, a low-risk result was not anticipated to result in a false sense of immunity. Unexpectedly, participants also wanted to receive cancer prevention advice in conjunction with genetic testing; screening alone was not regarded as sufficient. The encouraging results from this small study warrant further large-scale research into risk-stratified OC screening. Copyright © 2013 S. Karger AG, Basel.

  13. Channelopathies, genetic testing and risk stratification.

    Science.gov (United States)

    Wilde, Arthur A M; Amin, Ahmad

    2017-06-15

    The cardiac channelopathies are a group of diseases with (disease-) specific electrocardiographic (ECG) characteristics and a disease-specific risk of sudden cardiac death (SCD). This group includes the Long QT Syndromes (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada Syndrome (BrS), Short QT Syndromes (SQTS), and Early Repolarization Syndrome (ERS). In the past 2 decades the genetic basis for these disease entities has largely been unraveled and that, together with the identification of the genetic basis of the cardiomyopathies, has paved the way for the complete new field of Cardiogenetics. By virtue of the identification of the genetic underpinning of a given disease, presymptomatic carriers of the genetic aberrancy can be identified and timely treatment can be installed. In addition, it has become clear that the pathophysiological substrate of some diseases previously considered to be one disease is not identical, and this has led to gene-specific treatment in some and complete new treatment, based on the newly developed insight, in others. Finally, the genetic information proved to be important in the prediction of risk on lethal ventricular arrhythmias of affected individuals and that is the topic of this brief review. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Hydrochlorothiazide use is strongly associated with risk of lip cancer

    DEFF Research Database (Denmark)

    Pottegård, A; Hallas, J; Olesen, M

    2017-01-01

    Background: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. Objectives: To study the association between use of hydrochlorothia......Background: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. Objectives: To study the association between use...... of hydrochlorothiazide and squamous cell carcinoma of the lip. Methods: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk......-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined...

  15. Total and regional fat distribution is strongly influenced by genetic factors in young and elderly twins

    DEFF Research Database (Denmark)

    Malis, Charlotte; Rasmussen, Eva L; Poulsen, Pernille

    2005-01-01

    OBJECTIVE: Indirect estimates of obesity such as BMI seem to be strongly influenced by genetic factors in twins. Precise measurements of total and regional fat as determined by direct techniques such as DXA scan have only been applied in a few twin studies. The aim of the present study was to est......OBJECTIVE: Indirect estimates of obesity such as BMI seem to be strongly influenced by genetic factors in twins. Precise measurements of total and regional fat as determined by direct techniques such as DXA scan have only been applied in a few twin studies. The aim of the present study...... was to estimate the heritability (h(2)) of total and regional fat distribution in young and elderly Danish twins. RESEARCH METHODS AND PROCEDURES: Monozygotic (108) and dizygotic (88) twins in two age groups (25 to 32 and 58 to 66 years) underwent anthropometric measurements and DXA scans. Intraclass correlations...... genetic component (h(2)) of total (h(2)(young) = 0.83, h(2)(elderly) = 0.86) and regional fat percentages (trunk, h(2)(young) = 0.82, h(2)(elderly) = 0.85; lower body, h(2)(young) = 0.83, h(2)(elderly) = 0.81; and trunk/lower body, h(2)(young) = 0.83, h(2)(elderly) = 0.71) in both the young and elderly...

  16. Inflammatory Genetic Markers of Prostate Cancer Risk

    Energy Technology Data Exchange (ETDEWEB)

    Tindall, Elizabeth A.; Hayes, Vanessa M. [Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031 (Australia); University of New South Wales, Kensington Campus, Sydney, NSW 2052 (Australia); Petersen, Desiree C., E-mail: dpetersen@ccia.unsw.edu.au [Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031 (Australia)

    2010-06-08

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.

  17. Inflammatory Genetic Markers of Prostate Cancer Risk

    International Nuclear Information System (INIS)

    Tindall, Elizabeth A.; Hayes, Vanessa M.; Petersen, Desiree C.

    2010-01-01

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk

  18. Genetic and epigenetic risks of assisted reproduction.

    Science.gov (United States)

    Jiang, Ziru; Wang, Yinyu; Lin, Jing; Xu, Jingjing; Ding, Guolian; Huang, Hefeng

    2017-10-01

    Assisted reproductive technology (ART) is used primarily for infertility treatments to achieve pregnancy and involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and cryopreservation. Moreover, preimplantation genetic diagnosis (PGD) of ART is used in couples for genetic reasons. In ART treatments, gametes and zygotes are exposed to a series of non-physiological processes and culture media. Although the majority of children born with this treatment are healthy, some concerns remain regarding the safety of this technology. Animal studies and follow-up studies of ART-borne children suggested that ART was associated with an increased incidence of genetic, physical, or developmental abnormalities, although there are also observations that contradict these findings. As IVF, ICSI, frozen-thawed embryo transfer, and PGD manipulate gametes and embryo at a time that is important for reprogramming, they may affect epigenetic stability, leading to gamete/embryo origins of adult diseases. In fact, ART offspring have been reported to have an increased risk of gamete/embryo origins of adult diseases, such as early-onset diabetes, cardiovascular disease, and so on. In this review, we will discuss evidence related to genetic, especially epigenetic, risks of assisted reproduction. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Tamara ePhillips

    2015-09-01

    Full Text Available 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

  20. Medical radiation exposure and genetic risks

    International Nuclear Information System (INIS)

    Baker, D.G.

    1980-01-01

    Everyone is exposed to background radiation throughout life (100 mrem/year to the gonads or 4 to 5 rem during the reproductive years). A lumbosacral series might deliver 2500 mrem to the male or 400 mrem to the female gonads. A radiologic procedure is a cost/benefit decision, and genetic risk is a part of the cost. Although cost is usually very low compared to benefit, if the procedure is unnecessary then the cost may be unacceptable. On the basis of current estimates, the doubling dose is assumed to be 40 rem (range 20 to 200) for an acute dose, and 100 rem for protracted exposure. Although there is no satisfactory way to predict the size of the risk for an individual exposed, any risk should be incentive to avoid unnecessary radiation to the gonads. Conception should be delayed for at least ten months for women and three or four months for men after irradiation of the gonads. The current incidence of genetically related diseases in the United States population is 60,000 per million live births. Based on the most conservative set of assumptions, an average gonadal dose of 1000 mrem to the whole population would increase the incidence of genetically related diseases by 0.2%

  1. Low genetic diversity and strong population structure shaped by anthropogenic habitat fragmentation in a critically endangered primate, Trachypithecus leucocephalus.

    Science.gov (United States)

    Wang, W; Qiao, Y; Li, S; Pan, W; Yao, M

    2017-06-01

    Habitat fragmentation may strongly impact population genetic structure and reduce the genetic diversity and viability of small and isolated populations. The white-headed langur (Trachypithecus leucocephalus) is a critically endangered primate species living in a highly fragmented and human-modified habitat in southern China. We examined the population genetic structure and genetic diversity of the species and investigated the environmental and anthropogenic factors that may have shaped its population structure. We used 214 unique multi-locus genotypes from 41 social groups across the main distribution area of T. leucocephalus, and found strong genetic structure and significant genetic differentiation among local populations. Our landscape genetic analyses using a causal modelling framework suggest that a large habitat gap and geographical distance represent the primary landscape elements shaping genetic structure, yet high levels of genetic differentiation also exist between patches separated by a small habitat gap or road. This is the first comprehensive study that has evaluated the population genetic structure and diversity of T. leucocephalus using nuclear markers. Our results indicate strong negative impacts of anthropogenic land modifications and habitat fragmentation on primate genetic connectivity between forest patches. Our analyses suggest that two management units of the species could be defined, and indicate that habitat continuity should be enforced and restored to reduce genetic isolation and enhance population viability.

  2. Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk

    Directory of Open Access Journals (Sweden)

    Carayol Jerome

    2010-02-01

    Full Text Available Abstract Background Autism is a complex disorder characterized by deficits involving communication, social interaction, and repetitive and restrictive patterns of behavior. Twin studies have shown that autism is strongly heritable, suggesting a strong genetic component. In other disease states with a complex etiology, such as type 2 diabetes, cancer and cardiovascular disease, combined analysis of multiple genetic variants in a genetic score has helped to identify individuals at high risk of disease. Genetic scores are designed to test for association of genetic markers with disease. Method The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population. Results In both samples, odds ratios (ORs increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49. The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59. Conclusions These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk.

  3. Focusing light through strongly scattering media using genetic algorithm with SBR discriminant

    Science.gov (United States)

    Zhang, Bin; Zhang, Zhenfeng; Feng, Qi; Liu, Zhipeng; Lin, Chengyou; Ding, Yingchun

    2018-02-01

    In this paper, we have experimentally demonstrated light focusing through strongly scattering media by performing binary amplitude optimization with a genetic algorithm. In the experiments, we control 160 000 mirrors of digital micromirror device to modulate and optimize the light transmission paths in the strongly scattering media. We replace the universal target-position-intensity (TPI) discriminant with signal-to-background ratio (SBR) discriminant in genetic algorithm. With 400 incident segments, a relative enhancement value of 17.5% with a ground glass diffuser is achieved, which is higher than the theoretical value of 1/(2π )≈ 15.9 % for binary amplitude optimization. According to our repetitive experiments, we conclude that, with the same segment number, the enhancement for the SBR discriminant is always higher than that for the TPI discriminant, which results from the background-weakening effect of SBR discriminant. In addition, with the SBR discriminant, the diameters of the focus can be changed ranging from 7 to 70 μm at arbitrary positions. Besides, multiple foci with high enhancement are obtained. Our work provides a meaningful reference for the study of binary amplitude optimization in the wavefront shaping field.

  4. Strong incidence of Pseudomonas aeruginosa on bacterial rrs and ITS genetic structures of cystic fibrosis sputa.

    Directory of Open Access Journals (Sweden)

    Laurence Pages-Monteiro

    Full Text Available Cystic fibrosis (CF lungs harbor a complex community of interacting microbes, including pathogens like Pseudomonas aeruginosa. Meta-taxogenomic analysis based on V5-V6 rrs PCR products of 52 P. aeruginosa-positive (Pp and 52 P. aeruginosa-negative (Pn pooled DNA extracts from CF sputa suggested positive associations between P. aeruginosa and Stenotrophomonas and Prevotella, but negative ones with Haemophilus, Neisseria and Burkholderia. Internal Transcribed Spacer analyses (RISA from individual DNA extracts identified three significant genetic structures within the CF cohorts, and indicated an impact of P. aeruginosa. RISA clusters Ip and IIIp contained CF sputa with a P. aeruginosa prevalence above 93%, and of 24.2% in cluster IIp. Clusters Ip and IIIp showed lower RISA genetic diversity and richness than IIp. Highly similar cluster IIp RISA profiles were obtained from two patients harboring isolates of a same P. aeruginosa clone, suggesting convergent evolution in the structure of their microbiota. CF patients of cluster IIp had received significantly less antibiotics than patients of clusters Ip and IIIp but harbored the most resistant P. aeruginosa strains. Patients of cluster IIIp were older than those of Ip. The effects of P. aeruginosa on the RISA structures could not be fully dissociated from the above two confounding factors but several trends in these datasets support the conclusion of a strong incidence of P. aeruginosa on the genetic structure of CF lung microbiota.

  5. Genetic Risk Score for Essential Hypertension and Risk of Preeclampsia.

    Science.gov (United States)

    Smith, Caitlin J; Saftlas, Audrey F; Spracklen, Cassandra N; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

    2016-01-01

    Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria. Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores (GRSs) for hypertension and blood pressure are associated with preeclampsia. Subjects consisted of 162 preeclamptic cases and 108 normotensive pregnant controls, all of Iowa residence. Subjects' DNA was extracted from buccal swab samples and genotyped on the Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Missing genotypes were imputed using MaCH and Minimac software. GRSs were calculated for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using established genetic risk loci for each outcome. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of 516 cases and 1,097 controls of European ancestry. GRSs for hypertension, SBP, DBP, and MAP were not significantly associated with risk for preeclampsia (P > 0.189). The results of the replication analysis also yielded nonsignificant associations. GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

    Directory of Open Access Journals (Sweden)

    Jennifer Prescott

    Full Text Available 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.

  7. Genetic risk variants for social anxiety.

    Science.gov (United States)

    Stein, Murray B; Chen, Chia-Yen; Jain, Sonia; Jensen, Kevin P; He, Feng; Heeringa, Steven G; Kessler, Ronald C; Maihofer, Adam; Nock, Matthew K; Ripke, Stephan; Sun, Xiaoying; Thomas, Michael L; Ursano, Robert J; Smoller, Jordan W; Gelernter, Joel

    2017-03-01

    Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h 2 g  = 0.12, P = 2.17 × 10 -4 in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P = 1.55 × 10 -8 ; beta = 0.073) and AFR (rs78924501, Chr 1: BP 88406905, P = 3.58 × 10 -8 ; beta = 0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (r g  = -0.52, se = 0.22, P = 0.02) but not with neuroticism (r g  = 0.05, se = 0.22, P = 0.81) or with an anxiety disorder factor score (r g  = 0.02, se = 0.32, P = 0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. Population genetics inference for longitudinally-sampled mutants under strong selection.

    Science.gov (United States)

    Lacerda, Miguel; Seoighe, Cathal

    2014-11-01

    Longitudinal allele frequency data are becoming increasingly prevalent. Such samples permit statistical inference of the population genetics parameters that influence the fate of mutant variants. To infer these parameters by maximum likelihood, the mutant frequency is often assumed to evolve according to the Wright-Fisher model. For computational reasons, this discrete model is commonly approximated by a diffusion process that requires the assumption that the forces of natural selection and mutation are weak. This assumption is not always appropriate. For example, mutations that impart drug resistance in pathogens may evolve under strong selective pressure. Here, we present an alternative approximation to the mutant-frequency distribution that does not make any assumptions about the magnitude of selection or mutation and is much more computationally efficient than the standard diffusion approximation. Simulation studies are used to compare the performance of our method to that of the Wright-Fisher and Gaussian diffusion approximations. For large populations, our method is found to provide a much better approximation to the mutant-frequency distribution when selection is strong, while all three methods perform comparably when selection is weak. Importantly, maximum-likelihood estimates of the selection coefficient are severely attenuated when selection is strong under the two diffusion models, but not when our method is used. This is further demonstrated with an application to mutant-frequency data from an experimental study of bacteriophage evolution. We therefore recommend our method for estimating the selection coefficient when the effective population size is too large to utilize the discrete Wright-Fisher model. Copyright © 2014 by the Genetics Society of America.

  9. Genetic risk factors in colorectal cancer.

    Science.gov (United States)

    Bonaïti-Pellié, C

    1999-12-01

    Familial risk factors are known to play an important role in colorectal cancer (CRC) risk, particularly when the relatives are affected by early-onset cancer. Part of this familial aggregation can be accounted for by inherited forms of colorectal cancer, i.e. familial adenomatous polyposis (less than 1% of all CRC) and hereditary nonpolyposis colorectal cancer (about 3%). Other genetic factors may be involved in the development of adenoma or in the transformation of adenoma into carcinoma. That the existence of polymorphisms of the adenomatous polyposis coli gene increase susceptibility to both adenomas and cancer favours this hypothesis. Interactions between environmental factors, and most of all dietary factors, and polymorphisms of carcinogen-metabolizing enzymes may also be involved. Better knowledge of these mechanisms will substantially widen the scope of colorectal cancer prevention.

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

    Science.gov (United States)

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

    2015-06-01

    Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and observed five new associations that account for 18% of the genetic risk. Taking these new loci together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.

  11. The evolving genetic risk for sporadic ALS.

    Science.gov (United States)

    Gibson, Summer B; Downie, Jonathan M; Tsetsou, Spyridoula; Feusier, Julie E; Figueroa, Karla P; Bromberg, Mark B; Jorde, Lynn B; Pulst, Stefan M

    2017-07-18

    To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates. © 2017 American Academy of Neurology.

  12. Strong compound-risk factors: efficient discovery through emerging patterns and contrast sets.

    Science.gov (United States)

    Li, Jinyan; Yang, Qiang

    2007-09-01

    Odds ratio (OR), relative risk (RR) (risk ratio), and absolute risk reduction (ARR) (risk difference) are biostatistics measurements that are widely used for identifying significant risk factors in dichotomous groups of subjects. In the past, they have often been used to assess simple risk factors. In this paper, we introduce the concept of compound-risk factors to broaden the applicability of these statistical tests for assessing factor interplays. We observe that compound-risk factors with a high risk ratio or a big risk difference have an one-to-one correspondence to strong emerging patterns or strong contrast sets-two types of patterns that have been extensively studied in the data mining field. Such a relationship has been unknown to researchers in the past, and efficient algorithms for discovering strong compound-risk factors have been lacking. In this paper, we propose a theoretical framework and a new algorithm that unify the discovery of compound-risk factors that have a strong OR, risk ratio, or a risk difference. Our method guarantees that all patterns meeting a certain test threshold can be efficiently discovered. Our contribution thus represents the first of its kind in linking the risk ratios and ORs to pattern mining algorithms, making it possible to find compound-risk factors in large-scale data sets. In addition, we show that using compound-risk factors can improve classification accuracy in probabilistic learning algorithms on several disease data sets, because these compound-risk factors capture the interdependency between important data attributes.

  13. Mature habitats associated with genetic divergence despite strong dispersal ability in an arthropod

    Directory of Open Access Journals (Sweden)

    Taylor Derek J

    2007-04-01

    Full Text Available Abstract Background Populations may be bound by contemporary gene flow, selective sweeps, and extinction-recolonization processes. Indeed, existing molecular estimates indicate that species with low levels of gene flow are rare. However, strong priority effects and local selective regimes may hinder gene flow (despite dispersal sending populations on independent evolutionary trajectories. In this scenario (the monopolization hypothesis, population differentiation will increase with time and genealogical evidence should yield ample private haplotypes. Cyclical parthenogens (e.g. rotifers and cladocerans such as Daphnia have an increased capacity for rapid local adaptation and priority effects because sexual reproduction is followed by multiple generations of clonal selection and massive egg bank formation. We aimed to better understand the history of population differentiation and ongoing gene flow in Daphnia rosea s.l., by comparing population and regional divergences in mature unglaciated areas and younger previously glaciated areas. We also examined the timing and paths of colonization of previously-glaciated areas to assess the dispersal limitations of D. rosea s.l. We used DNA sequence variation (84 populations and >400 individuals at the mitochondrial ND2 and nuclear HSP90 loci from Holarctic populations for our genetic analyses. Results The genetic evidence indicated pronounced historical structure. Holarctic mtDNA phylogenies of D. rosea s.l. revealed three geographically restricted and divergent clades: European, Siberian and Japanese/American. The Japanese/American clade showed marked population genetic structure (FST > 0.8 that was weakly associated with geographic distance, and a high proportion of private haplotypes. Populations from older unglaciated habitats (i.e., Japan showed higher DNA sequence divergences than populations from presumed younger habitats (i.e. non-Beringian North America with nDNA and with mtDNA. Mismatch

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

    NARCIS (Netherlands)

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

    Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and

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

    Science.gov (United States)

    The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CA...

  16. SNP rs16969968 as a Strong Predictor of Nicotine Dependence and Lung Cancer Risk in a North Indian Population

    Science.gov (United States)

    Pandey, Namita; Pal, Soumyadip; Sharma, Lokesh Kumar; Guleria, Randeep; Mohan, Anant; Srivastava, Tapasya

    2017-01-01

    Background: The 15q24-25 loci contain genes (CHRNA5 and CHRNA3) encoding nicotinic acetylcholine receptor subunits. We here determined for the first time the association of genetic variants rs16969968 and rs3743074 in CHRNA5 and CHRNA3, respectively, on nicotine dependence and lung cancer risk in a North Indian population by a case-control approach. Methods: Venous blood samples were obtained from 324 participants (108 lung cancer patients and 216 healthy individuals). DNA was extracted and PCR amplified with primers flanking the SNPs rs16969968 and rs3743074. Amplicons were subjected to sequencing and logistic regression was used to analyze association between variables. Results: The risk variant SNP rs16969968 in both heterozygous and homozygous forms appeared to exert a significant effect on nicotine dependence [GA (OR=2.77) and AA (OR=2.53)]. As expected, smoking was strongly associated with lung cancer (OR= 2.62). Risk allele rs16969968 in CHRNA5 also showed a significant association with increased lung cancer risk in our cohort, alone (OR= 4.99) and with smoking as a co-variable (OR= 4.28). Comparison of our analysis with other populations suggested that individuals with rs16969968 risk allele in the Indian population are more susceptible to lung cancer. Conclusion: Overall, the results strongly indicated that, in our cohort North Indian population, the genetic variant rs16969968, but not rs3743074, is significantly associated with both nicotine dependence and increased risk of lung cancer. While the results are significant, there is further need to increase the sample size and improve precision of our risk prediction. PMID:29172281

  17. Birth Characteristics and Childhood Leukemia Risk: Correlations With Genetic Markers.

    Science.gov (United States)

    Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, Mehmet F; Scheurer, Michael E; Dorak, Mehmet T

    2015-07-01

    Birth characteristics such as birth order, birth weight, birth defects, and Down syndrome showed some of the first risk associations with childhood leukemia. Examinations of correlations between birth characteristics and leukemia risk markers have been limited to birth weight-related genetic polymorphisms. We integrated information on nongenetic and genetic markers by evaluating the relationship of birth characteristics, genetic markers for childhood acute lymphoblastic leukemia (ALL) susceptibility, and ALL risk together. The multiethnic study consisted of cases with childhood ALL (n=161) and healthy controls (n=261). Birth characteristic data were collected through questionnaires, and genotyping was achieved by TaqMan SNP Genotyping Assays. We observed risk associations for birth weight over 4000 g (odds ratios [OR]=1.93; 95% confidence interval [CI], 1.16-3.19), birth length (OR=1.18 per inch; 95% CI, 1.01-1.38), and with gestational age (OR=1.10 per week; 95% CI, 1.00-1.21). Only the HFE tag single-nucleotide polymorphism (SNP) rs9366637 showed an inverse correlation with a birth characteristic, gestational age, with a gene-dosage effect (P=0.005), and in interaction with a transferrin receptor rs3817672 genotype (Pinteraction=0.05). This correlation translated into a strong association for rs9366637 with preterm birth (OR=5.0; 95% CI, 1.19-20.9). Our study provides evidence for the involvement of prenatal events in the development of childhood ALL. The inverse correlation of rs9366637 with gestational age has implications on the design of HFE association studies in birth weight and childhood conditions using full-term newborns as controls.

  18. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    LENUS (Irish Health Repository)

    Sattar, Naveed

    2009-06-23

    Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Understanding Task Force Recommendations Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-related Cancer in Women The U.S. Preventive Services Task Force (Task Force) has issued a final recommendation ...

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

    Science.gov (United States)

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

  2. Comparative analyses of genetic risk prediction methods reveal ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 94; Issue 1. Comparative analyses of genetic risk prediction methods reveal extreme diversity of genetic predisposition to nonalcoholic fatty liver disease (NAFLD) among ethnic populations of India. Ankita Chatterjee Analabha Basu Abhijit Chowdhury Kausik Das Neeta ...

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

    Directory of Open Access Journals (Sweden)

    Tess Clendenen

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

  4. Genetic and environmental influences on risk of death due to infections assessed in Danish twins, 1943-2001

    DEFF Research Database (Denmark)

    Obel, Niels; Christensen, Kaare; Petersen, Inge

    2010-01-01

    Genetic differences have been proposed to play a strong role in risk of death from infectious diseases. The study base of 44,005 included all same-sex twin pairs born in 1870-2001, with both twins alive on January 1, 1943, or those born thereafter. Cause of death was obtained from the Danish Cause...... from infectious diseases could be demonstrated, the absolute effect of the genetic component on mortality was small....... genetic influence on the risk of death...

  5. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

    Science.gov (United States)

    Giri, Veda N; Knudsen, Karen E; Kelly, William K; Abida, Wassim; Andriole, Gerald L; Bangma, Chris H; Bekelman, Justin E; Benson, Mitchell C; Blanco, Amie; Burnett, Arthur; Catalona, William J; Cooney, Kathleen A; Cooperberg, Matthew; Crawford, David E; Den, Robert B; Dicker, Adam P; Eggener, Scott; Fleshner, Neil; Freedman, Matthew L; Hamdy, Freddie C; Hoffman-Censits, Jean; Hurwitz, Mark D; Hyatt, Colette; Isaacs, William B; Kane, Christopher J; Kantoff, Philip; Karnes, R Jeffrey; Karsh, Lawrence I; Klein, Eric A; Lin, Daniel W; Loughlin, Kevin R; Lu-Yao, Grace; Malkowicz, S Bruce; Mann, Mark J; Mark, James R; McCue, Peter A; Miner, Martin M; Morgan, Todd; Moul, Judd W; Myers, Ronald E; Nielsen, Sarah M; Obeid, Elias; Pavlovich, Christian P; Peiper, Stephen C; Penson, David F; Petrylak, Daniel; Pettaway, Curtis A; Pilarski, Robert; Pinto, Peter A; Poage, Wendy; Raj, Ganesh V; Rebbeck, Timothy R; Robson, Mark E; Rosenberg, Matt T; Sandler, Howard; Sartor, Oliver; Schaeffer, Edward; Schwartz, Gordon F; Shahin, Mark S; Shore, Neal D; Shuch, Brian; Soule, Howard R; Tomlins, Scott A; Trabulsi, Edouard J; Uzzo, Robert; Vander Griend, Donald J; Walsh, Patrick C; Weil, Carol J; Wender, Richard; Gomella, Leonard G

    2018-02-01

    Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

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

    Science.gov (United States)

    Dossus, Laure; Benusiglio, Patrick R

    2015-03-13

    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.

  7. Genetic Ancestry and Risk of Breast Cancer among US Latinas

    OpenAIRE

    Fejerman, Laura; John, Esther M.; Huntsman, Scott; Beckman, Kenny; Choudhry, Shweta; Perez-Stable, Eliseo; Burchard, Esteban González; Ziv, Elad

    2008-01-01

    US Latinas have a lower incidence of breast cancer compared to non-Latina White women. This difference is partially explained by differences in the prevalence of known risk factors. Genetic factors may also contribute to this difference in incidence. Latinas are an admixed population with most of their genetic ancestry from Europeans and Indigenous Americans. We used genetic markers to estimate the ancestry of Latina breast cancer cases and controls and assessed the association with genetic a...

  8. Temporal genetic stability in natural populations of the waterflea Daphnia magna in response to strong selection pressure.

    Science.gov (United States)

    Orsini, Luisa; Marshall, Hollie; Cuenca Cambronero, Maria; Chaturvedi, Anurag; Thomas, Kelley W; Pfrender, Michael E; Spanier, Katina I; De Meester, Luc

    2016-12-01

    Studies monitoring changes in genetic diversity and composition through time allow a unique understanding of evolutionary dynamics and persistence of natural populations. However, such studies are often limited to species with short generation times that can be propagated in the laboratory or few exceptional cases in the wild. Species that produce dormant stages provide powerful models for the reconstruction of evolutionary dynamics in the natural environment. A remaining open question is to what extent dormant egg banks are an unbiased representation of populations and hence of the species' evolutionary potential, especially in the presence of strong environmental selection. We address this key question using the water flea Daphnia magna, which produces dormant stages that accumulate in biological archives over time. We assess temporal genetic stability in three biological archives, previously used in resurrection ecology studies showing adaptive evolutionary responses to rapid environmental change. We show that neutral genetic diversity does not decline with the age of the population and it is maintained in the presence of strong selection. In addition, by comparing temporal genetic stability in hatched and unhatched populations from the same biological archive, we show that dormant egg banks can be consulted to obtain a reliable measure of genetic diversity over time, at least in the multidecadal time frame studied here. The stability of neutral genetic diversity through time is likely mediated by the buffering effect of the resting egg bank. © 2016 John Wiley & Sons Ltd.

  9. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    Directory of Open Access Journals (Sweden)

    Naveed Sattar

    2009-06-01

    Full Text Available BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD events, but robust prospective evidence is lacking. We tested whether interleukin (IL-6, C-reactive protein (CRP, and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER, baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672], fatal CVD (n = 190, death from other CV causes (n = 38, and non-CVD mortality (n = 300, over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12 than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31, in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction. The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001 improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20. CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

  10. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Directory of Open Access Journals (Sweden)

    Katie M O'Brien

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs and 95% confidence intervals (CIs for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT. Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836 and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836. CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively. Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic

  11. Does educational attainment shape reactions to genetic risk for Alzheimer's disease? Results from a national survey experiment.

    Science.gov (United States)

    Andersson, Matthew A; Gadarian, Shana Kushner; Almeling, Rene

    2017-05-01

    While higher education is associated with healthy lifestyles and health literacy, it remains unclear whether education shapes reactions to varying levels of genetic risk for Alzheimer's disease (AD). In this study, participants (N = 701) in the National Genetic Risk Survey Experiment (NGRISE) received a hypothetical genetic risk assessment for AD (ranging from 20 to 80% lifetime risk) and then completed items on their cognitive (perceived threat to health), emotional (general negative affect), and anticipated behavioral (seek information, improve health behaviors, engage in public or private civic action) reactions to this risk. Individuals with a college education showed reactions to increasing genetic risk approximately twice or several times as strong relative to those of individuals with lower (high school, HS) education. In fact, behavioral reactions do not significantly increase with AD risk among those with HS education. Some educational differences in risk response widen at older ages. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes.

    Science.gov (United States)

    Saunders, Colleen J; Jalali Sefid Dashti, Mahjoubeh; Gamieldien, Junaid

    2016-01-25

    Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation of human genes and identify candidate genes by ontology-seeded queries capturing the features of tendinopathy. Our BioOntological Relationship Graph database (BORG) integrates multiple sources of genomic and biomedical knowledge into an on-disk semantic network where human genes and their orthologs in mouse and rat are central concepts mapped to ontology terms. The BORG was used to screen all human genes for potential links to tendinopathy. Following further prioritisation, four strong candidate genes (COL11A2, ELN, ITGB3, LOX) were identified. These genes are differentially expressed in tendinopathy, functionally linked to features of tendinopathy and previously implicated in other connective tissue diseases. In conclusion, cross-domain semantic integration of multiple sources of biomedical knowledge, and interrogation of phenotypes and gene functions associated with disease, may significantly increase the probability of identifying strong and unobvious candidate genes in genetic association studies.

  13. Polygyny and strong genetic structuring within an isolated population of the wood ant Formica rufa

    Directory of Open Access Journals (Sweden)

    Wouter Dekoninck

    2014-12-01

    Full Text Available Social structuring of populations within some Formica species exhibits considerable variation going from monodomous and monogynous populations to polydomous, polygynous populations. The wood ant species Formica rufa appears to be mainly monodomous and monogynous throughout most of its distribution area in central and northern Europe. Only occasionally it was mentioned that F. rufa can have both polygynous and monogynous colonies in the same geographical region. We studied an isolated polydomous F. rufa population in a deciduous mixed forest in the north-west of Belgium. The level of polydomy within the colonies varied from monodomous to 11 nests per colony. Our genetic analysis of eight variable microsatellites suggest an oligo- to polygynous structure for at least the major part of the sampled nests. Relatedness amongst nest mate workers varies considerable within the population and colonies but confirms in general a polygynous structure. Additionally high genetic diversity (e.g. up to 8 out of 11 alleles per nest for the most variable locus and high within nest genetic variance (93% indicate that multiple queens contribute to the gene pool of workers of the same nest. Moreover significant genetic structuring among colonies indicates that gene flow between colonies is restricted and that exchange of workers between colonies is very limited. Finally we explain how possible factors as budding and the absence of Serviformica can explain the differences in genetic structure within this polygynous F. rufa population.

  14. Microsatellites reveal a strong subdivision of genetic structure in Chinese populations of the mite Tetranychus urticae Koch (Acari: Tetranychidae

    Directory of Open Access Journals (Sweden)

    Sun Jing-Tao

    2012-02-01

    Full Text Available Abstract Background Two colour forms of the two-spotted spider mite (Tetranychus urticae Koch coexist in China: a red (carmine form, which is considered to be native and a green form which is considered to be invasive. The population genetic diversity and population genetic structure of this organism were unclear in China, and there is a controversy over whether they constitute distinct species. To address these issues, we genotyped a total of 1,055 individuals from 18 red populations and 7 green populations in China using eight microsatellite loci. Results We identified 109 alleles. We found a highly significant genetic differentiation among the 25 populations (global FST = 0.506, global FST {ENA} = 0.473 and a low genetic diversity in each population. In addition, genetic diversity of the red form mites was found to be higher than the green form. Pearson correlations between statistics of variation (AR and HE and geographic coordinates (latitude and longitude showed that the genetic diversity of the red form was correlated with latitude. Using Bayesian clustering, we divided the Chinese mite populations into five clades which were well congruent with their geographic distributions. Conclusions Spider mites possess low levels of genetic diversity, limit gene flow between populations and significant and IBD (isolation by distance effect. These factors in turn contribute to the strong subdivision of genetic structure. In addition, population genetic structure results don't support the separation of the two forms of spider mite into two species. The morphological differences between the two forms of mites may be a result of epigenetic effects.

  15. Risk assessment: the importance of genetic polymorphisms in man

    DEFF Research Database (Denmark)

    E. Knudsen, Lisbeth; Loft, Steffen; Autrup, Herman

    2001-01-01

    Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. The relative risk estimates have shown large variations between such population studies. However, in most studies the relative risk estimates are in the range...... the application in insurance situations is criticised....

  16. Pubertal onset in girls is strongly influenced by genetic variation affecting FSH action

    DEFF Research Database (Denmark)

    Hagen, Casper P; Sørensen, Kaspar; Aksglaede, Lise

    2014-01-01

    Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian...... follicle maturation and estradiol synthesis which is responsible for breast development. We assessed the effect of three polymorphisms influencing FSH action on age at breast deveopment in a population-based cohort of 964 healthy girls. Girls homozygous for FSHR -29AA (reduced FSH receptor expression...

  17. Genetically Predicted Body Mass Index and Breast Cancer Risk

    DEFF Research Database (Denmark)

    Guo, Yan; Warren Andersen, Shaneda; Shu, Xiao-Ou

    2016-01-01

    BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or enviro...... for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer....

  18. Genetic toxicology and cancer risk assessment

    National Research Council Canada - National Science Library

    Choy, Wai Nang

    2001-01-01

    ... their risks to humans are obvious goals for the protection of public health. When exposure is unavoidable, an accurate estimation of human risk as a result of exposure is essential for making regulatory decisions. Quantitative cancer risk assessment is an intricate process that utilizes knowledge from many different scien...

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

    Science.gov (United States)

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

    2007-01-01

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

  20. A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea.

    Science.gov (United States)

    Bergström, Anders; Oppenheimer, Stephen J; Mentzer, Alexander J; Auckland, Kathryn; Robson, Kathryn; Attenborough, Robert; Alpers, Michael P; Koki, George; Pomat, William; Siba, Peter; Xue, Yali; Sandhu, Manjinder S; Tyler-Smith, Chris

    2017-09-15

    New Guinea shows human occupation since ~50 thousand years ago (ka), independent adoption of plant cultivation ~10 ka, and great cultural and linguistic diversity today. We performed genome-wide single-nucleotide polymorphism genotyping on 381 individuals from 85 language groups in Papua New Guinea and find a sharp divide originating 10 to 20 ka between lowland and highland groups and a lack of non-New Guinean admixture in the latter. All highlanders share ancestry within the last 10 thousand years, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in Papua New Guinea is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies. Copyright © 2017, American Association for the Advancement of Science.

  1. A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea

    Science.gov (United States)

    Bergström, Anders; Oppenheimer, Stephen J; Mentzer, Alexander J; Auckland, Kathryn; Robson, Kathryn; Attenborough, Robert; Alpers, Michael P; Koki, George; Pomat, William; Siba, Peter; Xue, Yali; Sandhu, Manjinder S; Tyler-Smith, Chris

    2018-01-01

    New Guinea shows human occupation since ~50 thousand years ago (kya), independent adoption of plant cultivation ~10 kya, and great cultural and linguistic diversity today. We performed genome-wide SNP genotyping on 381 individuals from 85 language groups in Papua New Guinea (PNG) and find a sharp divide originating 10-20 kya between lowland and highland groups, and a lack of non-New Guinean admixture in the latter. All highlanders share ancestry within the last 10 kya, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in PNG is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies. PMID:28912245

  2. Candidate genes detected in transcriptome studies are strongly dependent on genetic background.

    Directory of Open Access Journals (Sweden)

    Pernille Sarup

    2011-01-01

    Full Text Available Whole genome transcriptomic studies can point to potential candidate genes for organismal traits. However, the importance of potential candidates is rarely followed up through functional studies and/or by comparing results across independent studies. We have analysed the overlap of candidate genes identified from studies of gene expression in Drosophila melanogaster using similar technical platforms. We found little overlap across studies between putative candidate genes for the same traits in the same sex. Instead there was a high degree of overlap between different traits and sexes within the same genetic backgrounds. Putative candidates found using transcriptomics therefore appear very sensitive to genetic background and this can mask or override effects of treatments. The functional importance of putative candidate genes emerging from transcriptome studies needs to be validated through additional experiments and in future studies we suggest a focus on the genes, networks and pathways affecting traits in a consistent manner across backgrounds.

  3. Winemaking and bioprocesses strongly shaped the genetic diversity of the ubiquitous yeast Torulaspora delbrueckii.

    Directory of Open Access Journals (Sweden)

    Warren Albertin

    Full Text Available The yeast Torulaspora delbrueckii is associated with several human activities including oenology, bakery, distillery, dairy industry, etc. In addition to its biotechnological applications, T. delbrueckii is frequently isolated in natural environments (plant, soil, insect. T. delbrueckii is thus a remarkable ubiquitous yeast species with both wild and anthropic habitats, and appears to be a perfect yeast model to search for evidence of human domestication. For that purpose, we developed eight microsatellite markers that were used for the genotyping of 110 strains from various substrates and geographical origins. Microsatellite analysis showed four genetic clusters: two groups contained most nature strains from Old World and Americas respectively, and two clusters were associated with winemaking and other bioprocesses. Analysis of molecular variance (AMOVA confirmed that human activities significantly shaped the genetic variability of T. delbrueckii species. Natural isolates are differentiated on the basis of geographical localisation, as expected for wild population. The domestication of T. delbrueckii probably dates back to the Roman Empire for winemaking (∼ 1900 years ago, and to the Neolithic era for bioprocesses (∼ 4000 years ago. Microsatellite analysis also provided valuable data regarding the life-cycle of the species, suggesting a mostly diploid homothallic life. In addition to population genetics and ecological studies, the microsatellite tool will be particularly useful for further biotechnological development of T. delbrueckii strains for winemaking and other bioprocesses.

  4. Winemaking and bioprocesses strongly shaped the genetic diversity of the ubiquitous yeast Torulaspora delbrueckii.

    Science.gov (United States)

    Albertin, Warren; Chasseriaud, Laura; Comte, Guillaume; Panfili, Aurélie; Delcamp, Adline; Salin, Franck; Marullo, Philippe; Bely, Marina

    2014-01-01

    The yeast Torulaspora delbrueckii is associated with several human activities including oenology, bakery, distillery, dairy industry, etc. In addition to its biotechnological applications, T. delbrueckii is frequently isolated in natural environments (plant, soil, insect). T. delbrueckii is thus a remarkable ubiquitous yeast species with both wild and anthropic habitats, and appears to be a perfect yeast model to search for evidence of human domestication. For that purpose, we developed eight microsatellite markers that were used for the genotyping of 110 strains from various substrates and geographical origins. Microsatellite analysis showed four genetic clusters: two groups contained most nature strains from Old World and Americas respectively, and two clusters were associated with winemaking and other bioprocesses. Analysis of molecular variance (AMOVA) confirmed that human activities significantly shaped the genetic variability of T. delbrueckii species. Natural isolates are differentiated on the basis of geographical localisation, as expected for wild population. The domestication of T. delbrueckii probably dates back to the Roman Empire for winemaking (∼ 1900 years ago), and to the Neolithic era for bioprocesses (∼ 4000 years ago). Microsatellite analysis also provided valuable data regarding the life-cycle of the species, suggesting a mostly diploid homothallic life. In addition to population genetics and ecological studies, the microsatellite tool will be particularly useful for further biotechnological development of T. delbrueckii strains for winemaking and other bioprocesses.

  5. Computerised Genetic Risk Assessment and Decision Support in Primary Care

    Directory of Open Access Journals (Sweden)

    Andrew Coulson

    2000-09-01

    To address these issues, a new computer application called RAGs (Risk Assessment in Genetics has been designed. The system allows a doctor to create family trees and assess genetic risk of breast cancer. RAGs possesses two features that distinguish it from similar software: (a a user-centred design, which takes into account the requirements of the doctor-patient encounter; (b risk reporting using qualitative evidence for or against an increased risk, which the authors believe to be more useful and accessible than numerical probabilities are. In that the system allows for any genetic risk guideline to be implemented, it can be used with all diseases for which evaluation guidelines exist. The software may be easily modified to cater for the amount of detail required by different specialists.

  6. Referral for genetic counselling during pregnancy: limited alertness and awareness about genetic risk factors among GPs

    NARCIS (Netherlands)

    Aalfs, Cora M.; Smets, Ellen M. A.; de Haes, Hanneke C. J. M.; Leschot, Nico J.

    2003-01-01

    Background. In many countries, GPs play a key role in the referral to other medical specialists. Referral for reproductive genetic counselling during a pregnancy of women with a genetic risk factor already present before pregnancy has many disadvantages. Nevertheless, some 10-20% of the counsellees

  7. Common Genetic Risk for Melanoma Encourages Preventive Behavior Change

    Directory of Open Access Journals (Sweden)

    Lori Diseati

    2015-02-01

    Full Text Available 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.

  8. Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk.

    Directory of Open Access Journals (Sweden)

    Yan Ding

    Full Text Available Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT, a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's chi(2 = 12.34, df 1, P = 0.00045 and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's chi(2 = 11.50, df 1, P = 0.00070. In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (pi = 0.0072, Tajima's D = 3.31, 14 SNPs and the Japanese (pi = 0.0049, Fay & Wu's H = 8.05, 14 SNPs, as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs. These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer.

  9. Risk assessment: the importance of genetic polymorphisms in man

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E.; Loft, S H; Autrup, H

    2001-01-01

    Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. The relative risk estimates have shown large variations between such population studies. However, in most studies the relative risk estimates are in the range...... and increased cancer risk, such results indicate effect modification regarding cancer risk. In risk assessment the safety 'factor' of 10 is generally accepted to allow for variation in individual susceptibility. Reviewing the literature justifies the factor of 10 when considering single polymorphisms. However...... in an individual with several susceptible metabolism genotypes as well as other determinants of susceptibility, e.g. defective DNA repair, poor-nutritional state, etc. the risk may increase far above a safety of 10.Historically, genetic polymorphisms have been taken into consideration in employment and currently...

  10. Automatic Creation of Machine Learning Workflows with Strongly Typed Genetic Programming

    Czech Academy of Sciences Publication Activity Database

    Křen, T.; Pilát, M.; Neruda, Roman

    2017-01-01

    Roč. 26, č. 5 (2017), č. článku 1760020. ISSN 0218-2130 R&D Projects: GA ČR GA15-19877S Grant - others:GA MŠk(CZ) LM2015042 Institutional support: RVO:67985807 Keywords : genetic programming * machine learning workflows * asynchronous evolutionary algorithm Subject RIV: IN - Informatics, Computer Science OBOR OECD: Computer sciences, information science, bioinformathics (hardware development to be 2.2, social aspect to be 5.8) Impact factor: 0.778, year: 2016

  11. Genetic risk factors of venous thrombosis

    NARCIS (Netherlands)

    Franco, R. F.; Reitsma, P. H.

    2001-01-01

    Venous thrombosis, whose main clinical presentations include deep vein thrombosis and pulmonary embolism, represents a major health problem worldwide. Numerous conditions are known to predispose to venous thrombosis and these conditions are commonly referred to as risk indicators or risk factors.

  12. Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease.

    Science.gov (United States)

    Lang, B M; Biedermann, L; van Haaften, W T; de Vallière, C; Schuurmans, M; Begré, S; Zeitz, J; Scharl, M; Turina, M; Greuter, T; Schreiner, P; Heinrich, H; Kuntzen, T; Vavricka, S R; Rogler, G; Beerenwinkel, N; Misselwitz, B

    2018-01-01

    Smoking is a strong environmental factor leading to adverse outcomes in Crohn's disease, but a more benign course in ulcerative colitis. Several single nucleotide polymorphisms (SNPs) are associated with smoking quantity and behaviour. To assess whether smoking-associated SNPs interact with smoking to influence the clinical course of inflammatory bowel diseases. Genetic and prospectively obtained clinical data from 1434 Swiss inflammatory bowel disease cohort patients (821 Crohn's disease and 613 ulcerative colitis) were analysed. Six SNPs associated with smoking quantity and behaviour (rs588765, rs1051730, rs1329650, rs4105144, rs6474412 and rs3733829) were combined to form a risk score (range: 0-12) by adding the number of risk alleles. We calculated multivariate models for smoking, risk of surgery, fistula, Crohn's disease location and ulcerative colitis disease extent. In Crohn's disease patients who smoke, the number of surgeries was associated with the genetic risk score. This translates to a predicted 3.5-fold (95% confidence interval: 2.4- to 5.7-fold, Prisk alleles than individuals with the lowest risk. Patients with a risk score >7 had a significantly shorter time to first intestinal surgery. The genetic risk score did not predict surgery in ulcerative colitis or occurrence of fistulae in Crohn's disease. SNP rs6265 was associated with ileal disease in Crohn's disease (Prisk for surgery in Crohn's disease patients who smoke. Our data provide an example of genetics interacting with the environment to influence the disease course of inflammatory bowel disease. © 2017 John Wiley & Sons Ltd.

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

    DEFF Research Database (Denmark)

    Moutsianas, Loukas; Jostins, Luke; Beecham, Ashley H

    2015-01-01

    ,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles...

  14. A Strong Impact of Genetic Background on Gut Microflora in Mice

    Directory of Open Access Journals (Sweden)

    R. Steven Esworthy

    2010-01-01

    Full Text Available Genetic background affects susceptibility to ileocolitis in mice deficient in two intracellular glutathione peroxidases, GPx1 and GPx2. The C57BL/6 (B6 GPx1/2 double-knockout (DKO mice have mild ileocolitis, and 129S1/Sv (129 DKO mice have severe inflammation. We used diet to modulate ileocolitis; a casein-based defined diet with AIN76A micronutrients (AIN attenuates inflammation compared to conventional LabDiets. Because luminal microbiota induce DKO ileocolitis, we assessed bacterial composition with automated ribosomal intergenic-spacer analysis (ARISA on cecal DNA. We found that mouse strain had the strongest impact on the composition of microbiota than diet and GPx genotypes. In comparing AIN and LabDiet, DKO mice were more resistant to change than the non-DKO or WT mice. However, supplementing yeast and inulin to AIN diet greatly altered microflora profiles in the DKO mice. From 129 DKO strictly, we found overgrowth of Escherichia coli. We conclude that genetic background predisposes mice to colonization of potentially pathogenic E. coli.

  15. Atrial Fibrillation Genetic Risk and Ischemic Stroke Mechanisms.

    Science.gov (United States)

    Lubitz, Steven A; Parsons, Owen E; Anderson, Christopher D; Benjamin, Emelia J; Malik, Rainer; Weng, Lu-Chen; Dichgans, Martin; Sudlow, Cathie L; Rothwell, Peter M; Rosand, Jonathan; Ellinor, Patrick T; Markus, Hugh S; Traylor, Matthew

    2017-06-01

    Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association ( P =6×10 - 4 ) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P risk and stroke were enriched in the cardioembolic stroke subset (strongest P =1.2×10 - 9 , 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses. © 2017 American Heart Association, Inc.

  16. Breast magnetic resonance imaging significance for breast cancer diagnostic in women with genetic predisposition and a strong family history

    Directory of Open Access Journals (Sweden)

    M. S. Karpova

    2013-01-01

    Full Text Available Screening of breast cancer with mammography recommended to women over 40 has been shown to decrease breast cancer mortality. But mam- mography has much lower accuracy in young women with BRCA1/2 mutations and women with a strong family history. Therefore new screening methods in young high-risk women are necessary to detect early-stage cancer.

  17. Genetic Cancer Risk Assessment for Breast Cancer in Latin America

    Science.gov (United States)

    Chavarri-Guerra, Yanin; Blazer, Kathleen Reilly; Weitzel, Jeffrey Nelson

    2017-01-01

    In Latin America, breast cancer is the most common malignancy in women, and limited available data suggest that up to 15% of all breast cancer cases in the region are hereditary. Genetic cancer risk assessment and counseling is a critical component of the appropriate clinical care of patients with hereditary breast cancer and their families. Unfortunately, genetic services are underdeveloped across Latin America, and access to genetic testing and counseling is very scarce in the region. Barriers contributing to the access to genetic care are high cost and lack of insurance coverage for genetic tests, insufficient oncogenetics training or expertise, nonexistence of genetic counseling as a clinical discipline and lack of supportive healthcare policies. In this review, we highlight relevant initiatives undertaken in several Latin American countries aimed at creating genetic cancer risk assessment programs. Additionally, we present a review of the scientific literature on the current status of breast cancer genomics in Latin America, with specific emphasis on demographic indicators, access to cancer genetic care, training and strategies to improve outcomes and international collaborations. PMID:28453507

  18. Channelopathies, genetic testing and risk stratification

    NARCIS (Netherlands)

    Wilde, Arthur A. M.; Amin, Ahmad

    2017-01-01

    The cardiac channelopathies are a group of diseases with (disease-) specific electrocardiographic (ECG) characteristics and a disease-specific risk of sudden cardiac death (SCD). This group includes the Long QT Syndromes (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada

  19. Self-Conscious Shyness: Growth during Toddlerhood, Strong Role of Genetics, and No Prediction from Fearful Shyness.

    Science.gov (United States)

    Eggum-Wilkens, Natalie D; Lemery-Chalfant, Kathryn; Aksan, Nazan; Goldsmith, H Hill

    2015-01-01

    Fearful and self-conscious subtypes of shyness have received little attention in the empirical literature. Study aims included: 1) determining if fearful shyness predicted self-conscious shyness, 2) describing development of self-conscious shyness, and 3) examining genetic and environmental contributions to fearful and self-conscious shyness. Observed self-conscious shyness was examined at 19, 22, 25, and 28 months in same-sex twins (MZ = 102, DZ = 111, missing zygosity = 3 pairs). Self-conscious shyness increased across toddlerhood, but onset was earlier than predicted by theory. Fearful shyness (observed [6 and 12 months] and parents' reports [12 and 22 months]) was not predictive of self-conscious shyness. Independent genetic factors made strong contributions to parent-reported (but not observed) fearful shyness (additive genetic influence = .69 and .72 at 12 and 22 months, respectively) and self-conscious shyness (additive genetic influence = .90 for the growth model intercept). Results encourage future investigation of patterns of change and interrelations in shyness subtypes.

  20. Quantification of the genetic risk of environmental mutagens

    International Nuclear Information System (INIS)

    Ehling, U.H.

    1988-01-01

    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

  1. Novel genetic markers improve measures of atrial fibrillation risk prediction

    Science.gov (United States)

    Everett, Brendan M.; Cook, Nancy R.; Conen, David; Chasman, Daniel I.; Ridker, Paul M; Albert, Christine M.

    2013-01-01

    Aims Atrial fibrillation (AF) is associated with adverse outcome. Whether recently discovered genetic risk markers improve AF risk prediction is unknown. Methods and results We derived and validated a novel AF risk prediction model from 32 possible predictors in the Women's Health Study (WHS), a cohort of 20 822 women without cardiovascular disease (CVD) at baseline followed prospectively for incident AF (median: 14.5 years). We then created a genetic risk score (GRS) comprised of 12 risk alleles in nine loci and assessed model performance in the validation cohort with and without the GRS. The newly derived WHS AF risk algorithm included terms for age, weight, height, systolic blood pressure, alcohol use, and smoking (current and past). In the validation cohort, this model was well calibrated with good discrimination [C-index (95% CI) = 0.718 (0.684–0.753)] and improved all reclassification indices when compared with age alone. The addition of the genetic score to the WHS AF risk algorithm model improved the C-index [0.741 (0.709–0.774); P = 0.001], the category-less net reclassification [0.490 (0.301–0.670); P < 0.0001], and the integrated discrimination improvement [0.00526 (0.0033–0.0076); P < 0.0001]. However, there was no improvement in net reclassification into 10-year risk categories of <1, 1–5, and 5+% [0.041 (−0.044–0.12); P = 0.33]. Conclusion Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF. The addition of genetic information resulted in modest improvements in predictive accuracy that did not translate into improved reclassification into discrete AF risk categories. PMID:23444395

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

    Science.gov (United States)

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

    2016-02-01

    We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition

    OpenAIRE

    Husted, Janice A.; Ahmed, Rashid; Chow, Eva W.C.; Brzustowicz, Linda M.; Bassett, Anne S.

    2012-01-01

    There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood tr...

  4. Strong genetic structure corresponds to small-scale geographic breaks in the Australian alpine grasshopper Kosciuscola tristis.

    Science.gov (United States)

    Slatyer, Rachel A; Nash, Michael A; Miller, Adam D; Endo, Yoshinori; Umbers, Kate D L; Hoffmann, Ary A

    2014-10-02

    Mountain landscapes are topographically complex, creating discontinuous 'islands' of alpine and sub-alpine habitat with a dynamic history. Changing climatic conditions drive their expansion and contraction, leaving signatures on the genetic structure of their flora and fauna. Australia's high country covers a small, highly fragmented area. Although the area is thought to have experienced periods of relative continuity during Pleistocene glacial periods, small-scale studies suggest deep lineage divergence across low-elevation gaps. Using both DNA sequence data and microsatellite markers, we tested the hypothesis that genetic partitioning reflects observable geographic structuring across Australia's mainland high country, in the widespread alpine grasshopper Kosciuscola tristis (Sjösted). We found broadly congruent patterns of regional structure between the DNA sequence and microsatellite datasets, corresponding to strong divergence among isolated mountain regions. Small and isolated mountains in the south of the range were particularly distinct, with well-supported divergence corresponding to climate cycles during the late Pliocene and Pleistocene. We found mixed support, however, for divergence among other mountain regions. Interestingly, within areas of largely contiguous alpine and sub-alpine habitat around Mt Kosciuszko, microsatellite data suggested significant population structure, accompanied by a strong signature of isolation-by-distance. Consistent patterns of strong lineage divergence among different molecular datasets indicate genetic breaks between populations inhabiting geographically distinct mountain regions. Three primary phylogeographic groups were evident in the highly fragmented Victorian high country, while within-region structure detected with microsatellites may reflect more recent population isolation. Despite the small area of Australia's alpine and sub-alpine habitats, their low topographic relief and lack of extensive glaciation

  5. PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors.

    Science.gov (United States)

    de Quervain, Dominique J-F; Kolassa, Iris-Tatjana; Ackermann, Sandra; Aerni, Amanda; Boesiger, Peter; Demougin, Philippe; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hadziselimovic, Nils; Hanser, Edveena; Heck, Angela; Hieber, Petra; Huynh, Kim-Dung; Klarhöfer, Markus; Luechinger, Roger; Rasch, Björn; Scheffler, Klaus; Spalek, Klara; Stippich, Christoph; Vogler, Christian; Vukojevic, Vanja; Stetak, Attila; Papassotiropoulos, Andreas

    2012-05-29

    Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity--including aversive memory--in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.

  6. Illusions of controlling the future: Risk and genetic inheritance.

    Science.gov (United States)

    Finkler, Kaja

    2003-01-01

    The aim of this paper is to analyse the implications of current beliefs that human beings can control the risk of inheriting a genetic disease and influence their present and future health. To accomplish this goal, materials will be drawn from disparate literatures bearing on concepts of probability, risk and genetic inheritance, and on empirical data gathered on cancer survivors and healthy persons with a family history of cancer. The concept of risk has been theorised on a grand scale but, as Lupton (1999, Introduction, Risk and Sociological Theory , Cambridge University Press) correctly observes, there has been very little empirical work done on how people experience risk as part of their lived world. In this paper, notions of probabilities and risk will be examined as applied to beliefs in genetic inheritance that are shaped by historical and cultural forces and in turn how they shape people's lives. It will be proposed that the belief that knowledge of one's genetic inheritance can control one's future health and disease is an illusion, and also replicates in part a religious notion of predestination.

  7. Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

    Directory of Open Access Journals (Sweden)

    Costain G

    2012-02-01

    Full Text Available Gregory Costain1,2, Anne S Bassett1–41Clinical Genetics Research Program, Centre for Addiction and Mental Health, 2Institute of Medical Science, University of Toronto, 3Division of Cardiology, Department of Medicine and Department of Psychiatry, University Health Network, 4Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaAbstract: Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete progress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.2 microdeletions, and more recently in large-scale, genome-wide case-control studies. These advances promise to help many families afflicted with this disease. In this review, we critically appraise recent developments in the field of schizophrenia genetics through the lens of immediate clinical applicability. Much work remains in translating the recent surge of genetic research discoveries into the clinic. The epidemiology and basic genetic parameters (such as penetrance and expression of most genomic disorders associated with schizophrenia are not yet well characterized. To date, 22q11.2 deletion syndrome is the only established genetic subtype of schizophrenia of proven clinical relevance. We use this well-established association as a model to chart the pathway for translating emerging genetic discoveries into clinical practice. We also propose new directions for research involving general genetic risk prediction and counseling in schizophrenia.Keywords: schizophrenia, genetics, 22q11 deletion syndrome, copy number variation, genetic counseling, genetic predisposition to disease

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

    Directory of Open Access Journals (Sweden)

    Gabrielle T Goodlin

    Full Text Available 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.

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

    Science.gov (United States)

    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. Copyright

  10. THERAPEUTIC IMPLICATIONS OF GENETIC RISK VARIANTS FOR CORONARY ARTERY DISEASE

    Directory of Open Access Journals (Sweden)

    Rajiv Kumar Srivastava

    2017-02-01

    Full Text Available BACKGROUND This review covers therapeutic implication of genetic risk variant responsible for coronary artery disease by utilising the highdensity single-nucleotide microarrays to screen the entire human genome. The sequence of the human genome provides the blueprint for life. Approximately, 99.5% of the human genome Deoxyribonucleic Acid (DNA sequence is identical among humans with 0.5% of the genome sequence (15 million bps accounting for all individual differences. MATERIALS AND METHODS The new technology of the computerised chip array of millions of Single-Nucleotide Polymorphisms (SNPs as Deoxyribonucleic Acid (DNA markers makes it possible to study and detect genetic predisposition to common polygenic disorders such as Coronary Artery Disease (CAD. The sample sizes required for these studies are massive and large; worldwide consortiums such as Coronary Artery Disease Genome-wide Replication and Meta-Analysis (CARDIoGRAM study have been formed to accommodate this requirement. After the identification of 9p21 progress to detect genetic predisposition has been remarkable. RESULTS There are currently a total of 50 genetic risk variants predisposing to CAD of genome-wide significance with confirmation in independent populations. Rare variants (Minor Allele Frequency, MAF <5% will require direct sequencing to detect genetic predisposition. CONCLUSION We can develop new biomarkers for detecting early CAD as well as unique targets for novel therapy. The challenge for the future will be to identify the molecular mechanisms mediating the risk of those genetic risk variants that act through nonconventional risk factors. The ultimate objective for the future is the sequencing and functional analysis of the causative polymorphisms for its therapeutic implications.

  11. Risks from mammography - Physical and genetics aspects

    International Nuclear Information System (INIS)

    Frankenberg, D.; Kuehn, H.; Frankenberg-Schwager, M.

    1996-01-01

    Prevention and early diagnosis are the most intelligent and powerful methods in the battle against cancer. Breast cancer is one of the most frequent cancers of women. Therefore, methods for early diagnosis were developed among which mammography using soft X-rays is most frequently applied. Experimental data about chromosomal aberrations and neoplastic cell transformation induced by soft and ultrasoft X-rays show that the quality factor Q of one currently used for soft X-rays of mammography is by far too low. About 5% of all women with breast cancer carry a familial predisposition (heterozygocity of the gene BRCA1 or BRCA2). In Germany about 2000-2500 women per year develop breast cancer because of this heterozygocity. Therfore, an urgent need exists to determine for these women the elevated radiation risk by mammography using soft X-rays. Based on the mutation frequency of the HPRT-gene by ionizing radiation the probability of homozygocity by knocking out the other allel of the BRCA1- or BRCA2-gene in one of the target cells of the breast was calculated. This probability is elevated by a factor of 10 7 compared with women carrying both allels of the BRCA1- and BRCA2-gene which have to be knocked out both to become homozygous. A similar elevated radiation risk of breast cancer for women heterozygous in the BRCA1- or BRCA2-gene was calculated by Chakraborty and Sankaranarayanan [11]. (orig.) [de

  12. Genetically Modified Crops: Risks and Promise

    Directory of Open Access Journals (Sweden)

    Gordon Conway

    2000-07-01

    Full Text Available GM foods have the potential to provide significant benefits for developing countries. Over 800 million people are chronically undernourished, and 180 million children are severely underweight for their age. By 2020, there will be an extra two billion mouths to feed. Ecological approaches that underpin sustainable agriculture (e.g., integrated pest management and participatory approaches that strengthen farmers' own experimentation and decision making are key. Biotechnology will be an essential partner, if yield ceilings are to be raised, if crops are to be grown without excessive reliance on pesticides, and if farmers on less favored lands are to be provided with crops that are resistant to drought and salinity, and that can use nitrogen and other nutrients more efficiently. Over the past 10 years, in addition supporting ecological approaches, the Rockefeller Foundation has funded the training of some 400 developing-country scientists in the techniques of biotechnology. Most of the new crop varieties are the result of tissue culture and marker-aided selection. The Foundation also supports the production of genetically engineered rices, including a new rice engineered for beta carotene (the precursor of Vitamin A in the grain. Some specific steps can be taken by Monsanto that would improve acceptance of plant biotechnology in both the developing and the industrialized worlds: label; disavow gene protection (terminator systems; phase out the use of antibiotic resistance markers; agree (with big seed companies to use the plant variety protection system, rather than patents, in developing countries; establish an independently administered fellowship program to train developing-country scientists in crop biotechnology, biosafety, and intellectual property; donate useful technologies to developing countries; agree to share financial rewards from intellectual property rights on varieties such as basmati or jasmine rice with the countries of origin; and

  13. Genetic risk factors for type 1 diabetes

    DEFF Research Database (Denmark)

    Pociot, Flemming; Lernmark, Åke

    2016-01-01

    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 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....... 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...

  14. Retinal vein occlusion: genetic predisposition and systemic risk factors.

    Science.gov (United States)

    Giannaki, Kassiani; Politou, Marianna; Rouvas, Alexandros; Merkouri, Efrossyni; Travlou, Anthi; Theodosiadis, Panayiotis; Gialeraki, Argyri

    2013-04-01

    The role of systemic risk factors (age, smoking, diabetes, arterial hypertension) in the development of retinal vein occlusion (RVO) is well established. However, the association of RVO with genetic predisposition to thrombosis remains poorly understood. The aim of the study was to assess any possible additional effect of genetic predisposition to the already well known 'classical' risk factors of RVO in a cohort of elderly Greek patients. Fifty-one elderly patients with RVO and 51 healthy individuals matched for age and sex were evaluated for systemic risk factors (smoking, diabetes, dyslipidemia, arterial hypertension) and coagulation defects (lupus anticoagulant, natural inhibitors of coagulation). Additionally, genotyping was performed for mutations/polymorphisms involved in haemostasis such as: FV G1691A, FV G4070A, FIIG 20210A, MTHFR C677T and A1298C, PAI-1-675 4G/5G, F XIII exon 2G/T, EPCR A4600G and G4678C. We identified systemic risk factors in the majority of the patients Hypertension (P=0.001), dyslipidemia (P=0.029) and diabetes (P=0.01) are associated with RVO in the majority of the patients. The prevalence of prothrombotic risk factors was not significantly different in the patients with RVO compared to controls. Apart from systemic risk factors, genetic predisposition to thrombosis does not seem to have an important association with RVO in this group of elderly patients.

  15. Genetic, Maternal, and Environmental Risk Factors for Cryptorchidism

    DEFF Research Database (Denmark)

    Barthold, Julia Spencer; Reinhardt, Susanne; Thorup, Jorgen

    2016-01-01

    Unilateral or bilateral cryptorchidism is an isolated anomaly in the majority of cases, with evidence to date suggesting that it is a complex disorder resulting from interactions between genetic and environmental factors. Population, family, and limited genome-wide association data suggest moderate...... or gubernacular response to hormonal stimulation. However, we have yet to determine the degree to which EDCs contribute to cryptorchidism risk in humans, in part due to the varying methodology used in epidemiological and exposure studies. Large populations will be required to define the gene......-environment interactions that predispose to cryptorchidism, in view of multiple small effect genetic susceptibility loci, ubiquitous exposure to mixtures of EDCs, and possible epigenetic effects. The present review provides an update of potential genetic and environmental risk factors for cryptorchidism, and future work...

  16. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    Background--Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and

  17. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND

  18. Associations between genetic risk, functional brain network organization and neuroticism

    NARCIS (Netherlands)

    Servaas, Michelle N.; Geerligs, Linda; Bastiaansen, Jojanneke A.; Renken, Remco J.; Marsman, Jan-Bernard C.; Nolte, Ilja M.; Ormel, Johan; Aleman, Andre; Riese, Harriette

    2017-01-01

    Neuroticism and genetic variation in the serotonin-transporter (SLC6A4) and catechol-O-methyltransferase (COMT) gene are risk factors for psychopathology. Alterations in the functional integration and segregation of neural circuits have recently been found in individuals scoring higher on

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

    African Journals Online (AJOL)

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

  20. Genetically Manipulated Foods: Is the Human Health Risk, Real or

    African Journals Online (AJOL)

    Genetically Manipulated Foods: Is the Human Health Risk, Real or. Imaginary? Wilfred MBACHAM, ScD ... From when Thomas Malthus 'vropounded his theory of world population growth outpacing food production, rich and poor world populations have .... are rarely broken down fast, there is the possibil- ity that antibiotic ...

  1. Risk assessment of genetically modified organisms (GMOs) | Amin ...

    African Journals Online (AJOL)

    Risk assessment is a procedure normally carried out prior to decision-making on the release of genetically modified organisms (GMOs) into the environment. ... biosafety laws of more developed countries and to ensure adequate level of protection for the Malaysian people against any adverse effects of GMOs and products.

  2. Genetic Variants Influencing Lipid Levels and Risk of Dyslipidemia ...

    Indian Academy of Sciences (India)

    Navya

    2017-03-24

    Mar 24, 2017 ... Provincial People's Hospital,32 The First Ring Road West ,Chengdu, Sichuan. 610072,china;;Email:liny042000@aliyun.com. All other author' contacted ..... identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40,161-169. Yan T. T., Yin R. X., Li Q., Huang P., Zeng ...

  3. Occupational and genetic risk factors associated with intervertebral disc disease.

    Science.gov (United States)

    Virtanen, Iita M; Karppinen, Jaro; Taimela, Simo; Ott, Jürg; Barral, Sandra; Kaikkonen, Kaisu; Heikkilä, Olli; Mutanen, Pertti; Noponen, Noora; Männikkö, Minna; Tervonen, Osmo; Natri, Antero; Ala-Kokko, Leena

    2007-05-01

    Cross-sectional epidemiologic study. To evaluate the interaction between known genetic risk factors and whole-body vibration for symptomatic intervertebral disc disease (IDD) in an occupational sample. Risk factors of IDD include, among others, whole-body vibration and heredity. In this study, the importance of a set of known genetic risk factors and whole-body vibration was evaluated in an occupational sample of train engineers and sedentary controls. Eleven variations in 8 genes (COL9A2, COL9A3, COL11A2, IL1A, IL1B, IL6, MMP-3, and VDR) were genotyped in 150 male train engineers with an average of 21-year exposure to whole-body vibration and 61 male paper mill workers with no exposure to vibration. Subjects were classified into IDD-phenotype and asymptomatic groups, based on the latent class analysis. The number of individuals belonging to the IDD-phenotype was significantly higher among train engineers (42% of train engineers vs. 17.5% of sedentary workers; P = 0.005). IL1A -889T allele represented a significant risk factor for the IDD-phenotype both in the single marker allelic association test (P = 0.043) and in the logistic regression analysis (P = 0.01). None of the other allele markers was significantly associated with symptoms when analyzed independently. However, for all the SNP markers considered, whole-body vibration represents a nominally significant risk factor. The results suggest that whole-body vibration is a risk factor for symptomatic IDD. Moreover, whole-body vibration had an additive effect with genetic risk factors increasing the likelihood of belonging to the IDD-phenotype group. Of the independent genetic markers, IL1A -889T allele had strongest association with IDD-phenotype.

  4. Genetic Predisposition to Dyslipidemia and Risk of Preeclampsia.

    Science.gov (United States)

    Spracklen, Cassandra N; Saftlas, Audrey F; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

    2015-07-01

    Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia. Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL-C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04). Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. The Aftershock Risk Index - quantification of aftershock impacts during ongoing strong-seismic sequences

    Science.gov (United States)

    Schaefer, Andreas; Daniell, James; Khazai, Bijan; Wenzel, Friedemann

    2016-04-01

    The occurrence and impact of strong earthquakes often triggers the long-lasting impact of a seismic sequence. Strong earthquakes are generally followed by many aftershocks or even strong subsequently triggered ruptures. The Nepal 2015 earthquake sequence is one of the most recent examples where aftershocks significantly contributed to human and economic losses. In addition, rumours about upcoming mega-earthquakes, false predictions and on-going cycles of aftershocks induced a psychological burden on the society, which caused panic, additional casualties and prevented people from returning to normal life. This study shows the current phase of development of an operationalised aftershock intensity index, which will contribute to the mitigation of aftershock hazard. Hereby, various methods of earthquake forecasting and seismic risk assessments are utilised and an integration of the inherent aftershock intensity is performed. A spatio-temporal analysis of past earthquake clustering provides first-hand data about the nature of aftershock occurrence. Epidemic methods can additionally provide time-dependent variation indices of the cascading effects of aftershock generation. The aftershock hazard is often combined with the potential for significant losses through the vulnerability of structural systems and population. A historical database of aftershock socioeconomic effects from CATDAT has been used in order to calibrate the index based on observed impacts of historical events and their aftershocks. In addition, analytical analysis of cyclic behaviour and fragility functions of various building typologies are explored. The integration of many different probabilistic computation methods will provide a combined index parameter which can then be transformed into an easy-to-read spatio-temporal intensity index. The index provides daily updated information about the probability of the inherent seismic risk of aftershocks by providing a scalable scheme fordifferent aftershock

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

    Science.gov (United States)

    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.

  7. Multiple sclerosis in families: risk factors beyond known genetic polymorphisms.

    Science.gov (United States)

    Akkad, Denis A; Lee, De-Hyung; Bruch, Kathrin; Haghikia, Aiden; Epplen, Jörg T; Hoffjan, Sabine; Linker, Ralf A

    2016-04-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by genome wide association studies and independent replication studies. A weighted genetic risk score (wGRS) was recently established using the identified MS risk loci in order to predict MS outcome including clinical and paraclinical features. Here, we present the results on a family with several affected siblings including a monozygotic triplet. The individuals were genotyped for 57 non-MHC risk loci as well as the HLA DRB1*1501 tagging SNP rs3135388 with subsequent calculation of the wGRS. Additionally, SNP array based analyses for aberrant chromosomal regions were performed for all individuals.

  8. Genetic risk from diagnostic X-ray procedures

    International Nuclear Information System (INIS)

    Stephan, G.

    1980-01-01

    This essay introduces epidemiologic studies concerned with the question whether diagnostic X-ray procedures might be the cause of an increased genetic risk. All studies have selected Down's syndrome (mongolism) as genetic indicator. They indiscriminately present the opinion of the respective author. Approximately one half of the studies conclude that radiation exposure will not influence the spontaneous incidence of Down's syndrome in diagnostics, the other half finds a positive relationship between frequent radiation exposure and the incidence of the syndrome. For various reasons, explained in detail, the results of the studies under discussion are suitable for forming hypotheses, but should not be viewed as providing evidence. (orig.) [de

  9. Micro-social risk factors and genetic predisposition to micro-social risk factors and genetic predisposition to digestive diseases among adolescents living in georgia.

    Science.gov (United States)

    Chikava, M; Bakradze, M; Varsimashvili, M

    2013-02-01

    The purpose of the study was to analyse the genetic predisposition to digestive diseases, micro-social stressors and other risk factors among adolescents and compare them to each other by strength of association with Chronic Digestive Diseases (CDD). One phase epidemiological research was conducted in population of adolescents aged 14-21 years, living in Georgia. The representative contigent - 430 adolescents were selected by the method of simple randomization. The two groups were separated from the research contingent: 84 adolescents with the CDD (the experimental group) and 346 condtionally healthy adolescents (the control group). The degree of relationship between the defined risk factor and CDD among adolescents was studied through case-control study method. Statistical processing of the obtained data was provided through SPSS v.11,5. The risk factors ranking was held according to decrease of OR values. Analysis of micro-social and hereditary risk factors showed that the associations between CDD and the combination of chronic psychological overloads, calculated together, is stronger (OR=15,3 (95% CI: 9,06-37,8)), than with genetic predisposition to digestive diseases (OR=11,5). From chronic psychological overloads, the most strong relationship with CDD have adolescents study overloads (OR=7,1) and conflict situations at the family (OR=6,0), as well as adolescents bad habits (OR=5,14) and unsatisfactory living conditions (OR=3,74). The listed above OR indicies may be used for planning preventive measures, needed for decrease CDD prevalence among adolescents.

  10. Modelling the genetic risk in age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Felix Grassmann

    Full Text Available Late-stage age-related macular degeneration (AMD is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05 than patients aged 75 and above (1.45, 95% CI: 1.36-1.54. Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96 for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population. The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.

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

    Science.gov (United States)

    Shaukat, Uzma; Ismail, Muhammad; Mehmood, Nasir

    2013-01-01

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

  12. The Two Edged Sword; Illinois' Risk Reduction Success Through Managed Retreat And Strong Regulations

    Science.gov (United States)

    Osman, P.

    2017-12-01

    Illinois has the nation's largest inland system of rivers, lakes, and streams. Two thirds of the continental US and two Canadian provinces drain thru Illinois. Although a blessing, these waterways also result in frequent flooding. Historically, Illinois ranked among the top five states in the nation for flood losses. However, using a combination of strong floodplain regulations and proactive flood mitigation programs, Illinois now ranks near the bottom of flood loss states. Following the 1993 flood, the State of Illinois began an aggressive program to remove flood prone structures from the floodplain. Using a combination of state, federal, and local funds, towns like Valmeyer and Grafton have largely been relocated outside of the floodplain. Likewise, in dozens of communities across the state, thousands of structures have been have purchased to create open space in the floodplain. In addition, new structures in the floodplain must meet strict state and local floodplain construction standards. Major floods now routinely pass Illinois unnoticed. Many communities once ravaged by flooding now pass large floods unscathed. Due largely to climate change, flood losses in many areas are evolving. The majority of flood losses in Illinois now occur outside of the mapped floodplain. The State of Illinois has recently completed a detailed analysis of the state's urban flood exposure. Flood risk is changing and methods to address that risk must evolve accordingly. Accurate climate change data on major inland waterways and urban areas remain elusive. This presentation will highlight simple steps any state or community can take to reduce existing flood losses and be better prepared to address changing impacts due to climate change.

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

    Science.gov (United States)

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

    2004-01-01

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

  14. Genetic Predisposition, Nongenetic Risk Factors, and Coronary Infarct

    Science.gov (United States)

    Trichopoulou, Antonia; Yiannakouris, Nikos; Bamia, Christina; Benetou, Vassiliki; Trichopoulos, Dimitrios; Ordovas, Jose M.

    2015-01-01

    Background Using a genetic predisposition score (GPS), additively integrating the associations of 11 polymorphisms with coronary heart disease (CHD), we examined the consequences of the joint presence of a high GPS and nongenetic CHD risk factors. Methods Within the European Prospective Investigation Into Cancer and Nutrition, 202 case patients with medically confirmed incident coronary infarct and 197 control subjects were identified in Greece. Each polymorphism contributed 1 unit (high-risk homozygous), one-half unit (heterozygous), or no units (low-risk homozygous) to the GPS. Odds ratios of coronary infarction for those at high risk because of genetic predisposition and simultaneous presence of an established CHD risk factor were estimated, compared with subjects at low risk, for both GPS and each CHD risk factor. Results The joint presence of a high GPS (≥3.5) and each studied CHD risk factor was in all instances associated with a significantly increased risk of coronary infarction. The odds ratio (95% confidence interval) was 2.62 (1.14–6.02) for ever smoking, 2.88 (1.33–6.24) for hypertension, 3.50 (1.67–7.33) for low high-density lipoprotein (HDL) level, 3.05 (1.53–6.08) for high non-HDL level, and 3.66 (1.75–7.65) for poor adherence to the Mediterranean diet. The odds ratios were always lower and nonsignificant when the GPS was low. There was suggestive evidence for interaction of a high GPS with hypertension (P =.05) and non-HDL cholesterol level (P =.13). Conclusions Genetic predisposition may interact with hypertension and, perhaps, also with the level of non-HDL cholesterol, in the causation of CHD. Genetic predisposition and the other studied exposures seem to have converging effects. Thus, the GPS may identify individuals who could realize disproportional benefits by controlling their hypertension and, possibly, their non-HDL cholesterol level. PMID:18443266

  15. Guidance on the environmental risk assessment of genetically modified plants

    DEFF Research Database (Denmark)

    Bartsch, Detlef; Chueca, Cristina; De-Schrijver, Adinda

    relatives, including plant-to-plant gene transfer ; (2) plant-to-micro-organism gene transfer; (3) interaction of the GM plant with target organisms and (4) interaction of the GM plant with non-target organisms, including criteria for selection of appropriate species and relevant functional groups for risk......This document provides guidance for the environmental risk assessment (ERA) of genetically modified (GM) plants submitted within the framework of Regulation (EC) No. 1829/2003 on GM food and feed or under Directive 2001/18/EC on the deliberate release into the environment of genetically modified...... organisms (GMOs). This document provides guidance for assessing potential effects of GM plants on the environment and the rationales for the data requirements for a comprehensive ERA of GM plants. The ERA should be carried out on a case-by-case basis, following a step-by-step assessment approach...

  16. An overall genetic risk assessment for radiological protection purposes

    International Nuclear Information System (INIS)

    Oftedal, P.; Searle, A.G.

    1980-01-01

    Risks of serious hereditary damage in the first and second generations after low level radiation exposure and at equilibrium were calculated by using a doubling dose of 100 rem (based on experimental work with the mouse) and by considering separately the various categories of genic and chromosomal defect. Prenatal lethality was not included. It is estimated that after the exposure of a population of future parents to a collective dose of 1 million man-rem, about 125 extra cases of serious genetic ill health would appear in children and grandchildren. In all future generations, a total of about 320 cases is expected, provided the population remains of constant size. It is emphasised however, that a number of major assumptions have to be made in order to arrive at any overall genetic risk estimate, so that the confidence limits of these figures are bound to be wide. (author)

  17. PCSK9 genetic variants and risk of type 2 diabetes

    DEFF Research Database (Denmark)

    Schmidt, Amand F; Swerdlow, Daniel I; Holmes, Michael V

    2017-01-01

    diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we...... used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using...... a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL...

  18. Skin barrier and contact allergy: Genetic risk factor analyses

    DEFF Research Database (Denmark)

    Ross-Hansen, Katrine

    2013-01-01

    Background Contact allergy is frequent in the general population and arises from prolonged or repeated skin contact with chemical substances. The environmental risk factor is obvious, yet some studies report on associations between genetic variance and an increased risk of developing contact...... by extracting epidermal proteins from human surgical waste samples and stratum corneum scrapings followed by binding studies using immobilized metal affinity chromatography. Results As suggested by Kaplan-Meier event history analyses, FLG null mutations lowered the age of onset of nickel dermatitis, when ear...

  19. Summary of the BEIR V committee's estimates of genetic risks

    International Nuclear Information System (INIS)

    Grahn, D.

    1990-01-01

    The Committee on the Biological Effects of Ionizing Radiations (BEIR V) was constituted in late 1986 to conduct a comprehensive review of the biological effects of ionizing radiations focusing on information reported since the conclusion of the 1980 BEIR study, and to provide new estimates of the risks of genetic and somatic effects in humans due to low-level exposures of ionizing radiation. The Committee preferred the doubling-dose method of genetic risk estimation over the direct method. Data from animal (mouse) studies provide a median value of 100 to 114 cGy for long-term low dose rate exposure doubling doses. These values are lower than the median from human studies. The BEIR Committee believed that a doubling dose of 100 cGy would be a prudent value leading to conservative estimates. The estimated risks themselves are not much different from those generated by previous BEIR committees, UNSCEAR, and other published estimates. The Committee estimates that between 100 and 200 added cases per million live births will be observed at genetic equilibrium if the population is exposed each generation to a dose of 0.01 Sv (1 rem). Nearly half ware attributed to clinically mild dominant defects, and the balance to congenital abnormalities. (L.L.) (2 tabs.)

  20. Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation.

    Science.gov (United States)

    Weng, Lu-Chen; Preis, Sarah R; Hulme, Olivia L; Larson, Martin G; Choi, Seung Hoan; Wang, Biqi; Trinquart, Ludovic; McManus, David D; Staerk, Laila; Lin, Honghuang; Lunetta, Kathryn L; Ellinor, Patrick T; Benjamin, Emelia J; Lubitz, Steven A

    2018-03-06

    The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4-9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3-55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition ( P <0.001). In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk. © 2018 American Heart Association, Inc.

  1. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors.

    Science.gov (United States)

    Riley, Bronson D; Culver, Julie O; Skrzynia, Cécile; Senter, Leigha A; Peters, June A; Costalas, Josephine W; Callif-Daley, Faith; Grumet, Sherry C; Hunt, Katherine S; Nagy, Rebecca S; McKinnon, Wendy C; Petrucelli, Nancie M; Bennett, Robin L; Trepanier, Angela M

    2012-04-01

    Updated from their original publication in 2004, these cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of counseling at-risk individuals through genetic cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Familial Cancer Risk Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Essential components include the intake, cancer risk assessment, genetic testing for an inherited cancer syndrome, informed consent, disclosure of genetic test results, and psychosocial assessment. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

  2. Cerivastatin, Genetic Variants, and the Risk of Rhabdomyolysis

    Science.gov (United States)

    Marciante, Kristin D.; Durda, Jon P.; Heckbert, Susan R.; Lumley, Thomas; Rice, Ken; McKnight, Barbara; Totah, Rheem A.; Tamraz, Bani; Kroetz, Deanna L.; Fukushima, Hisayo; Kaspera, Rüdiger; Bis, Joshua C.; Glazer, Nicole L.; Li, Guo; Austin, Thomas R.; Taylor, Kent D.; Rotter, Jerome I.; Jaquish, Cashell E.; Kwok, Pui-Yan; Tracy, Russell P.; Psaty, Bruce M.

    2011-01-01

    Objective The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. Methods The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Results Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p rhabdomyolysis (OR: 0.48; 95% CI: 0.36 to 0.63). Conclusion We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin. PMID:21386754

  3. Genetic susceptibility loci, pesticide exposure and prostate cancer risk.

    Directory of Open Access Journals (Sweden)

    Stella Koutros

    Full Text Available Uncovering SNP (single nucleotide polymorphisms-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs and 95% confidence intervals (CIs. Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1 SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44-8.15 (P-interaction= 0.003. Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41 (P-interaction= 0.006. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.

  4. Quantification of genetically modified soya using strong anion exchange chromatography and time-of-flight mass spectrometry.

    Science.gov (United States)

    Chang, Po-Chih; Reddy, P Muralidhar; Ho, Yen-Peng

    2014-09-01

    Stable-isotope dimethyl labeling was applied to the quantification of genetically modified (GM) soya. The herbicide-resistant gene-related protein 5-enolpyruvylshikimate-3-phosphate synthase (CP4 EPSPS) was labeled using a dimethyl labeling reagent, formaldehyde-H2 or -D2. The identification and quantification of CP4 EPSPS was performed using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The CP4 EPSPS protein was separated from high abundance proteins using strong anion exchange chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Then, the tryptic peptides from the samples and reference were labeled with formaldehyde-H2 and formaldehyde-D2, respectively. The two labeled pools were mixed and analyzed using MALDI-MS. The data showed a good correlation between the peak ratio of the H- and D-labeled peptides and the GM soya percentages at 0.5, 1, 3, and 5 %, with R (2) of 0.99. The labeling reagents are readily available. The labeling experiments and the detection procedures are simple. The approach is useful for the quantification of GM soya at a level as low as 0.5 %.

  5. Genetic evidence strongly support an essential role for PfPV1 in intra-erythrocytic growth of P. falciparum.

    Directory of Open Access Journals (Sweden)

    Trang Chu

    Full Text Available Upon invading the host erythrocyte, the human malaria parasite P. falciparum lives and replicates within a membrane bound compartment referred to as the parasitophorous vacuole. Recently, interest in this compartment and its protein content has grown, due to the important roles these play in parasite egress and protein traffic to the host cell. Surprisingly, the function of many proteins within this compartment has not been experimentally addressed. Here, we study the importance of one of these proteins, termed PfPV1, for intra-erythrocytic parasite survival. Despite numerous attempts to inactivate the gene encoding PfPV1, we were unable to recover deletion mutants. Control experiments verified that the pv1 gene locus was per se open for gene targeting experiments, allowing us to exclude technical limitations in our experimental strategy. Our data provide strong genetic evidence that PfPV1 is essential for survival of blood stage P. falciparum, and further highlight the importance of parasitophorous vacuole proteins in this part of the parasite's life cycle.

  6. Benefits and risks associated with genetically modified food products

    Directory of Open Access Journals (Sweden)

    Marta Kramkowska

    2013-09-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  8. Characterizing genetic syndromes involved in cancer and radiogenic cancer risk

    International Nuclear Information System (INIS)

    Unrau, P.; Doerffer, K.

    1998-01-01

    The COG project 2806A (1995), reviewed the On-line Mendelian Inheritance in Man (OMIM) database of genetic syndromes to identify those syndromes, genes, and DNA sequences implicated in some way in the cancer process, and especially in radiogenic cancer risk. The current report describes a recent update of the survey in light of two years of further progress in the Human Genome project, and is intended to supply a comprehensive list of those genetic syndromes, genes, DNA sequences and map locations that define genes likely to be involved in cancer risk. Of the 8203 syndromes in OMIM in 1997 June, 814 are associated, even if marginally, with cancer. Of the 814 syndromes so linked, 672 have been mapped to a chromosome, and 476 have been mapped to a chromosome and had a DNA sequence associated with their messenger RNA (or cDNA) sequences. In addition, 35 syndromes have sequences not associated with map locations, and the remaining 107 have neither been mapped nor sequenced. We supply the list of the various genetic syndromes sorted by chromosome location and by OMIM descriptor, together with all the associated but unmapped and unsequenced syndromes. (author)

  9. Skin barrier and contact allergy: Genetic risk factor analyses

    DEFF Research Database (Denmark)

    Ross-Hansen, Katrine

    2013-01-01

    piercing status was regarded. Nickel patch test readings indicated that proportionally more mutation carriers than wild types had stronger reactions. Epidermally derived filaggrin binds nickel. The GST gene polymorphisms did not associate with contact allergy among adult Danes. The CLDN1 polymorphisms rs......Background Contact allergy is frequent in the general population and arises from prolonged or repeated skin contact with chemical substances. The environmental risk factor is obvious, yet some studies report on associations between genetic variance and an increased risk of developing contact...... allergy. Objectives To evaluate the effect of specific gene polymorphisms on the risk of developing contact allergy by a candidate gene approach. These included polymorphisms in the glutathione S-transferase genes (GSTM1, -T1 and -P1 variants), the claudin-1 gene (CLDN1), and the filaggrin gene (FLG...

  10. Lead, genetic susceptibility, and risk of adult brain tumors.

    Science.gov (United States)

    Rajaraman, Preetha; Stewart, Patricia A; Samet, Jonathan M; Schwartz, Brian S; Linet, Martha S; Zahm, Shelia Hoar; Rothman, Nathaniel; Yeager, Meredith; Fine, Howard A; Black, Peter M; Loeffler, Jay; Shapiro, William R; Selker, Robert G; Inskip, Peter D

    2006-12-01

    Although few etiologic factors for brain tumors have been identified, limited data suggest that lead may increase the risk of brain tumors, particularly meningioma. The ALAD G177C polymorphism affects the toxicokinetics of lead and may confer genetic susceptibility to adverse effects of lead exposure. We examined occupational exposure to lead and risk of brain tumors in a multisite, hospital-based, case-control study of 489 patients with glioma, 197 with meningioma, and 799 non-cancer controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to hospital. ALAD genotype was assessed by a Taqman assay for 355 glioma patients, 151 meningioma patients, and 505 controls. Exposure to lead was estimated using a rigorous questionnaire-based exposure assessment strategy incorporating lead measurement and other occupational data abstracted from published articles and reports. Increased risk of meningioma with occupational lead exposure (estimated by odds ratios and 95% confidence intervals) was most apparent in individuals with the ALAD2 variant allele, for whom risk increased from 1.1 (0.3-4.5) to 5.6 (0.7-45.5) and 12.8 (1.4-120.8) for estimated cumulative lead exposures of 1 to 49 microg/m3-y, 50 to 99 microg/m3-y, and >or=100 microg/m3-y, respectively, compared with unexposed individuals (two-sided P trend = 0.06). This relationship became stronger after excluding occupational lead exposures characterized by a low confidence level or occurring in the 10 years before meningioma diagnosis. Occupational lead exposure was not associated with glioma risk. Although our results indicate that lead may be implicated in meningioma risk in genetically susceptible individuals, these results need to be interpreted with caution given the small numbers of exposed cases with a variant genotype.

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

    Science.gov (United States)

    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.

  12. Woman's Pre-Conception Evaluation: Genetic and Fetal Risk Considerations for Counselling and Informed Choice.

    Science.gov (United States)

    Wilson, R Douglas

    2017-10-11

    To inform reproductive and other health care providers about genetic and fetal risk information to consider during a woman/couples' pre-conception evaluation, including considerations for genetic risk assessment, genetic screening, or testing to allow for improved counselling and informed choice. This genetic information can be used for patient education, planning, and possible pre-conception and/or prenatal testing. This information may allow improved risk assessment for pre-conception counselling for individual patients and their families. PubMed or Medline and the Cochrane Database were searched in May 2017 using appropriate key words ("pre-conception," "genetic disease," "maternal," "family history," "genetic," "health risk," "genetic health surveillance," "prenatal screening," "prenatal diagnosis," "birth defects," and "teratogen"). Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. The benefits for the patient and her family include an increased understanding of relevant genetic risk pre-conception and in early pregnancy, and better pregnancy outcomes as a result of use of the information. The harm includes potential increased anxiety or psychological stress associated with the possibility of identifying genetic risks. The evidence obtained was peer-reviewed by the Genetics Committee of The Society of Obstetricians and Gynaecologists of Canada. Consideration for Care Statements For this review article, the Consideration for Care Statements use the GRADE strength and quality as it is comparable for the clinician and the patient/public user. [GRADE from the Canadian Task Force on Preventive Health Care (www.canadiantaskforce.ca). For clinicians, Strong = The recommendation would apply to most individuals. Formal discussion aids are not likely to be

  13. Molecular genetics and livestock selection. Approaches, opportunities and risks

    International Nuclear Information System (INIS)

    Williams, J.L.

    2005-01-01

    Following domestication, livestock were selected both naturally through adaptation to their environments and by man so that they would fulfil a particular use. As selection methods have become more sophisticated, rapid progress has been made in improving those traits that are easily measured. However, selection has also resulted in decreased diversity. In some cases, improved breeds have replaced local breeds, risking the loss of important survival traits. The advent of molecular genetics provides the opportunity to identify the genes that control particular traits by a gene mapping approach. However, as with selection, the early mapping studies focused on traits that are easy to measure. Where molecular genetics can play a valuable role in livestock production is by providing the means to select effectively for traits that are difficult to measure. Identifying the genes underpinning particular traits requires a population in which these traits are segregating. Fortunately, several experimental populations have been created that have allowed a wide range of traits to be studied. Gene mapping work in these populations has shown that the role of particular genes in controlling variation in a given trait can depend on the genetic background. A second finding is that the most favourable alleles for a trait may in fact. be present in animals that perform poorly for the trait. In the long term, knowledge of -the genes controlling particular traits, and the way they interact with the genetic background, will allow introgression between breeds and the assembly of genotypes that are best suited to particular environments, producing animals with the desired characteristics. If used wisely, this approach will maintain genetic diversity while improving performance over a wide range of desired traits. (author)

  14. The MY09B gene is a strong risk factor for developing refractory Celiac disease

    NARCIS (Netherlands)

    Wolters, Victorien M.; Verbeek, Wieke H. M.; Zhernakova, Alexandra; Onland-Moret, Charlotte; Schreurs, Marco W. J.; Monsuur, Alienke J.; Verduijn, Willem; Wijmenga, Cisca; Mulder, Chris J. J.

    2007-01-01

    Background & Aims: Celiac disease (CD) is associated with HLA-DQ2 and HLA-DQ8 and has been linked to genetic variants in the MY09B gene on chromosome 19. HLA-DQ2 homozygosity is associated with complications of CD such as refractory celiac disease type II (RCD II) and enteropathy-associated T-cell

  15. The plant pathogen Pseudomonas syringae pv. tomato is genetically monomorphic and under strong selection to evade tomato immunity.

    Directory of Open Access Journals (Sweden)

    Rongman Cai

    2011-08-01

    Full Text Available Recently, genome sequencing of many isolates of genetically monomorphic bacterial human pathogens has given new insights into pathogen microevolution and phylogeography. Here, we report a genome-based micro-evolutionary study of a bacterial plant pathogen, Pseudomonas syringae pv. tomato. Only 267 mutations were identified between five sequenced isolates in 3,543,009 nt of analyzed genome sequence, which suggests a recent evolutionary origin of this pathogen. Further analysis with genome-derived markers of 89 world-wide isolates showed that several genotypes exist in North America and in Europe indicating frequent pathogen movement between these world regions. Genome-derived markers and molecular analyses of key pathogen loci important for virulence and motility both suggest ongoing adaptation to the tomato host. A mutational hotspot was found in the type III-secreted effector gene hopM1. These mutations abolish the cell death triggering activity of the full-length protein indicating strong selection for loss of function of this effector, which was previously considered a virulence factor. Two non-synonymous mutations in the flagellin-encoding gene fliC allowed identifying a new microbe associated molecular pattern (MAMP in a region distinct from the known MAMP flg22. Interestingly, the ancestral allele of this MAMP induces a stronger tomato immune response than the derived alleles. The ancestral allele has largely disappeared from today's Pto populations suggesting that flagellin-triggered immunity limits pathogen fitness even in highly virulent pathogens. An additional non-synonymous mutation was identified in flg22 in South American isolates. Therefore, MAMPs are more variable than expected differing even between otherwise almost identical isolates of the same pathogen strain.

  16. Seagrass radiation after Messinian salinity crisis reflected by strong genetic structuring and out-of-Africa scenario (Ruppiaceae.

    Directory of Open Access Journals (Sweden)

    Ludwig Triest

    Full Text Available Many aquatic plant and seagrass species are widespread and the origin of their continent-wide ranges might result from high gene flow levels. The response of species when extending northwards since the Last Glacial Maximum can be opposed to the structuring of their populations that survived glaciation cycles in southern regions. The peri-Mediterranean is a complex series of sea basins, coastlines, islands and river deltas with a unique history since the Messinian Crisis that potentially influenced allopatric processes of aquatic life. We tested whether vast ranges across Europe and the peri-Mediterranean of a global seagrass group (Ruppia species complexes can be explained by either overall high levels of gene flow or vicariance through linking population genetics, phylogeography and shallow phylogenetics. A multigene approach identified haplogroup lineages of two species complexes, of ancient and recent hybrids with most of the diversity residing in the South. High levels of connectivity over long distances were only observed at recently colonized northern ranges and in recently-filled seas following the last glaciation. A strong substructure in the southern Mediterranean explained an isolation-by-distance model across Europe. The oldest lineages of the southern Mediterranean Ruppia dated back to the period between the end of the Messinian and Late Pliocene. An imprint of ancient allopatric origin was left at basin level, including basal African lineages. Thus both vicariance in the South and high levels of connectivity in the North explained vast species ranges. Our findings highlight the need for interpreting global distributions of these seagrass and euryhaline species in the context of their origin and evolutionary significant units for setting up appropriate conservation strategies.

  17. Implications of host genetic variation on the risk and prevalence of infectious diseases transmitted through the environment.

    Science.gov (United States)

    Doeschl-Wilson, Andrea B; Davidson, R; Conington, J; Roughsedge, T; Hutchings, M R; Villanueva, B

    2011-07-01

    Previous studies have shown that host genetic heterogeneity in the response to infectious challenge can affect the emergence risk and the severity of diseases transmitted through direct contact between individuals. However, there is substantial uncertainty about the degree and direction of influence owing to different definitions of genetic variation, most of which are not in line with the current understanding of the genetic architecture of disease traits. Also, the relevance of previous results for diseases transmitted through environmental sources is unclear. In this article a compartmental genetic-epidemiological model was developed to quantify the impact of host genetic diversity on epidemiological characteristics of diseases transmitted through a contaminated environment. The model was parameterized for footrot in sheep. Genetic variation was defined through continuous distributions with varying shape and degree of dispersion for different disease traits. The model predicts a strong impact of genetic heterogeneity on the disease risk and its progression and severity, as well as on observable host phenotypes, when dispersion in key epidemiological parameters is high. The impact of host variation depends on the disease trait for which variation occurs and on environmental conditions affecting pathogen survival. In particular, compared to homogeneous populations with the same average susceptibility, disease risk and severity are substantially higher in populations containing a large proportion of highly susceptible individuals, and the differences are strongest when environmental contamination is low. The implications of our results for the recording and analysis of disease data and for predicting response to selection are discussed.

  18. Genetic risk scores for body fat distribution attenuate weight loss in women during dietary intervention

    DEFF Research Database (Denmark)

    Svendstrup, M; Allin, K H; Sørensen, T I A

    2018-01-01

    suggest that genetic variants influencing body fat distribution attenuate weight loss in women independently on the effect on WHR. The stronger effect of the GRSwomen implies heterogenic effects of the WHRadjBMI variants on weight loss. A strong effect of rs1358980-T in the VEGFA locus suggests......BACKGROUND AND AIM: The well-established link between body fat distribution and metabolic health has been suggested to act through an impact on the remodeling capacity of the adipose tissue. Remodeling of the adipose tissue has been shown to affect body fat distribution and might affect the ability...... to lose weight. We aimed to study the effect of weighted genetic risk scores (GRSs) on weight loss based on single-nucleotide polymorphisms (SNPs) associated with waist-hip-ratio adjusted for body mass index (WHRadjBMI). METHOD: We included 707 participants (533 women and 174 men) from the NUGENOB multi...

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

    Science.gov (United States)

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

    2016-01-01

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

  20. Genetic variation of Lymnaea stagnalis tolerance to copper: A test of selection hypotheses and its relevance for ecological risk assessment

    International Nuclear Information System (INIS)

    Côte, Jessica; Bouétard, Anthony; Pronost, Yannick; Besnard, Anne-Laure; Coke, Maïra; Piquet, Fabien; Caquet, Thierry; Coutellec, Marie-Agnès

    2015-01-01

    The use of standardized monospecific testing to assess the ecological risk of chemicals implicitly relies on the strong assumption that intraspecific variation in sensitivity is negligible or irrelevant in this context. In this study, we investigated genetic variation in copper sensitivity of the freshwater snail Lymnaea stagnalis, using lineages stemming from eight natural populations or strains found to be genetically differentiated at neutral markers. Copper-induced mortality varied widely among populations, as did the estimated daily death rate and time to 50% mortality (LT50). Population genetic divergence in copper sensitivity was compared to neutral differentiation using the Q ST -F ST approach. No evidence for homogenizing selection could be detected. This result demonstrates that species-level extrapolations from single population studies are highly unreliable. The study provides a simple example of how evolutionary principles could be incorporated into ecotoxicity testing in order to refine ecological risk assessment. - Highlights: • Genetic variation in copper tolerance occurs between Lymnaea stagnalis populations. • We used the Q ST -F ST approach to test evolutionary patterns in copper tolerance. • No evidence for uniform selection was found. • Results suggest that extrapolations to the species level are not safe. • A method is proposed to refine ecological risk assessment using genetic parameters. - Genetic variation in copper tolerance occurs in Lymnaea stagnalis. A method is proposed for considering evolutionary parameters in ecological risk assessment

  1. Environmental Risk Assessment of Genetically Modified Organisms (GMOs)

    DEFF Research Database (Denmark)

    Strandberg, B.; Kjær, C.; Hindar, K.

    of genetically modified plants. This chapter describes both the legislation within the EU and the state of the technology (existing and coming cases). Furthermore, a presentation of the ecological concerns discussed in the report, i.e. invasion, introgression and adverse effects on non-target organisms...... for annual plants, trees and fish, respectively, and suggests a structural/hierarchical decision system for information requirements. The latter should aid to eliminate the 'high-risk' products at an early stage and to improve the design of tests at higher tiers. The second section works with specific...... requirements for the ecological risk assessment of long-lived species like tree species and fish. The third and last section characterises the specific conditions and requirements prevailing in the Nordic region. It is recommended that new field releases and applications for marketing are accompanied...

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

    Science.gov (United States)

    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.

  3. Changes to perceptions of the pros and cons of genetic susceptibility testing after APOE genotyping for Alzheimer disease risk

    Science.gov (United States)

    Christensen, Kurt D.; Roberts, J. Scott; Uhlmann, Wendy R.; Green, Robert C.

    2011-01-01

    Purpose Perceptions about the pros and cons of genetic susceptibility testing are among the best predictors of test utilization. How actual testing changes such perceptions has yet to be examined. Methods In a clinical trial, first-degree relatives of patients with Alzheimer disease received genetic risk assessments for Alzheimer disease including APOE disclosure. Participants rated 11 possible benefits associated with genetic testing (pros) and 10 risks or limitations (cons) before genetic risk disclosure and again 12 months afterward. Results Pros were rated higher than cons at baseline (3.53 vs. 1.83, P cons did not change (1.88 vs. 1.83, P = 0.199) except for a three-item discrimination subscale which increased (2.07 vs. 1.92, P = 0.012). Among specific pros and cons, three items related to prevention and treatment changed the most. Conclusion The process of APOE genetic risk assessment for Alzheimer disease sensitizes some to its limitations and the risks of discrimination; however, 1-year after disclosure, test recipients still consider the pros to strongly outweigh the cons. PMID:21270636

  4. Constant, cycling, hot and cold thermal environments: strong effects on mean viability but not on genetic estimates

    DEFF Research Database (Denmark)

    Ketola, Tarmo; Kellermann, Vanessa; Kristensen, Torsten Nygård

    2012-01-01

    and their fluctuations. How species will respond to these changes is uncertain, particularly as there is a lack of studies which compare genetic performances in constant vs. fluctuating environments. In this study, we used a nested full-sib/half-sib breeding design to examine how the genetic variances and heritabilities...

  5. The Expression of Genetic Risk for Aggressive and Non-aggressive Antisocial Behavior is Moderated by Peer Group Norms.

    Science.gov (United States)

    Vitaro, Frank; Brendgen, Mara; Girard, Alain; Boivin, Michel; Dionne, Ginette; Tremblay, Richard E

    2015-07-01

    Numerous studies have shown that aggressive and non-aggressive antisocial behaviors are important precursors of later adjustment problems. There is also strong empirical evidence that both types of antisocial behavior are partially influenced by genetic factors. However, despite its important theoretical and practical implications, no study has examined the question whether environmental factors differentially moderate the expression of genetic influences on the two types of antisocial behavior. Using a genetically informed design based on 266 monozygotic and dizygotic twin pairs, this study examined whether the expression of genetic risk for aggressive and non-aggressive antisocial behavior varies depending on the peer group's injunctive norms (i.e., the degree of acceptability) of each type of antisocial behavior. Self-reported aggressive and non-aggressive antisocial behavior and classroom-based sociometric nominations were collected when participants were 10 years old. Multivariate genetic analyses revealed some common genetic factors influencing both types of antisocial behavior (i.e., general antisocial behavior) as well as genetic influences specific to non-aggressive antisocial behavior. However, genetic influences on general antisocial behavior, as well as specific genetic influences on non-aggressive antisocial behavior, vary depending on the injunctive classroom norms regarding these behaviors. These findings speak to the power of peer group norms in shaping aggressive and non-aggressive antisocial behavior. They also contribute further to understanding the distinctive development of both types of antisocial behavior. Finally, they may have important implications for prevention purposes.

  6. Polygenic Risk for Depression Increases Risk of Ischemic Stroke: From the Stroke Genetics Network Study.

    Science.gov (United States)

    Wassertheil-Smoller, Sylvia; Qi, Qibin; Dave, Tushar; Mitchell, Braxton D; Jackson, Rebecca D; Liu, Simin; Park, Ki; Salinas, Joel; Dunn, Erin C; Leira, Enrique C; Xu, Huichun; Ryan, Kathleen; Smoller, Jordan W

    2018-03-01

    Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. The depression PRS was associated with higher risk of ischemic stroke overall in both European ( P =0.025) and African ancestry ( P =0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry. © 2018 American Heart Association, Inc.

  7. Genetics of Triglycerides and the Risk of Atherosclerosis.

    Science.gov (United States)

    Dron, Jacqueline S; Hegele, Robert A

    2017-07-01

    Plasma triglycerides are routinely measured with a lipid profile, and elevated plasma triglycerides are commonly encountered in the clinic. The confounded nature of this trait, which is correlated with numerous other metabolic perturbations, including depressed high-density lipoprotein cholesterol (HDL-C), has thwarted efforts to directly implicate triglycerides as causal in atherogenesis. Human genetic approaches involving large-scale populations and high-throughput genomic assessment under a Mendelian randomization framework have undertaken to sort out questions of causality. We review recent large-scale meta-analyses of cohorts and population-based sequencing studies designed to address whether common and rare variants in genes whose products are determinants of plasma triglycerides are also associated with clinical cardiovascular endpoints. The studied loci include genes encoding lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and angiopoietin-like proteins 3 and 4, and common polymorphisms identified in genome-wide association studies. Triglyceride-raising variant alleles of these genes showed generally strong associations with clinical cardiovascular endpoints. However, in most cases, a second lipid disturbance-usually depressed HDL-C-was concurrently associated. While the findings collectively shift our understanding towards a potential causal role for triglycerides, we still cannot rule out the possibilities that triglycerides are a component of a joint phenotype with low HDL-C or that they are but markers of deeper causal metabolic disturbances that are not routinely measured in epidemiological-scale genetic studies.

  8. PROLARM: Cancer risk from medical diagnostic exposures is strongly dependent upon patients' prognosis

    International Nuclear Information System (INIS)

    Eschner, Wolfgang; Schmidt, Matthias; Dietlein, Markus; Schicha, Harald

    2008-01-01

    Full text: Purpose: a) To evaluate the impact of the reduced life expectancy of patients (compared to a non-patient group with same age distribution) on their risk of developing cancer from the diagnostic use of radiation. b) To find an approximation to such reduction in risk which depends only on the patient's age, a, and his life expectancy, but is independent of the choice of values for the baseline risk of cancer incidence, m(a), and the enhanced relative risk ERR(a) from radiation exposure. Method: The lifetime attributable risk LAR (of a radiation-induced malignancy to manifest itself) is a function of age at exposure, e, and given by integrating over attained age, a, the product of ERR(a), baseline cancer risk m(a) and the relative probability of surviving to age a, S'(a,e). We define a 'prognosis-based LAR modifier' (PROLARM) as the ratio of risks for non-patient, LAR(a), and patient, LAR p (a), a dimensionless quantity that gives a measure of reduction of LAR due to the patient's prognosis. With the survival of the patient group, S p ' (a,e), and for any choice of fitted function for ERR(a) like those used in BEIR VII report, PROLARM ≥∫d'(a,e) da/∫S p '(a,e) da, i.e. the ratio of the survival integrals gives a lower (thus conservative) estimate of the reduction in risk. Results: The method was applied to n=4285 patients with metastatic breast cancer for whom survival as a function of age at metastasis was known. Figure shows that LAR is decreased significantly for all ages at exposure. At younger ages, this decrease is more pronounced (PROLARM ≥ 20 for e ≤ 65). Example: using ERR values of BEIR VII, the LAR due to 10 mSv effective dose at age a = 50 would drop from 1.2 E-3 for non-patient to 4.3E-5 for a patient, i.e. by a factor (PROLARM) of 29. Using only survival data, that factor is 27 (but no LAR can be computed). In other words: 10 mSv for a patient correspond risk-wise to 0.4 mSv for non-patient. The method can be applied to any pathology

  9. A rapid, strong, and convergent genetic response to urban habitat fragmentation in four divergent and widespread vertebrates

    Science.gov (United States)

    Delaney, Kathleen Semple; Riley, Seth P.D.; Fisher, Robert N.

    2010-01-01

    Background: Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding. Methodology/Principal Findings: We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation. Conclusions/Significance: Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix.

  10. A rapid, strong, and convergent genetic response to urban habitat fragmentation in four divergent and widespread vertebrates.

    Directory of Open Access Journals (Sweden)

    Kathleen Semple Delaney

    2010-09-01

    Full Text Available Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding.We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation.Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix.

  11. A rapid, strong, and convergent genetic response to urban habitat fragmentation in four divergent and widespread vertebrates.

    Science.gov (United States)

    Delaney, Kathleen Semple; Riley, Seth P D; Fisher, Robert N

    2010-09-16

    Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding. We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation. Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix.

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

    Directory of Open Access Journals (Sweden)

    Haoyan Chen

    2011-04-01

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

  13. Empty creditors and strong shareholders: The real effects of credit risk trading. Second draft

    OpenAIRE

    Colonnello, Stefano; Efing, Matthias; Zucchi, Francesca

    2016-01-01

    Credit derivatives give creditors the possibility to transfer debt cash flow rights to other market participants while retaining control rights. We use the market for credit default swaps (CDSs) as a laboratory to show that the real effects of such debt unbundling crucially hinge on shareholder bargaining power. We find that creditors buy more CDS protection when facing strong shareholders to secure themselves a valuable outside option in distressed renegotiations. After the start of CDS trad...

  14. Genetic risk factors for ovarian cancer and their role for endometriosis risk.

    Science.gov (United States)

    Burghaus, Stefanie; Fasching, Peter A; Häberle, Lothar; Rübner, Matthias; Büchner, Kathrin; Blum, Simon; Engel, Anne; Ekici, Arif B; Hartmann, Arndt; Hein, Alexander; Beckmann, Matthias W; Renner, Stefan P

    2017-04-01

    Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions. In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray™ analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors. rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis. As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    S. Ravi Rajan

    2012-01-01

    Full Text Available 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.

  17. <strong>Application of risk perception and communication strategies to manage disease outbreaks of coastal shrimp farming in developing countriesstrong>

    DEFF Research Database (Denmark)

    Ahsan, Dewan

    2008-01-01

      Risk and uncertainty are very common issues in coastal shrimp industry like in any other business. A variety of risks are associated in shrimp farming like, production risks, technical risks, economical risks and disease of shrimp. However, risk of economic losses due to shrimp mortality (for...... diseases) is the major concern of shrimp producers of developing countries like Bangladesh, India, Thailand, China and many other countries. The risk of disease outbreaks in shrimp farms could be effectively prevented and managed by early identification of disease occurrence and by rapid communication...

  18. Risk Perception and Psychological Distress in Genetic Counselling for Hereditary Breast and/or Ovarian Cancer.

    Science.gov (United States)

    Cicero, G; De Luca, R; Dorangricchia, P; Lo Coco, G; Guarnaccia, C; Fanale, D; Calò, V; Russo, A

    2017-10-01

    Oncological Genetic Counselling (CGO) allows the identification of a genetic component that increases the risk of developing a cancer. Individuals' psychological reactions are influenced by both the content of the received information and the subjective perception of their own risk of becoming ill or being a carrier of a genetic mutation. This study included 120 participants who underwent genetic counselling for breast and/or ovarian cancer. The aim of the study was to examine the relation between their cancer risk perception and the genetic risk during CGO before receiving genetic test results, considering the influence of some psychological variables, in particular distress, anxiety and depression. Participants completed the following tools during a psychological interview: a socio-demographic form, Cancer Risk Perception (CRP) and Genetic Risk Perception (GRP), Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer (DT). The data seem to confirm our hypothesis. Positive and significant correlations were found between the observed variables. Moreover, genetic risk perception determined an increase in depressive symptomatology and cancer risk perception led to an increase in anxious symptomatology, specifically in participants during cancer treatment. The present results suggest the importance of assessing genetic and cancer risk perception in individuals who undergo CGO, to identify those who are at risk of a decrease in psychological well-being and of developing greater psychological distress.

  19. Making sense of risk diagnosis in case of prenatal and reproductive genetic counselling for neuromuscular diseases.

    Science.gov (United States)

    Zaccaro, Antonella; Freda, Maria Francesca

    2014-03-01

    This study explored the processes of significance about the risk communication in prenatal/preconception setting within 1 month to the end of genetic counselling intervention. Participants were all attending a programme of Cardiomyology and Medical Genetics in Naples, Italy, for the first time. Transcripts of 18 semi-structured interviews were analysed using interpretative phenomenological analysis. Themes arising included the following: the familiar outcomes of genetic counselling, the risk representation and the impacts on decision-making. The findings suggest the significance of the experience of genetic risk and the implications for the support of individuals and their family after the conclusion of the genetic counselling intervention.

  20. Genetic risk prediction and neurobiological understanding of alcoholism.

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  2. Gross proteinuria is a strong risk predictor for cardiovascular mortality in Brazilian type 2 diabetic patients

    OpenAIRE

    Cardoso, C.R.L.; Salles, G.F.

    2008-01-01

    Increased proteinuria is recognized as a risk predictor for all-cause and cardiovascular mortality in diabetic patients; however, no study has evaluated these relationships in Brazilian patients. The aim of this study was to investigate the prognostic value of gross proteinuria for all-cause and cardiovascular mortalities and for cardiovascular morbidity in a cohort study of 471 type 2 diabetic individuals followed for up to 7 years. Several clinical, laboratory and electrocardiographic varia...

  3. Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies.

    Science.gov (United States)

    Hüls, Anke; Krämer, Ursula; Carlsten, Christopher; Schikowski, Tamara; Ickstadt, Katja; Schwender, Holger

    2017-12-16

    Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects ("GRS-marginal-internal") are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect. In this paper, we present a weighting approach for such predominant interactions ("GRS-interaction-training") in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS-marginal-internal approach and to GRS with external weights. Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS-interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations). When appropriate external weights are unavailable, we

  4. Genetic risk profiles for a childhood with severe overweight.

    Science.gov (United States)

    González, J R; Estévez, M N; Giralt, P S; Cáceres, A; Pérez, L M L; González-Carpio, M; Ballester, F; Sunyer, J; Rodríguez-López, R

    2014-08-01

    The objective of this study was the description of a valid genetic risk score (GRS) to predict individuals with high susceptibility to childhood overweight by their genetic profiles. Case-control study including a group of children with high-risk familial predisposition to morbid obesity. Birth cohort from general population constituted the validation sample. For the discovery sample, 218 children with non-syndromic obesity and 190 control individuals were included. The validation sample was 653 children from two birth cohorts belonging to the INMA (Infancia y Medio Ambiente [Environment and Childhood] )project. 109 SNPs located in the genes FTO, SEC16B, BDNF, ETV5, SH2B1, GNPDA2, LYPLAL1, MSRA, TFAP2, KCTD15, MTCH2 and NEGR1, previously reported in association to body mass index (BMI) were analysed. For the validation sample, association between genome-wide data and BMI measurements between 3.5 and 5 years of age, were evaluated. The GRS includes six SNPs in the genes FTO, TFAP2B, SEC16B, ETV5 and SH2B1. The score distribution differs among cases and controls (P = 9.2 × 10(-14) ) showing a significant linear association with obesity (odds ratio [OR] per allele = 1.69; confidence interval [CI] 95% = 1.46-1.97; P = 4.3 × 10(-1) and area under the receiver operating characteristic curve [AUC] = 0.727; CI 95% = 0.676-0.778). The results were validated by the INMA cohort (OR per allele = 1.23 CI 95% = 1.03-1.48 and AUC = 0.601 CI 95% = 0.522-0.680). The use of our proposed genetic score provides useful information to determine those children who are susceptible to obesity. To improve the efficiency of clinical prevention and treatment of obesity, it is essential to design individualized based protocols in advance knowledge of the molecular basis of inherited susceptibility. © 2013 The Authors. Pediatric Obesity © 2013 International Association for the Study of Obesity.

  5. The Impact of KIR Polymorphism on the Risk of Developing Cancer: Not as Strong as Imagined?

    Science.gov (United States)

    Augusto, Danillo G.

    2016-01-01

    The polymorphism of killer cell immunoglobulin-like receptors (KIR) has been associated with several diseases, including infection, autoimmunity and cancer. KIR molecules are a family of receptors expressed on the surface of natural killer cells (NK), frontline defense of innate immunity against microorganisms and neoplastic cells. Some studies have shown conflicting results concerning the role that KIR polymorphism plays in tumor susceptibility, particularly in leukemia and lymphoma. Interestingly, the presence of HLA ligands is sometimes strongly associated with several types of cancer and apparently is not related with their interaction with KIR. This manuscript briefly reviews the uncommon polymorphism of KIR and critically summarizes the recent findings with regards of the importance of KIR variation for cancer susceptibility. PMID:27446203

  6. Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks.

    Science.gov (United States)

    Sherva, Richard; Wang, Qian; Kranzler, Henry; Zhao, Hongyu; Koesterer, Ryan; Herman, Aryeh; Farrer, Lindsay A; Gelernter, Joel

    2016-05-01

    Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated. To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics. This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015. Criterion count for DSM-IV CAD. Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54, P = 4.32 × 10-10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54, P = 1.33 × 10-9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (β = 0.29, P = 2.13 × 10-8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and

  7. Quantitative autistic trait measurements index background genetic risk for ASD in Hispanic families.

    Science.gov (United States)

    Page, Joshua; Constantino, John Nicholas; Zambrana, Katherine; Martin, Eden; Tunc, Ilker; Zhang, Yi; Abbacchi, Anna; Messinger, Daniel

    2016-01-01

    Recent studies have indicated that quantitative autistic traits (QATs) of parents reflect inherited liabilities that may index background genetic risk for clinical autism spectrum disorder (ASD) in their offspring. Moreover, preferential mating for QATs has been observed as a potential factor in concentrating autistic liabilities in some families across generations. Heretofore, intergenerational studies of QATs have focused almost exclusively on Caucasian populations-the present study explored these phenomena in a well-characterized Hispanic population. The present study examined QAT scores in siblings and parents of 83 Hispanic probands meeting research diagnostic criteria for ASD, and 64 non-ASD controls, using the Social Responsiveness Scale-2 (SRS-2). Ancestry of the probands was characterized by genotype, using information from 541,929 single nucleotide polymorphic markers. In families of Hispanic children with an ASD diagnosis, the pattern of quantitative trait correlations observed between ASD-affected children and their first-degree relatives (ICCs on the order of 0.20), between unaffected first-degree relatives in ASD-affected families (sibling/mother ICC = 0.36; sibling/father ICC = 0.53), and between spouses (mother/father ICC = 0.48) were in keeping with the influence of transmitted background genetic risk and strong preferential mating for variation in quantitative autistic trait burden. Results from analysis of ancestry-informative genetic markers among probands in this sample were consistent with that from other Hispanic populations. Quantitative autistic traits represent measurable indices of inherited liability to ASD in Hispanic families. The accumulation of autistic traits occurs within generations, between spouses, and across generations, among Hispanic families affected by ASD. The occurrence of preferential mating for QATs-the magnitude of which may vary across cultures-constitutes a mechanism by which background genetic liability

  8. The 8.1 ancestral MHC haplotype is strongly associated with colorectal cancer risk.

    Science.gov (United States)

    Tóth, Eva Katalin; Kocsis, Judit; Madaras, Balázs; Bíró, Adrienn; Pocsai, Zsuzsa; Fust, George; Blaskó, Bernadett; Karádi, István; Adány, Róza; Laki, Judit

    2007-10-15

    Many recent data indicate that some alleles encoded in the central major histocompatibility complex (MHC) region (Class III) of short arm of chromosome 6 may modify the risk of cancer development. Therefore we determined 4 single nucleotide polymorphisms (SNPs) of this region (TNF-alpha -308 G > A, RAGE -429 T > C, HSP70-2 -1267 A > G, LTA 252 A > G) in genomic DNA samples from 183 Hungarian patients with colorectal cancer and 141 age matched control subjects representing the Hungarian population of the same age and gender. No significant differences were found in either SNP tested. When, however, three- or four-locus haplotypes consisting of known constituents of the so-called 8.1 ancestral haplotype (8.1AH) were considered, marked differences were observed. Frequency of TNF-alpha -308A, RAGE -429C, HSP70-2 -1267G, LTA 252G (8.1AH) haplotype was significantly (p = 0.006) more frequent (19.1%) among patients than in the controls (7.7%). Age- and gender-adjusted ratio of the 8.1AH carriers vs. non-carriers to have colorectal cancer was 2.514 (1.130-5.594). This risk was higher in cancer-indicate that carriers of the 8.1AH, encoding for an altered immune response and known to be associated with alterations of several immune functions and autoimmune diseases have an increased risk for some cancer types. These findings may contribute to better understanding how the defense mechanisms against tumors could be enhanced/strengthened. (c) 2007 Wiley-Liss, Inc.

  9. Influence of the larval phase on connectivity: strong differences in the genetic structure of brooders and broadcasters in the Ophioderma longicauda species complex.

    Science.gov (United States)

    Weber, A A-T; Mérigot, B; Valière, S; Chenuil, A

    2015-12-01

    Closely related species with divergent life history traits are excellent models to infer the role of such traits in genetic diversity and connectivity. Ophioderma longicauda is a brittle star species complex composed of different genetic clusters, including brooders and broadcasters. These species diverged very recently and some of them are sympatric and ecologically syntopic, making them particularly suitable to study the consequences of their trait differences. At the scale of the geographic distribution of the broadcasters (Mediterranean Sea and northeastern Atlantic), we sequenced the mitochondrial marker COI and genotyped an intron (i51) for 788 individuals. In addition, we sequenced 10 nuclear loci newly developed from transcriptome sequences, for six sympatric populations of brooders and broadcasters from Greece. At the large scale, we found a high genetic structure within the brooders (COI: 0.07 lecithotrophic larval stage allows on average a 50-fold increase in migration rates, a 280-fold increase in effective size and a threefold to fourfold increase in genetic diversity. Our work, investigating complementary genetic markers on sympatric and syntopic taxa, highlights the strong impact of the larval phase on connectivity and genetic diversity. © 2015 John Wiley & Sons Ltd.

  10. No Genetic Diversity at Molecular Markers and Strong Phenotypic Plasticity in Populations of Ranunculus nodiflorus, an Endangered Plant Species in France

    Science.gov (United States)

    Noel, Florence; Machon, Nathalie; Porcher, Emmanuelle

    2007-01-01

    Background and Aims Although conservation biology has long focused on population dynamics and genetics, phenotypic plasticity is likely to play a significant role in population viability. Here, an investigation is made into the relative contribution of genetic diversity and phenotypic plasticity to the phenotypic variation in natural populations of Ranunculus nodiflorus, a rare annual plant inhabiting temporary puddles in the Fontainebleau forest (Paris region, France) and exhibiting metapopulation dynamics. Methods The genetic diversity and phenotypic plasticity of quantitative traits (morphological and fitness components) were measured in five populations, using a combination of field measurements, common garden experiments and genotyping at microsatellite loci. Key Results It is shown that populations exhibit almost undetectable genetic diversity at molecular markers, and that the variation in quantitative traits observed among populations is due to a high level of phenotypic plasticity. Despite the lack of genetic diversity, the natural population of R. nodiflorus exhibits large population sizes and does not appear threatened by extinction; this may be attributable to large phenotypic plasticity, enabling the production of numerous seeds under a wide range of environmental conditions. Conclusions Efficient conservation of the populations can only be based on habitat management, to favour the maintenance of microenvironmental variation and the resulting strong phenotypic plasticity. In contrast, classical actions aiming to improve genetic diversity are useless in the present case. PMID:17468109

  11. Genetic and other risk factors for suicidal ideation and the relationship with depression.

    Science.gov (United States)

    Dutta, R; Ball, H A; Siribaddana, S H; Sumathipala, A; Samaraweera, S; McGuffin, P; Hotopf, M

    2017-10-01

    There is a genetic contribution to the risk of suicide, but sparse prior research on the genetics of suicidal ideation. Active and passive suicidal ideation were assessed in a Sri Lankan population-based twin registry (n = 3906 twins) and a matched non-twin sample (n = 2016). Logistic regression models were used to examine associations with socio-demographic factors, environmental exposures and psychiatric symptoms. The heritability of suicidal ideation was assessed using structural equation modelling. The lifetime prevalence of any suicidal ideation was 13.0% (11.7-14.3%) for men; 21.8% (20.3-23.2%) for women, with no significant difference between twins and non-twins. Factors that predicted suicidal ideation included female gender, termination of marital relationship, low education level, urban residence, losing a parent whilst young, low standard of living and stressful life events in the preceding 12 months. Suicidal ideation was strongly associated with depression, but also with abnormal fatigue and alcohol and tobacco use. The best fitting structural equation model indicated a substantial contribution from genetic factors (57%; CI 47-66) and from non-shared environmental factors (43%; CI 34-53) in both men and women. In women this genetic component was largely mediated through depression, but in men there was a significant heritable component to suicidal ideation that was independent of depression. These are the first results to show a genetic contribution to suicidal ideation that is independent of depression outside of a high-income country. These phenomena may be generalizable, because previous research highlights similarities between the aetiology of mental disorders in Sri Lanka and higher-income countries.

  12. Geoethical suggestions for reducing risk of next (not only strong) earthquakes

    Science.gov (United States)

    Nemec, Vaclav

    2013-04-01

    Three relatively recent examples of earthquakes can be used as a background for suggesting geoethical views into any prediction accompanied by a risk analysis. ĹAquila earthquake (Italy - 2009): ĹAquila was largely destroyed by earthquakes in 1315, 1319, 1452, 1461, 1501, 1646, 1703 (until that time altogether about 3000 victims) and 1786 (about 6000 victims of this event only). The city was rebuilt and remained stable until October 2008, when tremors began again. From January 1 through April 5, 2009, additional 304 tremors were reported. When after measuring increased levels of radon emitted from the ground a local citizen (for many years working for the Italian National Institute of Astrophysics) predicted a major earthquake on Italian television, he was accused of being alarmist. Italy's National Commission for Prediction and Prevention of Major Risks met in L'Aquila for one hour on March 31, 2009, without really evaluating and characterising the risks that were present. On April 6 a 6.3 magnitude earthquake struck Aquila and nearby towns, killing 309 people and injuring more than 1,500. The quake also destroyed roughly 20,000 buildings, temporarily displacing another 65,000 people. In July 2010, prosecutor Fabio Picuti charged the Commission members with manslaughter and negligence for failing to warn the public of the impending risk. Many international organizations joined the chorus of criticism wrongly interpreting the accusation and sentence at the first stage as a problem of impossibility to predict earthquakes. - The Eyjafjallajokull volcano eruption (Iceland - 2010) is a reminder that in our globalized, interconnected world because of the increased sensibility of the new technology even a relatively small natural disaster may cause unexpected range of problems. - Earthquake and tsunami (Japan - 2011) - the most powerful known earthquake ever to have hit Japan on March 11. Whereas the proper earthquake with the magnitude of 9.0 has caused minimum of

  13. Why Are High Altitude Natives So Strong at High Altitude? Nature vs. Nurture: Genetic Factors vs. Growth and Development.

    Science.gov (United States)

    Brutsaert, Tom

    Among high-altitude natives there is evidence of a general hypoxia tolerance leading to enhanced performance and/or increased capacity in several important domains. These domains likely include an enhanced physical work capacity, an enhanced reproductive capacity, and an ability to resist several common pathologies of chronic high-altitude exposure. The "strength" of the high-altitude native in this regard may have both a developmental and a genetic basis, although there is better evidence for the former (developmental effects) than for the latter. For example, early-life hypoxia exposure clearly results in lung growth and remodeling leading to an increased O2 diffusing capacity in adulthood. Genetic research has yet to reveal a population genetic basis for enhanced capacity in high-altitude natives, but several traits are clearly under genetic control in Andean and Tibetan populations e.g., resting and exercise arterial O2 saturation (SaO2). This chapter reviews the effects of nature and nurture on traits that are relevant to the process of gas exchange, including pulmonary volumes and diffusion capacity, the maximal oxygen consumption (VO2max), the SaO2, and the alveolar-arterial oxygen partial pressure difference (A-aDO2) during exercise.

  14. Strong genetic structure among coral populations within a conservation priority region, the Bird's Head Seascape (Papua, Indonesia

    Directory of Open Access Journals (Sweden)

    Craig John Starger

    2015-11-01

    Full Text Available Marine Protected Areas (MPAs are widely considered to be one of the best strategies available for protecting species diversity and ecosystem processes in marine environments. While data on connectivity and genetic structure of marine populations are critical to designing appropriately sized and spaced networks of MPAs, such data are rarely available. This study examines genetic structure in reef-building corals from Papua and West Papua, Indonesia, one of the most biodiverse and least disturbed coral reef regions in the world. We focused on two common reef-building corals, Pocillopora damicornis (Linnaeus 1758 and Seriatopora hystrix (family: Pocilloporidae, from three regions under different management regimes: Teluk Cenderawasih, Raja Ampat, and southwest Papua. Analyses of molecular variance, assignment tests, and genetical bandwidth mapping based on microsatellite variation revealed significant genetic structure in both species, although there were no clear regional filters to gene flow among regions. Overall, P. damicornis populations were less structured (FST = 0.139, p < 0.00001 than S. hystrix (FST = 0.357, p < 0.00001. Despite occurring in one of the most pristine marine habitats in Indonesia, populations of both species showed evidence of recent declines. Furthermore, exclusion of individual populations from connectivity analyses resulted in marked increases in self-recruitment. Maintaining connectivity within and among regions of Eastern Indonesia will require coral conservation on the local scales and regional networks of MPAs. 

  15. Strong population genetic structuring in an annual fish, Nothobranchius furzeri, suggests multiple savannah refugia in southern Mozambique

    Czech Academy of Sciences Publication Activity Database

    Bartáková, V.; Reichard, M.; Janko, Karel; Polačik, M.; Blažek, R.; Reichwald, K.; Cellerino, A.; Bryja, J.

    2013-01-01

    Roč. 13, č. 196 (2013), s. 1-15 ISSN 1471-2148 Institutional support: RVO:67985904 Keywords : temporary pool * pyhlogeography * population genetics Subject RIV: EG - Zoology Impact factor: 3.407, year: 2013 http://www.biomedcentral.com/1471-2148/13/196

  16. Population Genetics of the São Tomé Caecilian (Gymnophiona: Dermophiidae: Schistometopum thomense) Reveals Strong Geographic Structuring

    Science.gov (United States)

    Stoelting, Ricka E.; Measey, G. John; Drewes, Robert C.

    2014-01-01

    Islands provide exciting opportunities for exploring ecological and evolutionary mechanisms. The oceanic island of São Tomé in the Gulf of Guinea exhibits high diversity of fauna including the endemic caecilian amphibian, Schistometopum thomense. Variation in pigmentation, morphology and size of this taxon over its c. 45 km island range is extreme, motivating a number of taxonomic, ecological, and evolutionary hypotheses to explain the observed diversity. We conducted a population genetic study of S. thomense using partial sequences of two mitochondrial DNA genes (ND4 and 16S), together with morphological examination, to address competing hypotheses of taxonomic or clinal variation. Using Bayesian phylogenetic analysis and Spatial Analysis of Molecular Variance, we found evidence of four geographic clades, whose range and approximated age (c. 253 Kya – 27 Kya) are consistent with the spread and age of recent volcanic flows. These clades explained 90% of variation in ND4 (φCT = 0.892), and diverged by 4.3% minimum pairwise distance at the deepest node. Most notably, using Mismatch Distributions and Mantel Tests, we identified a zone of population admixture that dissected the island. In the northern clade, we found evidence of recent population expansion (Fu's Fs = −13.08 and Tajima's D = −1.80) and limited dispersal (Mantel correlation coefficient = 0.36, p = 0.01). Color assignment to clades was not absolute. Paired with multinomial regression of chromatic data, our analyses suggested that the genetic groups and a latitudinal gradient together describe variation in color of S. thomense. We propose that volcanism and limited dispersal ability are the likely proximal causes of the observed genetic structure. This is the first population genetic study of any caecilian and demonstrates that these animals have deep genetic divisions over very small areas in accordance with previous speculations of low dispersal abilities. PMID:25171066

  17. Genetic polymorphisms in DPF3 associated with risk of breast cancer and lymph node metastases

    Directory of Open Access Journals (Sweden)

    Hoyal Carolyn R

    2005-08-01

    Full Text Available Abstract Background Several studies have identified rare genetic variations responsible for many cases of familial breast cancer but their contribution to total breast cancer incidence is relatively small. More common genetic variations with low penetrance have been postulated to account for a higher proportion of the population risk of breast cancer. Methods and Results In an effort to identify genes that influence non-familial breast cancer risk, we tested over 25,000 single nucleotide polymorphisms (SNPs located within approximately 14,000 genes in a large-scale case-control study in 254 German women with breast cancer and 268 age-matched women without malignant disease. We identified a marker on chromosome 14q24.3-q31.1 that was marginally associated with breast cancer status (OR = 1.5, P = 0.07. Genotypes for this SNP were also significantly associated with indicators of breast cancer severity, including presence of lymph node metastases (P = 0.006 and earlier age of onset (P = 0.01. The association with breast cancer status was replicated in two independent samples (OR = 1.35, P = 0.05. High-density association fine mapping showed that the association spanned about 80 kb of the zinc-finger gene DPF3 (also known as CERD4. One SNP in intron 1 was found to be more strongly associated with breast cancer status in all three sample collections (OR = 1.6, P = 0.003 as well as with increased lymph node metastases (P = 0.01 and tumor size (P = 0.01. Conclusion Polymorphisms in the 5' region of DPF3 were associated with increased risk of breast cancer development, lymph node metastases, age of onset, and tumor size in women of European ancestry. This large-scale association study suggests that genetic variation in DPF3 contributes to breast cancer susceptibility and severity.

  18. Kalirin: a novel genetic risk factor for ischemic stroke.

    Science.gov (United States)

    Krug, Tiago; Manso, Helena; Gouveia, Liliana; Sobral, João; Xavier, Joana M; Albergaria, Isabel; Gaspar, Gisela; Correia, Manuel; Viana-Baptista, Miguel; Simões, Rita Moiron; Pinto, Amélia Nogueira; Taipa, Ricardo; Ferreira, Carla; Fontes, João Ramalho; Silva, Mário Rui; Gabriel, João Paulo; Matos, Ilda; Lopes, Gabriela; Ferro, José M; Vicente, Astrid M; Oliveira, Sofia A

    2010-03-01

    Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.

  19. A genetic risk score predicts cardiovascular events in patients with stable coronary artery disease

    DEFF Research Database (Denmark)

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

    2017-01-01

    BACKGROUND: Genetic risk scores (GRSs) may predict cardiovascular risk in community-based populations. However, studies investigating the association with recurrent cardiovascular events in patients with established coronary artery disease (CAD) are conflicting. METHODS: We genotyped 879 patients...

  20. Identification of Hotspots of Genetic Risk for Type 2 Diabetes Using GIS Methods

    Science.gov (United States)

    BACKGROUND: Having the ability to scan the entire country for potential "hotspots" with increased risk of developing chronic diseases due to various environmental, demographic, and genetic susceptibility factors may inform risk management decisions and enable better env...

  1. Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

    Science.gov (United States)

    Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

    2017-10-01

    Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

  2. Chronic arsenic exposure and risk of carotid artery disease: The Strong Heart Study.

    Science.gov (United States)

    Mateen, Farrah J; Grau-Perez, Maria; Pollak, Jonathan S; Moon, Katherine A; Howard, Barbara V; Umans, Jason G; Best, Lyle G; Francesconi, Kevin A; Goessler, Walter; Crainiceanu, Ciprian; Guallar, Eliseo; Devereux, Richard B; Roman, Mary J; Navas-Acien, Ana

    2017-08-01

    Inorganic arsenic exposure from naturally contaminated groundwater is related to vascular disease. No prospective studies have evaluated the association between arsenic and carotid atherosclerosis at low-moderate levels. We examined the association of long-term, low-moderate inorganic arsenic exposure with carotid arterial disease. American Indians, 45-74 years old, in Arizona, Oklahoma, and North and South Dakota had arsenic concentrations (sum of inorganic and methylated species, μg/g urine creatinine) measured from baseline urine samples (1989-1991). Carotid artery ultrasound was performed in 1998-1999. Vascular disease was assessed by the carotid intima media thickness (CIMT), the presence of atherosclerotic plaque in the carotid, and by the number of segments containing plaque (plaque score). 2402 participants (mean age 55.3 years, 63.1% female, mean body mass index 31.0kg/m 2 , diabetes 45.7%, hypertension 34.2%) had a median (interquintile range) urine arsenic concentration of 9.2 (5.00, 17.06) µg/g creatinine. The mean CIMT was 0.75mm. 64.7% had carotid artery plaque (3% with >50% stenosis). In fully adjusted models comparing participants in the 80th vs. 20th percentile in arsenic concentrations, the mean difference in CIMT was 0.01 (95% confidence interval (95%CI): 0.00, 0.02) mm, the relative risk of plaque presence was 1.04 (95%CI: 0.99, 1.09), and the geometric mean ratio of plaque score was 1.05 (95%CI: 1.01, 1.09). Urine arsenic was positively associated with CIMT and increased plaque score later in life although the association was small. The relationship between urinary arsenic and the presence of plaque was not statistically significant when adjusted for other risk factors. Arsenic exposure may play a role in increasing the severity of carotid vascular disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Environmental and genetic risk factors for eating disorders: what the clinician needs to know.

    Science.gov (United States)

    Mazzeo, Suzanne E; Bulik, Cynthia M

    2009-01-01

    Patients and families often are aware of research on genetic factors influencing eating disorders. Accurate interpretations of research on environmental and genetic risk factors can be empowering to patients and families; however, misinterpretations could prove detrimental. Clinicians who are not versed in genetic research may believe they are ill prepared to discuss the nuances of genetic research with patients and families. In this article the authors discuss what is known about genetic and environmental risk factors with an emphasis on gene-environment interplay to improve clinicians' comfort level in discussing these complex issues with their patients.

  4. Subjective versus objective risk in genetic counseling for hereditary breast and/or ovarian cancers

    Directory of Open Access Journals (Sweden)

    Sperduti Isabella

    2009-12-01

    Full Text Available Abstract Background Despite the fact that genetic counseling in oncology provides information regarding objective risks, it can be found a contrast between the subjective and objective risk. The aims of this study were to evaluate the accuracy of the perceived risk compared to the objective risk estimated by the BRCApro computer model and to evaluate any associations between medical, demographic and psychological variables and the accuracy of risk perception. Methods 130 subjects were given medical-demographic file, Cancer and Genetic Risk Perception, Hospital Anxiety-Depression Scale. It was also computed an objective evaluation of the risk by the BRCApro model. Results The subjective risk was significantly higher than objective risk. The risk of tumour was overestimated by 56%, and the genetic risk by 67%. The subjects with less cancer affected relatives significantly overestimated their risk of being mutation carriers and made a more innacurate estimation than high risk subjects. Conclusion The description of this sample shows: general overestimation of the risk, inaccurate perception compared to BRCApro calculation and a more accurate estimation in those subjects with more cancer affected relatives (high risk subjects. No correlation was found between the levels of perception of risk and anxiety and depression. Based on our findings, it is worth pursuing improved communication strategies about the actual cancer and genetic risk, especially for subjects at "intermediate and slightly increased risk" of developing an hereditary breast and/or ovarian cancer or of being mutation carrier.

  5. Impact of a Genetic Risk Score on Myocardial Infarction Risk Across Different Ethnic Populations.

    Science.gov (United States)

    Joseph, Philip G; Pare, Guillaume; Asma, Senay; Engert, James C; Yusuf, Salim; Anand, Sonia S

    2016-12-01

    Myocardial infarction (MI) risk varies by ethnicity, although the influence of genetic factors remains unclear. Using a genetic risk score (GRS), we examined the association between 25 coronary artery disease (CAD)-related single nucleotide polymorphisms and MI across 6 ethnic groups. We studied 8556 participants in the INTERHEART case-control study from 6 ethnic groups: Europeans, South Asians, Southeast Asians, Arabs, Latin Americans, and Africans. Associations between the GRS and MI were tested in each group by logistic regression and overall by meta-analysis. Overall, the GRS increased the odds of MI by 1.07 (95% confidence interval [CI], 1.04-1.09) per risk allele in the unadjusted model, with little change (odds ratio, 1.06; 95% CI, 1.04-1.09) after adjusting for demographic and modifiable factors. In Europeans, South Asians, Southeast Asians, and Arabs, the GRS was significantly associated with MI, with minimal heterogeneity observed. In these groups, a score > 23 risk alleles (highest 4 quintiles) was associated with only a 5% difference in population attributable risk (PAR) (36% to 41%) for MI. The GRS was not significant in Latin Americans or Africans. In the overall cohort, modest changes, beyond clinical factors, in PAR (88% to 91%), concordance statistic (0.73 to 0.74), and continuous net reclassification improvement (12%) were observed with the GRS. A CAD GRS is associated with MI across a multiethnic cohort, with significant and consistent effects across 4 distinct ethnicities. However, it only modestly improves MI risk prediction beyond clinical factors. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  6. Self-Conscious Shyness: Growth during Toddlerhood, Strong Role of Genetics, and No Prediction from Fearful Shyness

    OpenAIRE

    Eggum-Wilkens, Natalie D.; Lemery-Chalfant, Kathryn; Aksan, Nazan; Goldsmith, H. Hill

    2014-01-01

    Fearful and self-conscious subtypes of shyness have received little attention in the empirical literature. Study aims included: 1) determining if fearful shyness predicted self-conscious shyness, 2) describing development of self-conscious shyness, and 3) examining genetic and environmental contributions to fearful and self-conscious shyness. Observed self-conscious shyness was examined at 19, 22, 25, and 28 months in same-sex twins (MZ = 102, DZ = 111, missing zygosity = 3 pairs). Self-consc...

  7. Strong population genetic structuring in an annual fish, Nothobranchius furzeri, suggests multiple savannah refugia in southern Mozambique

    Czech Academy of Sciences Publication Activity Database

    Bartáková, Veronika; Reichard, Martin; Janko, Karel; Polačik, Matej; Blažek, Radim; Reichwald, K.; Cellerino, A.; Bryja, Josef

    2013-01-01

    Roč. 13, č. 196 (2013), s. 196 ISSN 1471-2148 R&D Projects: GA ČR GA206/09/0815; GA ČR GBP505/12/G112 Institutional support: RVO:68081766 Keywords : Temporary pool * Phylogeography * Population genetics * Cyprinodontiformes * Senescence * Pluvials * Pleistocene climate changes * Dispersal * Founder effect * Killifish Subject RIV: EG - Zoology Impact factor: 3.407, year: 2013 http://www.biomedcentral.com/1471-2148/13/196

  8. Strong genetic influence on a UK nationwide test of educational achievement at the end of compulsory education at age 16.

    Science.gov (United States)

    Shakeshaft, Nicholas G; Trzaskowski, Maciej; McMillan, Andrew; Rimfeld, Kaili; Krapohl, Eva; Haworth, Claire M A; Dale, Philip S; Plomin, Robert

    2013-01-01

    We have previously shown that individual differences in educational achievement are highly heritable in the early and middle school years in the UK. The objective of the present study was to investigate whether similarly high heritability is found at the end of compulsory education (age 16) for the UK-wide examination, called the General Certificate of Secondary Education (GCSE). In a national twin sample of 11,117 16-year-olds, heritability was substantial for overall GCSE performance for compulsory core subjects (58%) as well as for each of them individually: English (52%), mathematics (55%) and science (58%). In contrast, the overall effects of shared environment, which includes all family and school influences shared by members of twin pairs growing up in the same family and attending the same school, accounts for about 36% of the variance of mean GCSE scores. The significance of these findings is that individual differences in educational achievement at the end of compulsory education are not primarily an index of the quality of teachers or schools: much more of the variance of GCSE scores can be attributed to genetics than to school or family environment. We suggest a model of education that recognizes the important role of genetics. Rather than a passive model of schooling as instruction (instruere, 'to build in'), we propose an active model of education (educare, 'to bring out') in which children create their own educational experiences in part on the basis of their genetic propensities, which supports the trend towards personalized learning.

  9. Analyses of historical and current populations of black grouse in Central Europe reveal strong effects of genetic drift and loss of genetic diversity

    NARCIS (Netherlands)

    Segelbacher, G.; Strand, T.M.; Quintela, M.; Axelsson, T.; Jansman, H.A.H.; Koelewijn, H.P.; Hoglund, J.

    2014-01-01

    Black grouse (Tetrao tetrix) in Central Europe have undergone a severe contraction of their range in recent decades with only a few small isolated remaining populations. Here we compare genetic diversity of two contemporary isolated populations (Sallandse Heuvelrug, Netherlands and Luneburger Heide,

  10. Genetic variants influencing lipid levels and risk of dyslipidemia in ...

    Indian Academy of Sciences (India)

    Keywords. dyslipidemia; lipid levels; single-nucleotide polymorphisms; cardiovascular disease; genetics. Abstract. Recently, several human genetic and genomewide association studies (GWAS) have discovered many genetic loci that are associated with the concentration of the blood lipids. To confirm the reported loci in ...

  11. Interaction between common breast cancer susceptibility variants, genetic ancestry, and non-genetic risk factors in Hispanic women

    Science.gov (United States)

    Fejerman, Laura; Stern, Mariana C.; John, Esther M.; Torres-Mejía, Gabriela; Hines, Lisa M.; Wolff, Roger K.; Baumgartner, Kathy B.; Giuliano, Anna R.; Ziv, Elad; Pérez-Stable, Eliseo J.; Slattery, Martha L.

    2015-01-01

    Background Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified single nucleotide polymorphisms (SNPs) among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population. Methods We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions. Results We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele odds ratio (OR): 0.94 (95% confidence interval 0.74–1.20), 1.20 (0.94–1.53) and 1.49 (1.28–1.75) for current, former and never hormone therapy users, respectively, P-interaction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72–1.42), 1.19 (0.98–1.45) and 1.69 (1.26–2.26) for never, 12 months breastfeeding, respectively, P-interaction 0.014]. Conclusions The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women. Impact These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and non-genetic risk factors and their contribution to breast cancer risk. PMID:26364163

  12. Genetic structure of the date palm (Phoenix dactylifera) in the Old World reveals a strong differentiation between eastern and western populations.

    Science.gov (United States)

    Zehdi-Azouzi, Salwa; Cherif, Emira; Moussouni, Souhila; Gros-Balthazard, Muriel; Abbas Naqvi, Summar; Ludeña, Bertha; Castillo, Karina; Chabrillange, Nathalie; Bouguedoura, Nadia; Bennaceur, Malika; Si-Dehbi, Farida; Abdoulkader, Sabira; Daher, Abdourahman; Terral, Jean-Frederic; Santoni, Sylvain; Ballardini, Marco; Mercuri, Antonio; Ben Salah, Mohamed; Kadri, Karim; Othmani, Ahmed; Littardi, Claudio; Salhi-Hannachi, Amel; Pintaud, Jean-Christophe; Aberlenc-Bertossi, Frédérique

    2015-07-01

    Date palms (Phoenix dactylifera, Arecaceae) are of great economic and ecological value to the oasis agriculture of arid and semi-arid areas. However, despite the availability of a large date palm germplasm spreading from the Atlantic shores to Southern Asia, improvement of the species is being hampered by a lack of information on global genetic diversity and population structure. In order to contribute to the varietal improvement of date palms and to provide new insights on the influence of geographic origins and human activity on the genetic structure of the date palm, this study analysed the diversity of the species. Genetic diversity levels and population genetic structure were investigated through the genotyping of a collection of 295 date palm accessions ranging from Mauritania to Pakistan using a set of 18 simple sequence repeat (SSR) markers and a plastid minisatellite. Using a Bayesian clustering approach, the date palm genotypes can be structured into two different gene pools: the first, termed the Eastern pool, consists of accessions from Asia and Djibouti, whilst the second, termed the Western pool, consists of accessions from Africa. These results confirm the existence of two ancient gene pools that have contributed to the current date palm diversity. The presence of admixed genotypes is also noted, which points at gene flows between eastern and western origins, mostly from east to west, following a human-mediated diffusion of the species. This study assesses the distribution and level of genetic diversity of accessible date palm resources, provides new insights on the geographic origins and genetic history of the cultivated component of this species, and confirms the existence of at least two domestication origins. Furthermore, the strong genetic structure clearly established here is a prerequisite for any breeding programme exploiting the effective polymorphism related to each gene pool. © The Author 2015. Published by Oxford University Press on

  13. Genetically modified organisms: do the benefits outweigh the risks?

    Science.gov (United States)

    Hug, Kristina

    2008-01-01

    The objective of this literature review is to analyze the implications of using genetically modified organisms (GMOs) as well as international and European position regarding such organisms. Review of international and European legal requirements and ethical guidelines and relevant publications, found and accessed with the help of PubMed and Lund University Library databases. The article discusses the main application areas of GMOs, the expansion of using GMOs in the world as well as the advantages and disadvantages of the implications of their usage. It further provides an overview of the suggested ways to tackle or avoid the GMO-related risks. The international and European positions regarding the application of GMOs are discussed and European Directives, Regulations, and ethical guidelines are overviewed. The article further presents the public attitudes towards GMOs in Europe as well as overviews surveys conducted at the national level. Suggested steps to tackle the challenge of developing and managing biotechnology for the benefit of public health and the environment are presented.

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

    Science.gov (United States)

    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.

  15. KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Polin Haghvirdizadeh

    2015-01-01

    Full Text Available 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.

  16. Applying Evolutionary Genetics to Developmental Toxicology and Risk Assessment

    Science.gov (United States)

    Leung, Maxwell C. K.; Procter, Andrew C.; Goldstone, Jared V.; Foox, Jonathan; DeSalle, Robert; Mattingly, Carolyn J.; Siddall, Mark E.; Timme-Laragy, Alicia R.

    2018-01-01

    Evolutionary thinking continues to challenge our views on health and disease. Yet, there is a communication gap between evolutionary biologists and toxicologists in recognizing the connections among developmental pathways, high-throughput screening, and birth defects in humans. To increase our capability in identifying potential developmental toxicants in humans, we propose to apply evolutionary genetics to improve the experimental design and data interpretation with various in vitro and whole-organism models. We review five molecular systems of stress response and update 18 consensual cell-cell signaling pathways that are the hallmark for early development, organogenesis, and differentiation; and revisit the principles of teratology in light of recent advances in high-throughput screening, big data techniques, and systems toxicology. Multiscale systems modeling plays an integral role in the evolutionary approach to cross-species extrapolation. Phylogenetic analysis and comparative bioinformatics are both valuable tools in identifying and validating the molecular initiating events that account for adverse developmental outcomes in humans. The discordance of susceptibility between test species and humans (ontogeny) reflects their differences in evolutionary history (phylogeny). This synthesis not only can lead to novel applications in developmental toxicity and risk assessment, but also can pave the way for applying an evo-devo perspective to the study of developmental origins of health and disease. PMID:28267574

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

    NARCIS (Netherlands)

    Claassen, E.A.M.; Henneman, L.; de Vet, H.C.W.; Knol, D.L.; Marteau, T.; Timmermans, D.R.M.

    2010-01-01

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. Populations genetically rifting within a complex geological system: The case of strong structure and low genetic diversity in the migratory freshwater catfish, Bagrus docmak, in East Africa

    OpenAIRE

    Basiita, Rose Komugisha; Zenger, Kyall Richard; Jerry, Dean Robert

    2017-01-01

    Abstract The complex geological history of East Africa has been a driving factor in the rapid evolution of teleost biodiversity. While there is some understanding of how macroevolutionary drivers have shaped teleost speciation in East Africa, there is a paucity of research into how the same biogeographical factors have affected microevolutionary processes within lakes and rivers. To address this deficiency, population genetic diversity, demography, and structure were investigated in a widely ...

  20. Genetic variants associated with breast size also influence breast cancer risk

    Directory of Open Access Journals (Sweden)

    Eriksson Nicholas

    2012-06-01

    Full Text Available Abstract Background While some factors of breast morphology, such as density, are directly implicated in breast cancer, the relationship between breast size and cancer is less clear. Breast size is moderately heritable, yet the genetic variants leading to differences in breast size have not been identified. Methods To investigate the genetic factors underlying breast size, we conducted a genome-wide association study (GWAS of self-reported bra cup size, controlling for age, genetic ancestry, breast surgeries, pregnancy history and bra band size, in a cohort of 16,175 women of European ancestry. Results We identified seven single-nucleotide polymorphisms (SNPs significantly associated with breast size (p−8: rs7816345 near ZNF703, rs4849887 and (independently rs17625845 flanking INHBB, rs12173570 near ESR1, rs7089814 in ZNF365, rs12371778 near PTHLH, and rs62314947 near AREG. Two of these seven SNPs are in linkage disequilibrium (LD with SNPs associated with breast cancer (those near ESR1 and PTHLH, and a third (ZNF365 is near, but not in LD with, a breast cancer SNP. The other three loci (ZNF703, INHBB, and AREG have strong links to breast cancer, estrogen regulation, and breast development. Conclusions These results provide insight into the genetic factors underlying normal breast development and show that some of these factors are shared with breast cancer. While these results do not directly support any possible epidemiological relationships between breast size and cancer, this study may contribute to a better understanding of the subtle interactions between breast morphology and breast cancer risk.

  1. Eating disorder-specific risk factors moderate the relationship between negative urgency and binge eating: A behavioral genetic investigation.

    Science.gov (United States)

    Racine, Sarah E; VanHuysse, Jessica L; Keel, Pamela K; Burt, S Alexandra; Neale, Michael C; Boker, Steven; Klump, Kelly L

    2017-07-01

    Theoretical models of binge eating and eating disorders include both transdiagnostic and eating disorder-specific risk factors. Negative urgency (i.e., the tendency to act impulsively when distressed) is a critical transdiagnostic risk factor for binge eating, but limited research has examined interactions between negative urgency and disorder-specific variables. Investigating these interactions can help identify the circumstances under which negative urgency is most strongly associated with binge eating. We examined whether prominent risk factors (i.e., appearance pressures, thin-ideal internalization, body dissatisfaction, dietary restraint) specified in well-established etiologic models of eating disorders moderate negative urgency-binge eating associations. Further, we investigated whether phenotypic moderation effects were due to genetic and/or environmental associations between negative urgency and binge eating. Participants were 988 female twins aged 11-25 years from the Michigan State University Twin Registry. Appearance pressures, thin-ideal internalization, and body dissatisfaction, but not dietary restraint, significantly moderated negative urgency-binge eating associations, with high levels of these risk factors and high negative urgency associated with the greatest binge eating. Twin moderation models revealed that genetic, but not environmental, sharing between negative urgency and binge eating was enhanced at higher levels of these eating disorder-specific variables. Future longitudinal research should investigate whether eating disorder risk factors shape genetic influences on negative urgency into manifesting as binge eating. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  2. Uric Acid Is a Strong Risk Marker for Developing Hypertension From Prehypertension: A 5-Year Japanese Cohort Study.

    Science.gov (United States)

    Kuwabara, Masanari; Hisatome, Ichiro; Niwa, Koichiro; Hara, Shigeko; Roncal-Jimenez, Carlos A; Bjornstad, Petter; Nakagawa, Takahiko; Andres-Hernando, Ana; Sato, Yuka; Jensen, Thomas; Garcia, Gabriela; Rodriguez-Iturbe, Bernardo; Ohno, Minoru; Lanaspa, Miguel A; Johnson, Richard J

    2018-01-01

    Prehypertension frequently progresses to hypertension, a condition associated with high morbidity and mortality from cardiovascular diseases and stroke. However, the risk factors for developing hypertension from prehypertension remain poorly understood. We conducted a retrospective cohort study using the data from 3584 prehypertensive Japanese adults (52.1±11.0 years, 2081 men) found to be prehypertensive in 2004 and reexamined in 2009. We calculated the cumulative incidences of hypertension over 5 years, examined risk factors, and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, body mass index, smoking and drinking habits, baseline systolic and diastolic blood pressure, pulse rate, diabetes mellitus, dyslipidemia, chronic kidney disease, and serum uric acid levels. The additional analysis evaluated whether serum uric acid (hyperuricemia) constituted an independent risk factor for developing hypertension. The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%. There were no significant differences between women and men (24.4% versus 26.0%; P =0.28). The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2858; 30.7% versus 24.0%; P uric acid (OR, 1.149; P uric acid is a strong risk marker for developing hypertension from prehypertension. Further studies are needed to determine whether treatment of hyperuricemia in prehypertensive subjects could impede the onset of hypertension. © 2017 American Heart Association, Inc.

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Low Genetic Diversity and Strong Geographical Structure of the Critically Endangered White-Headed Langur (Trachypithecus leucocephalus) Inferred from Mitochondrial DNA Control Region Sequences.

    Science.gov (United States)

    Wang, Weiran; Qiao, Yu; Pan, Wenshi; Yao, Meng

    2015-01-01

    Many Asian colobine monkey species are suffering from habitat destruction and population size decline. There is a great need to understand their genetic diversity, population structure and demographic history for effective species conservation. The white-headed langur (Trachypithecus leucocephalus) is a Critically Endangered colobine species endemic to the limestone karst forests in southwestern China. We analyzed the mitochondrial DNA (mtDNA) control region sequences of 390 fecal samples from 40 social groups across the main distribution areas, which represented one-third of the total extant population. Only nine haplotypes and 10 polymorphic sites were identified, indicating remarkably low genetic diversity in the species. Using a subset of 77 samples from different individuals, we evaluated genetic variation, population structure, and population demographic history. We found very low values of haplotype diversity (h = 0.570 ± 0.056) and nucleotide diversity (π = 0.00323 ± 0.00044) in the hypervariable region I (HVRI) of the mtDNA control region. Distribution of haplotypes displayed marked geographical pattern, with one population (Chongzuo, CZ) showing a complete lack of genetic diversity (having only one haplotype), whereas the other population (Fusui, FS) having all nine haplotypes. We detected strong population genetic structure among habit patches (ΦST = 0.375, P population size and modest population expansion in the last 2,000 years. Our results indicate different genetic diversity and possibly distinct population history for different local populations, and suggest that CZ and FS should be considered as one evolutionarily significant unit (ESU) and two management units (MUs) pending further investigation using nuclear markers.

  5. Genetic risk by experience interaction for childhood internalizing problems: converging evidence across multiple methods.

    Science.gov (United States)

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

    2011-05-01

    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 (G×E) in the development of childhood psychopathology. We used both co-twin and parent mental health as markers of genetic risk to test whether G×E 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. We found consistent evidence for G×E 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. 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. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health.

  6. Population genomic analysis suggests strong influence of river network on spatial distribution of genetic variation in invasive saltcedar across the southwestern United States

    Science.gov (United States)

    Lee, Soo-Rang; Jo, Yeong-Seok; Park, Chan-Ho; Friedman, Jonathan M.; Olson, Matthew S.

    2018-01-01

    Understanding the complex influences of landscape and anthropogenic elements that shape the population genetic structure of invasive species provides insight into patterns of colonization and spread. The application of landscape genomics techniques to these questions may offer detailed, previously undocumented insights into factors influencing species invasions. We investigated the spatial pattern of genetic variation and the influences of landscape factors on population similarity in an invasive riparian shrub, saltcedar (Tamarix L.) by analysing 1,997 genomewide SNP markers for 259 individuals from 25 populations collected throughout the southwestern United States. Our results revealed a broad-scale spatial genetic differentiation of saltcedar populations between the Colorado and Rio Grande river basins and identified potential barriers to population similarity along both river systems. River pathways most strongly contributed to population similarity. In contrast, low temperature and dams likely served as barriers to population similarity. We hypothesize that large-scale geographic patterns in genetic diversity resulted from a combination of early introductions from distinct populations, the subsequent influence of natural selection, dispersal barriers and founder effects during range expansion.

  7. Impact of strong selection for the PrP major gene on genetic variability of four French sheep breeds (Open Access publication

    Directory of Open Access Journals (Sweden)

    Pantano Thais

    2008-11-01

    Full Text Available Abstract Effective selection on the PrP gene has been implemented since October 2001 in all French sheep breeds. After four years, the ARR "resistant" allele frequency increased by about 35% in young males. The aim of this study was to evaluate the impact of this strong selection on genetic variability. It is focussed on four French sheep breeds and based on the comparison of two groups of 94 animals within each breed: the first group of animals was born before the selection began, and the second, 3–4 years later. Genetic variability was assessed using genealogical and molecular data (29 microsatellite markers. The expected loss of genetic variability on the PrP gene was confirmed. Moreover, among the five markers located in the PrP region, only the three closest ones were affected. The evolution of the number of alleles, heterozygote deficiency within population, expected heterozygosity and the Reynolds distances agreed with the criteria from pedigree and pointed out that neutral genetic variability was not much affected. This trend depended on breed, i.e. on their initial states (population size, PrP frequencies and on the selection strategies for improving scrapie resistance while carrying out selection for production traits.

  8. So Far Away, Yet So Close: Strong Genetic Structure in Homonota uruguayensis (Squamata, Phyllodactylidae), a Species with Restricted Geographic Distribution in the Brazilian and Uruguayan Pampas

    Science.gov (United States)

    Felappi, Jéssica F.; Vieira, Renata C.; Fagundes, Nelson J. R.; Verrastro, Laura V.

    2015-01-01

    The Pampas is a biologically rich South American biome, but is poorly represented in phylogeographic studies. While the Pleistocene glacial cycles may have affected the evolutionary history of species distributed in forested biomes, little is known about their effects on the habitats that remained stable through glacial cycles. The South American Pampas have been covered by grasslands during both glacial and interglacial periods and therefore represent an interesting system to test whether the genetic structure in such environments is less pronounced. In this study, we sampled Pampean populations of Homonota uruguayensis from Southern Brazil and Uruguay to assess the tempo and mode of population divergence, using both morphological measurements and molecular markers. Our results indicate that, in spite of its narrow geographic distribution, populations of H. uruguayensis show high levels of genetic structure. We found four major well-supported mtDNA clades with strong geographic associations. Estimates of their divergence times fell between 3.16 and 1.82 million years before the present. Populations from the central portion of the species distribution, on the border between Uruguay and Brazil, have high genetic diversity and may have undergone a population expansion approximately 250,000 years before the present. The high degree of genetic structure is reflected in the analyses of morphological characters, and most individuals could be correctly assigned to their parental population based on morphology alone. Finally, we discuss the biogeographic and conservation implications of these findings. PMID:25692471

  9. So far away, yet so close: strong genetic structure in Homonota uruguayensis (Squamata, Phyllodactylidae, a species with restricted geographic distribution in the Brazilian and Uruguayan Pampas.

    Directory of Open Access Journals (Sweden)

    Jéssica F Felappi

    Full Text Available The Pampas is a biologically rich South American biome, but is poorly represented in phylogeographic studies. While the Pleistocene glacial cycles may have affected the evolutionary history of species distributed in forested biomes, little is known about their effects on the habitats that remained stable through glacial cycles. The South American Pampas have been covered by grasslands during both glacial and interglacial periods and therefore represent an interesting system to test whether the genetic structure in such environments is less pronounced. In this study, we sampled Pampean populations of Homonota uruguayensis from Southern Brazil and Uruguay to assess the tempo and mode of population divergence, using both morphological measurements and molecular markers. Our results indicate that, in spite of its narrow geographic distribution, populations of H. uruguayensis show high levels of genetic structure. We found four major well-supported mtDNA clades with strong geographic associations. Estimates of their divergence times fell between 3.16 and 1.82 million years before the present. Populations from the central portion of the species distribution, on the border between Uruguay and Brazil, have high genetic diversity and may have undergone a population expansion approximately 250,000 years before the present. The high degree of genetic structure is reflected in the analyses of morphological characters, and most individuals could be correctly assigned to their parental population based on morphology alone. Finally, we discuss the biogeographic and conservation implications of these findings.

  10. The impact of advances in human molecular biology on radiation genetic risk estimation in man

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1996-01-01

    This paper provides an overview of the conceptual framework, the data base, methods and assumptions used thus far to assess the genetic risks of exposure of human populations to ionising radiation. These are then re-examined in the contemporary context of the rapidly expanding knowledge of the molecular biology of human mendelian diseases. This re-examination reveals that (i) many of the assumptions used thus far in radiation genetic risk estimation may not be fully valid and (ii) the current genetic risk estimates are probably conservative, but provide an adequate margin of safety for radiological protection. The view is expressed that further advances in the field of genetic risk estimation will be largely driven by advances in the molecular biology of human genetic diseases. (author). 37 refs., 5 tabs

  11. Network dysfunction of emotional and cognitive processes in those at genetic risk of bipolar disorder.

    Science.gov (United States)

    Breakspear, Michael; Roberts, Gloria; Green, Melissa J; Nguyen, Vinh T; Frankland, Andrew; Levy, Florence; Lenroot, Rhoshel; Mitchell, Philip B

    2015-11-01

    The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder. © The Author (2015). Published by Oxford University Press on behalf

  12. BRCA1 and BRCA2: Cancer Risk and Genetic Testing

    Science.gov (United States)

    ... MR imaging in women with a familial or genetic predisposition. Breast Cancer Research and Treatment 2010; 119(2):399–407. [PubMed Abstract] Evans DG, Gaarenstroom KN, Stirling D, et al. Screening for familial ovarian cancer: Poor ... Genetics 2009; 46(9):593–597. [PubMed Abstract] Domchek ...

  13. Perspectives of couples with high risk of transmitting genetic disorders.

    NARCIS (Netherlands)

    Musters, A.M.; Twisk, M.; Leschot, N.J.; Oosterwijk, C.; Korevaar, J.C.; Repping, S.; Veen, F. van der; Goddijn, M.

    2010-01-01

    Objective: To investigate the preference for preimplantation genetic diagnosis (PGD) as an alternative to prenatal diagnosis (PND) in a large group of couples representing a wide array of genetic disorders. We also investigated the couple's familiarity with PGD and presented time trade-off scenarios

  14. A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

    Science.gov (United States)

    Carmona, F. David; Mackie, Sarah L.; Martín, Jose-Ezequiel; Taylor, John C.; Vaglio, Augusto; Eyre, Stephen; Bossini-Castillo, Lara; Castañeda, Santos; Cid, Maria C.; Hernández-Rodríguez, José; Prieto-González, Sergio; Solans, Roser; Ramentol-Sintas, Marc; González-Escribano, M. Francisca; Ortiz-Fernández, Lourdes; Morado, Inmaculada C.; Narváez, Javier; Miranda-Filloy, José A.; Martínez-Berriochoa, Agustín; Unzurrunzaga, Ainhoa; Hidalgo-Conde, Ana; Madroñero-Vuelta, Ana B.; Fernández-Nebro, Antonio; Ordóñez-Cañizares, M. Carmen; Escalante, Begoña; Marí-Alfonso, Begoña; Sopeña, Bernardo; Magro, César; Raya, Enrique; Grau, Elena; Román, José A.; de Miguel, Eugenio; López-Longo, F. Javier; Martínez, Lina; Gómez-Vaquero, Carmen; Fernández-Gutiérrez, Benjamín; Rodríguez-Rodríguez, Luis; Díaz-López, J. Bernardino; Caminal-Montero, Luis; Martínez-Zapico, Aleida; Monfort, Jordi; Tío, Laura; Sánchez-Martín, Julio; Alegre-Sancho, Juan J.; Sáez-Comet, Luis; Pérez-Conesa, Mercedes; Corbera-Bellalta, Marc; García-Villanueva, M. Jesús; Fernández-Contreras, M. Encarnación; Sanchez-Pernaute, Olga; Blanco, Ricardo; Ortego-Centeno, Norberto; Ríos-Fernández, Raquel; Callejas, José L.; Fanlo-Mateo, Patricia; Martínez-Taboada, Víctor M.; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A.; Gianfreda, Davide; Santilli, Daniele; Ramirez, Giuseppe A.; Soriano, Alessandra; Muratore, Francesco; Pazzola, Giulia; Addimanda, Olga; Wijmenga, Cisca; Witte, Torsten; Schirmer, Jan H.; Moosig, Frank; Schönau, Verena; Franke, Andre; Palm, Øyvind; Molberg, Øyvind; Diamantopoulos, Andreas P.; Carette, Simon; Cuthbertson, David; Forbess, Lindsy J.; Hoffman, Gary S.; Khalidi, Nader A.; Koening, Curry L.; Langford, Carol A.; McAlear, Carol A.; Moreland, Larry; Monach, Paul A.; Pagnoux, Christian; Seo, Philip; Spiera, Robert; Sreih, Antoine G.; Warrington, Kenneth J.; Ytterberg, Steven R.; Gregersen, Peter K.; Pease, Colin T.; Gough, Andrew; Green, Michael; Hordon, Lesley; Jarrett, Stephen; Watts, Richard; Levy, Sarah; Patel, Yusuf; Kamath, Sanjeet; Dasgupta, Bhaskar; Worthington, Jane; Koeleman, Bobby P.C.; de Bakker, Paul I.W.; Barrett, Jennifer H.; Salvarani, Carlo; Merkel, Peter A.; González-Gay, Miguel A.; Morgan, Ann W.; Martín, Javier

    2015-01-01

    We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10−40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10−43) and HLA-DQα1 47 (p = 4.02 × 10−46), 56, and 76 (both p = 1.84 × 10−45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10−6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10−6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10−5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. PMID:25817017

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

    Directory of Open Access Journals (Sweden)

    Maha S. Al-Shammari

    2017-08-01

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

  16. Genetic Analysis of Elevated Mastitis Risk Based on Mastitis Indicator Data

    DEFF Research Database (Denmark)

    Sørensen, Lars Peter; Løvendahl, Peter

    . These modeling approaches have proven to be highly useful to determine population genetic parameters as well as prediction of genetic risk or value. We present statistical modelling approaches that use prior biological information for evaluating the collective action of sets of genetic variants. We have applied......Whole-genome sequences and multiple trait phenotypes from large numbers of individuals will soon be available. Well established statistical modeling approaches enable the genetic analyses of complex trait phenotypes while accounting for a variety of additive and non-additive genetic mechanisms...

  17. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors.

    Science.gov (United States)

    Gianfrancesco, Milena A; Acuna, Brigid; Shen, Ling; Briggs, Farren B S; Quach, Hong; Bellesis, Kalliope H; Bernstein, Allan; Hedstrom, Anna K; Kockum, Ingrid; Alfredsson, Lars; Olsson, Tomas; Schaefer, Catherine; Barcellos, Lisa F

    2014-01-01

    To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors. Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied. In analyses stratified by gender, being overweight at ages 10 and 20 were associated with MS in females (pchildhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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 Pgenetic 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. © 2015 American Heart Association, Inc.

  19. [Current problems of estimation of genetic risk of human exposure to radiation].

    Science.gov (United States)

    Shevchenko, V A

    2000-01-01

    The methodology of assessing the genetic risk of radiation exposure is based on the concept of "hitting the target" in development of which N.V. Timofeeff-Ressovsky has played and important role. To predict genetic risk posed by irradiation, the UN Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has worked out direct and indirect methods of assessment, extrapolational, integral and populational criteria of risk analysis that together permit calculating the risk from human exposure on the basis of data obtained for mice. Laboratory mice are the main objects in studying radiation mutagenesis due to the fact that the data on the frequency of radiation-induced human mutations are rather scarce. The method of doubling dose based on the determination of a dose doubling the level of natural mutational process in humans is the main one used to predict the genetic risk. The evolution of views about the genetics risk of human exposure to radiation for last 40 years is considered. Till 1972 the main model for assessing the genetic risk was the "human/mouse" model (the use of data on the spontaneous human variability and data on the frequency of induced mutations in mice). In the period form 1972 till 1994 the "mouse/mouse" model was intensively elaborated in many laboratories. This model was also used in this period by UNSCEAR experts to analyze the genetic risk from human irradiation. Recent achievements associated with the study of the molecular nature of many hereditary human diseases as well as the criticism of number fundamental principles of the "mouse/mouse" model for estimating the genetic risk on a new basis. The estimates of risk for the different classes of genetic diseases have been obtained using the doubling-dose method. The estimate of doubling dose used in the calculations is 1 Gy for low dose/chronic low-LET radiation conditions.

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

    Directory of Open Access Journals (Sweden)

    Yiming Hu

    2017-06-01

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

  1. The Structure of Genetic and Environmental Risk Factors for DSM-IV Personality Disorders

    Science.gov (United States)

    Kendler, Kenneth S.; Aggen, Steven H.; Czajkowski, Nikolai; Røysamb, Espen; Tambs, Kristian; Torgersen, Svenn; Neale, Michael C.; Reichborn-Kjennerud, Ted

    2009-01-01

    Context Although both genetic and environmental factors affect risk of individual personality disorders (PDs), we know little of how they contribute to the pattern of comorbidity between the PDs in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV). Objective To clarify the structure of the genetic and environmental risk factors for the 10 DSM-IV PDs. Design Assessment of PDs at personal interview and multivariate twin modeling with the Mx program. Setting General community. Participants A total of 2794 young adult members of the Norwegian Institute of Public Health Twin Panel. Main Outcome Measure Number of endorsed criteria for the 10 DSM-IV PDs. Results The best-fit multivariate twin model required 3 genetic and 3 individual-specific environmental factors and genetic and individual-specific factors unique to each PD. The first genetic factor had high loadings on PDs from all 3 clusters including paranoid, histrionic, borderline, narcissistic, dependent, and obsessive-compulsive. The second genetic factor had substantial loadings only on borderline and antisocial PD. The third genetic factor had high loadings only on schizoid and avoidant PD. Several PDs had substantial disorder-specific genetic risk factors. The first, second, and third individual-specific environmental factors had high loadings on the cluster B, A, and C PDs, respectively, with 1 exception: obsessive-compulsive PD loaded with cluster B and not cluster C PDs. Conclusions Genetic risk factors for DSM-IV PDs do not reflect the cluster A, B, and C typology. Rather, 1 genetic factor reflects a broad vulnerability to PD pathology and/or negative emotionality. The 2 other genetic factors are more specific and reflect high impulsivity/low agreeableness and introversion. Unexpectedly, the cluster A, B, and C typology is well reflected in the structure of environmental risk factors, suggesting that environmental experiences may be responsible for the tendency of cluster A

  2. Communication of Information about Genetic Risks: Putting Families at the Center.

    Science.gov (United States)

    Mendes, Álvaro; Metcalfe, Alison; Paneque, Milena; Sousa, Liliana; Clarke, Angus J; Sequeiros, Jorge

    2017-07-16

    Genetic information is a family affair. With the expansion of genomic technologies, many new causal genes and variants have been established and the potential for molecular diagnoses increased, with implications not only for patients but also their relatives. The need for genetic counseling and intrafamilial circulation of information on genetic risks grew accordingly. Also, the amount and, particularly, the complexity of the information to convey multiplied. Sharing information about genetic risks with family members, however, has never been an easy matter and often becomes a source of personal and familial conflicts and distress. Ethical requisites generally prevent healthcare professionals from directly contacting their consultands' relatives (affected or still at risk), who often feel unsupported throughout that process. We discuss here the communication of genetic risks to family members. We first consider genomic testing as a basis for family-centered health care, as opposed to a predominant focus on the individual. We reviewed the literature on sharing genetic risk information with family members, and the associated ethical issues for professionals. Some clinical cases are presented and discussed, and key issues for meeting the needs of individuals and families are addressed. We argue that genetic information is inextricably linked to the family and that communicating about genetic risks is a process grounded within the broader milieu of family relationships and functioning. We conclude for the need for a more family-centered approach and interventions that can promote sensitive attitudes to the provision of genetic information to and within the family, as well as its inclusion in educational and training programmes for genetic healthcare professionals. © 2017 Family Process Institute.

  3. Concerns about Genetic Testing for Schizophrenia among Young Adults at Clinical High Risk for Psychosis.

    Science.gov (United States)

    Lawrence, Ryan E; Friesen, Phoebe; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

    Genetic tests for schizophrenia may introduce risks and benefits. Among young adults at clinical high-risk for psychosis, little is known about their concerns and how they assess potential risks. We conducted semi-structured interviews with 15 young adults at clinical high-risk for psychosis to ask about their concerns. Participants expressed concerns about test reliability, data interpretation, stigma, psychological harm, family planning, and privacy. Participants' responses showed some departure from the ethics literature insofar as participants were primarily interested in reporting their results to people to whom they felt emotionally close, and expressed little consideration of biological closeness. Additionally, if tests showed an increased genetic risk for schizophrenia, four clinical high-risk persons felt obligated to tell an employer and another three would "maybe" tell an employer, even in the absence of clinical symptoms. These findings suggest opportunities for clinicians and genetic counselors to intervene with education and support.

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

    Science.gov (United States)

    Andriessen, Karl; Videtic-Paska, Alja

    2015-09-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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…

  7. Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

    NARCIS (Netherlands)

    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.; McArdle, Wendy; Cardon, Lon; Waeber, Gérard; Vollenweider, Peter; Chambers, John C.; Boehnke, Michael; Abecasis, Gonçalo R.; Salomaa, Veikko; Järvelin, Marjo-Riitta; Ruokonen, Aimo; 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.

    2010-01-01

    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 low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol

  8. A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering

    NARCIS (Netherlands)

    Leusink, Maarten; Maitland-van der Zee, Anke H.; Ding, Bo; Drenos, Fotios; van Iperen, Erik Pa; Warren, Helen R.; Caulfield, Mark J.; Cupples, L. Adrienne; Cushman, Mary; Hingorani, Aroon D.; Hoogeveen, Ron C.; Hovingh, G. Kees; Kumari, Meena; Lange, Leslie A.; Munroe, Patricia B.; Nyberg, Fredrik; Schreiner, Pamela J.; Sivapalaratnam, Suthesh; de Bakker, Paul Iw; de Boer, Anthonius; Keating, Brendan J.; Asselbergs, Folkert W.; Onland-Moret, N. Charlotte

    2016-01-01

    To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin

  9. Genetic Predisposition to Central Obesity and Risk of Type 2 Diabetes: Two Independent Cohort Studies.

    Science.gov (United States)

    Huang, Tao; Qi, Qibin; Zheng, Yan; Ley, Sylvia H; Manson, JoAnn E; Hu, Frank B; Qi, Lu

    2015-07-01

    Abdominal obesity is a major risk factor for type 2 diabetes (T2D). We aimed to examine the association between the genetic predisposition to central obesity, assessed by the waist-to-hip ratio (WHR) genetic score, and T2D risk. The current study included 2,591 participants with T2D and 3,052 participants without T2D of European ancestry from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Genetic predisposition to central obesity was estimated using a genetic score based on 14 established loci for the WHR. We found that the central obesity genetic score was linearly related to higher T2D risk. Results were similar in the NHS (women) and HPFS (men). In combined results, each point of the central obesity genetic score was associated with an odds ratio (OR) of 1.04 (95% CI 1.01-1.07) for developing T2D, and the OR was 1.24 (1.03-1.45) when comparing extreme quartiles of the genetic score after multivariate adjustment. The data indicate that genetic predisposition to central obesity is associated with higher T2D risk. This association is mediated by central obesity. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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

    Science.gov (United States)

    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...

  11. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

    NARCIS (Netherlands)

    S.A. Lubitz (Steven); K.L. Lunetta (Kathryn); H. Lin (Honghuang); D.E. Arking (Dan); S. Trompet (Stella); G. Li (Guo); B.P. Krijthe (Bouwe); D.I. Chasman (Daniel); J. Barnard (John); M.E. Kleber (Marcus); M. Dörr (Marcus); Y. Ozaki (Yukio); G.D. Smith; M. Müller-Nurasyid (Martina); S. Walter (Stefan); S.K. Agarwal (Sunil); J.C. Bis (Joshua); J. Brody (Jennifer); L. Chen (Lin); B.M. Everett (Brendan); I. Ford (Ian); O.H. Franco (Oscar); T.B. Harris (Tamara); A. Hofman (Albert); S. Kääb (Stefan); S. Mahida (Saagar); S. Kathiresan (Sekar); M. Kubo (Michiaki); L.J. Launer (Lenore); P.W. MacFarlane (Peter); J.W. Magnani (Jared); B. McKnight (Barbara); D.D. McManus (David); A. Peters (Annette); B.M. Psaty (Bruce); L.M. Rose (Lynda); J.I. Rotter (Jerome); G. Silbernagel (Günther); J.D. Smith (Jonathan); N. Sotoodehnia (Nona); D.J. Stott (David. J.); K.D. Taylor (Kent); A. Tomaschitz (Andreas); T. Tsunoda (Tatsuhiko); A.G. Uitterlinden (André); D.R. van Wagoner (David); U. Völker (Uwe); H. Völzke (Henry); J. Murabito (Joanne); M.F. Sinner (Moritz); V. Gudnason (Vilmundur); S.B. Felix (Stephan); W. März (Winfried); M.K. Chung (Mina); C.M. Albert (Christine); B.H.Ch. Stricker (Bruno); T. Tanaka (Toshihiro); S.R. Heckbert (Susan); J.W. Jukema (Jan Wouter); A. Alonso (Alvaro); E.J. Benjamin (Emelia); P.T. Ellinor (Patrick)

    2014-01-01

    textabstractObjectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple

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

    Science.gov (United States)

    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 ...

  13. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. Objectives:This meta-analysis ...

  14. Genetic and environmental influences on cardiovascular risk factors and cognitive function

    DEFF Research Database (Denmark)

    Xu, Chunsheng; Tian, Xiaocao; Sun, Jianping

    2018-01-01

    AIM: To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population. METHODS: Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure...

  15. Microarray Technology to Study the Role of Genetic Polymorphisms in Breast Cancer Risk

    National Research Council Canada - National Science Library

    Ozcelik, Hilmi

    2004-01-01

    .... In this study we took the candidate gene approach to study the association of 19 different genetic polymorphisms with breast cancer risk in a population-based sample using a high-throughput genotyping technology...

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

    Science.gov (United States)

    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

  17. Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci.

    Science.gov (United States)

    Evans, Jacquelyn M; Noorai, Rooksana E; Tsai, Kate L; Starr-Moss, Alison N; Hill, Cody M; Anderson, Kendall J; Famula, Thomas R; Clark, Leigh Anne

    2017-02-01

    Juvenile dermatomyositis (JDM) is a chronic inflammatory myopathy and vasculopathy driven by genetic and environmental influences. Here, we investigated the genetic underpinnings of an analogous, spontaneous disease of dogs also termed dermatomyositis (DMS). As in JDM, we observed a significant association with a haplotype of the major histocompatibility complex (MHC) (DLA-DRB1*002:01/-DQA1*009:01/-DQB1*001:01), particularly in homozygosity (P-val = 0.0001). However, the high incidence of the haplotype among healthy dogs indicated that additional genetic risk factors are likely involved in disease progression. We conducted genome-wide association studies in two modern breeds having common ancestry and detected strong associations with novel loci on canine chromosomes 10 (P-val = 2.3X10-12) and 31 (P-val = 3.95X10-8). Through whole genome resequencing, we identified primary candidate polymorphisms in conserved regions of PAN2 (encoding p.Arg492Cys) and MAP3K7CL (c.383_392ACTCCACAAA>GACT) on chromosomes 10 and 31, respectively. Analyses of these polymorphisms and the MHC haplotypes revealed that nine of 27 genotypic combinations confer high or moderate probability of disease and explain 93% of cases studied. The pattern of disease risk across PAN2 and MAP3K7CL genotypes provided clear evidence for a significant epistatic foundation for this disease, a risk further impacted by MHC haplotypes. We also observed a genotype-phenotype correlation wherein an earlier age of onset is correlated with an increased number of risk alleles at PAN2 and MAP3K7CL. High frequencies of multiple genetic risk factors are unique to affected breeds and likely arose coincident with artificial selection for desirable phenotypes. Described herein is the first three-locus association with a complex canine disease and two novel loci that provide targets for exploration in JDM and related immunological dysfunction.

  18. Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci.

    Directory of Open Access Journals (Sweden)

    Jacquelyn M Evans

    2017-02-01

    Full Text Available Juvenile dermatomyositis (JDM is a chronic inflammatory myopathy and vasculopathy driven by genetic and environmental influences. Here, we investigated the genetic underpinnings of an analogous, spontaneous disease of dogs also termed dermatomyositis (DMS. As in JDM, we observed a significant association with a haplotype of the major histocompatibility complex (MHC (DLA-DRB1*002:01/-DQA1*009:01/-DQB1*001:01, particularly in homozygosity (P-val = 0.0001. However, the high incidence of the haplotype among healthy dogs indicated that additional genetic risk factors are likely involved in disease progression. We conducted genome-wide association studies in two modern breeds having common ancestry and detected strong associations with novel loci on canine chromosomes 10 (P-val = 2.3X10-12 and 31 (P-val = 3.95X10-8. Through whole genome resequencing, we identified primary candidate polymorphisms in conserved regions of PAN2 (encoding p.Arg492Cys and MAP3K7CL (c.383_392ACTCCACAAA>GACT on chromosomes 10 and 31, respectively. Analyses of these polymorphisms and the MHC haplotypes revealed that nine of 27 genotypic combinations confer high or moderate probability of disease and explain 93% of cases studied. The pattern of disease risk across PAN2 and MAP3K7CL genotypes provided clear evidence for a significant epistatic foundation for this disease, a risk further impacted by MHC haplotypes. We also observed a genotype-phenotype correlation wherein an earlier age of onset is correlated with an increased number of risk alleles at PAN2 and MAP3K7CL. High frequencies of multiple genetic risk factors are unique to affected breeds and likely arose coincident with artificial selection for desirable phenotypes. Described herein is the first three-locus association with a complex canine disease and two novel loci that provide targets for exploration in JDM and related immunological dysfunction.

  19. A Model for Understanding the Genetic Basis for Disparity in Prostate Cancer Risk

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0529 TITLE: A Model for Understanding the Genetic Basis for Disparity in Prostate Cancer Risk PRINCIPAL INVESTIGATOR...reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215...AND SUBTITLE A Model for Understanding the Genetic Basis for Disparity in Prostate Cancer Risk 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1

  20. The relevance of animal experimental results for the assessment of radiation genetic risks in man

    International Nuclear Information System (INIS)

    Stephan, G.

    1981-01-01

    No suitable data are available from man for the quantitative assessment of genetic radiation risk. Therefore, the results from experiments on animals must be utilized. Two hypotheses are presented here in drawing analogical conclusions from one species to another. Although the extrapolation of results from animal experiments remains an open question, the use of experimental results from mice seems to be justified for an assessment of the genetic radiation risk in man. (orig.) [de

  1. Severe hypoalbuminemia is a strong independent risk factor for acute respiratory failure in COPD: a nationwide cohort study

    Directory of Open Access Journals (Sweden)

    Chen CW

    2015-06-01

    .87, P<0.001. However, as the annual average dose of albumin supplementation was higher than 13.8 g per year, the risk for ARF was the highest (adjusted HR: 11.13, 95% CI: 10.35–11.98, P<0.001.Conclusion: Hypoalbuminemia is a strong risk factor for ARF in patients with COPD. Therefore, further prospective studies are required to verify whether or not albumin supplementation or nutritional support may help to reduce the risk of ARF in patients with COPD.Keywords: COPD, acute respiratory failure, hypoalbuminemia

  2. Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson's disease: a genetic association study.

    Science.gov (United States)

    Bjørnarå, Kari Anne; Pihlstrøm, Lasse; Dietrichs, Espen; Toft, Mathias

    2018-02-21

    Parkinson's disease is a heterogeneous disorder where genetic factors may underlie clinical variability. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia strongly linked to synucleinopathies, including Parkinson's disease. We hypothesized that SNCA variants conferring risk of Parkinson's disease would also predispose to an RBD phenotype. We assessed possible RBD (pRBD) status using the RBD screening questionnaire and investigated known susceptibility variants for Parkinson's disease located in the α-synuclein (SNCA) and tau (MAPT) gene loci in 325 Parkinson's disease patients. Associations between genetic risk variants and RBD were investigated by logistic regression, and an independent dataset of 382 patients from the Parkinson's Progression Marker Initiative (PPMI) study was used for replication. pRBD was associated with rs3756063 located in the 5' region of SNCA (two-sided p = 0.018, odds ratio 1.44). We replicated this finding in the PPMI dataset (one-sided p = 0.036, odds ratio 1.35) and meta-analyzed the results (two-sided p = 0.0032, odds ratio 1.40). The Parkinson's disease risk variant in the 3' region of SNCA and the MAPT variant showed no association with pRBD. Our findings provide proof of principle that a largely stable, dichotomous clinical feature of Parkinson's disease can be linked to a specific genetic susceptibility profile. Indirectly, it also supports the hypothesis of RBD as relevant marker for a distinct subtype of the disorder.

  3. The risk for cancer and genetic abnormalities after radioiodine treatment of hyperthyroidism

    International Nuclear Information System (INIS)

    Reiners, C.

    1997-01-01

    According to recent studies, the risk for thyroid cancer is not increased after radioiodine treatment in patients with hyperthyroidism. Only the risk of cancer of the stomach seems to be increased slightly in patents treated with I-131 because of functional autonomy. However, the risk for gastric cancer is not increased after higher activities of I-131 because of thyroid cancer. There is no increased risk for genetic abnormalities after radioiodine treatment of hyperthyroidism. (orig.) [de

  4. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Klaus Stark

    2010-10-01

    Full Text Available Dilated cardiomyopathy (DCM is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39% and idiopathic DCM (p = 1.06 × 10⁻⁶, OR  = 0.67 [95% CI 0.57-0.79] for the minor allele T. Three more SNPs showed p < 2.21 × 10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92], France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR  = 0.74 [95% CI 0.60-0.91], and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻⁴, OR  = 0.63 [95% CI 0.50-0.81]. The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]. None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using

  5. Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

    Science.gov (United States)

    Stark, Klaus; Esslinger, Ulrike B.; Reinhard, Wibke; Petrov, George; Winkler, Thomas; Komajda, Michel; Isnard, Richard; Charron, Philippe; Villard, Eric; Cambien, François; Tiret, Laurence; Aumont, Marie-Claude; Dubourg, Olivier; Trochu, Jean-Noël; Fauchier, Laurent; DeGroote, Pascal; Richter, Anette; Maisch, Bernhard; Wichter, Thomas; Zollbrecht, Christa; Grassl, Martina; Schunkert, Heribert; Linsel-Nitschke, Patrick; Erdmann, Jeanette; Baumert, Jens; Illig, Thomas; Klopp, Norman; Wichmann, H.-Erich; Meisinger, Christa; Koenig, Wolfgang; Lichtner, Peter; Meitinger, Thomas; Schillert, Arne; König, Inke R.; Hetzer, Roland; Heid, Iris M.; Regitz-Zagrosek, Vera; Hengstenberg, Christian

    2010-01-01

    Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a

  6. Genetically predicted high body mass index is associated with increased gastric cancer risk.

    Science.gov (United States)

    Mao, Yingying; Yan, Caiwang; Lu, Qun; Zhu, Meng; Yu, Fei; Wang, Cheng; Dai, Juncheng; Ma, Hongxia; Hu, Zhibin; Shen, Hongbing; Jin, Guangfu

    2017-09-01

    Epidemiological studies have linked body mass index (BMI) with risk of gastrointestinal cancers. However, for gastric cancer, the relationship is more controversial. In particular, it is unclear whether the observed association is due to confounding or bias inherent in conventional observational studies. To investigate whether BMI is causally associated with gastric cancer risk, we applied Mendelian randomization using individual-level data from 2631 gastric cancer cases and 4373 cancer-free controls. We derived a weighted genetic risk score (wGRS) using 37 BMI-associated genetic variants as an instrumental variable. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between genetically predicted BMI and gastric cancer risk. We observed that higher genetically determined BMI was associated with increased gastric cancer risk (per standard deviation (SD) increase in the wGRS: OR=1.07, 95% CI: 1.02-1.13, P=4.94 × 10 -3 ). Compared with individuals in the bottom tertile of the BMI wGRS, those in the top tertile had 1.14-fold (95% CI: 1.01-1.29) increased risk of developing gastric cancer. Sensitivity analyses using alternative causal inference measures demonstrated consistent association. Our study indicated that genetically high BMI was associated with increased gastric cancer risk, suggesting that high BMI may have a causal role in the etiology of gastric cancer.

  7. Risks and benefits of genetically modified foods | Amin | African ...

    African Journals Online (AJOL)

    There are claims that fear towards new technology has been caused by the lack of information and education on the subject to the public. Modern biotechnology and its applications have been receiving the same criticism. Thus, the objective of this study is to analyze the trends and coverage of genetically modified food ...

  8. Assessing ecological risks and benefits of genetically modified crops

    OpenAIRE

    Bošković Jelena V.; Isajev Vasilije V.; Prijić Željana S.; Zečević Veselinka M.; Hojka Zdravko M.; Dozet Gordana K.

    2010-01-01

    Genetically modified (GM) crops and biotechnology are providing new opportunities for increasing crop productivity and tackling agriculture problems, such as diseases, pests and weeds, abiotic stress and nutritional limitations of staple food crops. As GM crops are being adopted in various locations with different ecosystems, a scientifically based understanding of the environmental effects of cultivations of GM crops would assist decision makers worldwide ...

  9. Barriers and Facilitators to BRCA Genetic Counseling Among At-Risk Latinas in New York City

    Science.gov (United States)

    Sussner, Katarina M.; Jandorf, Lina; Thompson, Hayley S.; Valdimarsdottir, Heiddis B.

    2012-01-01

    Objective Despite underuse of genetic services for hereditary breast and/or ovarian cancer risk among Latinas (including counseling and testing for BRCA mutations), there is little known about the barriers and facilitators to BRCA genetic counseling among this group. It is imperative to first understand factors that may impede Latinas seeking BRCA genetic counseling, as it is considered a prerequisite to testing. Methods Quantitative telephone interviews (N=120) were conducted with at-risk Latinas in New York City to investigate interest, barriers and beliefs about BRCA genetic counseling. Statistical analyses examined predictors of intention to undergo BRCA genetic counseling. Results Despite moderate levels of awareness, Latinas held largely positive beliefs, attitudes and knowledge about BRCA genetic counseling. Perceived barriers included logistic concerns (e.g., where to go, cost/health insurance coverage), emotional concerns (e.g., fear, distress) and competing life concerns (e.g, too many other things to worry about, too busy taking care of children or family members). Multivariate results showed that the strongest predictor of intention to undergo BRCA genetic counseling was competing life concerns; Latinas with more competing life concerns were less likely to intend to undergo BRCA genetic counseling (p=0.0002). Other significant predictors of intention included perceived risk of carrying a BRCA mutation (p=0.01) and referral by their physician (p=0.02). Conclusion Educational efforts to promote BRCA genetic counseling among at-risk Latinas and increase referrals by their physicians should incorporate discussion of perceived barriers to counseling, such as competing life concerns that Latinas may need to overcome in order to seek genetic counseling. PMID:22987526

  10. Provider Discussions of Genetic Tests With U.S. Women at Risk for a BRCA Mutation.

    Science.gov (United States)

    Hull, Leland E; Haas, Jennifer S; Simon, Steven R

    2018-02-01

    The U.S. Preventive Services Task Force recommends that primary care providers screen unaffected women with a family history of BRCA mutation-associated cancers, but without a personal history of BRCA-related cancer, for referral to genetic counseling and potential genetic testing. The 2015 National Health Interview Survey was analyzed in January 2017 to determine the rates at which unaffected adult women with a positive family history of BRCA-related cancers, assessed using the Family History Screen-7, reported discussing genetic testing with a provider, using genetic counseling services, and having genetic testing for increased cancer risk. Clinical correlates associated with these outcomes were assessed using multivariable logistic regression (AOR with 95% CI). Among unaffected Family History Screen-7 screen-positive women, 9.5% reported discussing genetic testing with a provider, 5.1% reported genetic counseling, and 2.7% reported uptake of genetic testing. Younger women (aged 18-39 and 40-49 years) were more likely to discuss genetic testing than women aged ≥60 years (AOR=1.50, 95% CI=1.09, 2.06 and AOR=1.64, 95% CI=1.15, 2.33, respectively). Women of black race (AOR=1.50, 95% CI=1.09, 2.07) and women with greater than a high school education (AOR=1.85, 95% CI=1.41, 2.43) were more likely to discuss genetic testing than women of white race and women with a high school education or less, respectively. Among a higher risk subgroup with an even stronger family history of BRCA-associated cancers, 18.5% of women reported discussions. Despite a decade-old U.S. Preventive Services Task Force recommendation, few unaffected women at risk for BRCA-associated cancer report discussing genetic testing with a provider. Published by Elsevier Inc.

  11. Risk perception among women receiving genetic counseling: a population-based follow-up study

    DEFF Research Database (Denmark)

    Mikkelsen, Ellen M; Sunde, Lone; Johansen, Christoffer

    2007-01-01

    BACKGROUND: We aimed to explore the impact of genetic counseling on perceived personal lifetime risk of breast cancer, the accuracy of risk perception, and possible predictors of inaccurate risk perception 1 year following counseling. METHODS: We conducted a population-based prospective follow...... counseling, compared to a reduction of 5% (p=0.03) and 2% (p=0.01) in Reference Groups I and II, respectively. Risk communicated only in words, inaccurate risk perception at baseline, and presence of a familial mutation appeared to be predictors of inaccurate risk perception 12 months after counseling...

  12. Entangled local biologies: genetic risk, bodies and inequities in Brazilian cancer genetics.

    Science.gov (United States)

    Gibbon, Sahra

    2017-08-01

    Engaging recent social science work examining the truth making claims of science and biomedicine, this paper explores how biology is being localised in Brazilian cancer genetics. It draws from ethnographic fieldwork in urban regions of southern Brazil working with and alongside patients, families and practitioners in cancer genetic clinics. It examines how different sorts of 'local biologies' are articulated in the context of research, clinical practice and among implicated patient communities and the way these can 'recursively' move across different spheres and scales of social action to extend and transform the meaning of the biological. It shows how the mattering of the biological in Brazilian cancer genetics is fundamentally informed by questions of inequity and care, even while multiple local biologies may obscure rather than reveal the biopolitics of cancer. In an era of epigenetics this raises new opportunities and challenges for anthropological analysis as intervention.

  13. Diffusion-weighted MRI for detecting prostate tumour in men at increased genetic risk

    International Nuclear Information System (INIS)

    Souza, Nandita M. de; Morgan, Veronica A.; Bancroft, Elizabeth; Sohaib, S. Aslam; Giles, Sharon L.; Kote-Jarai, Zsofia; Castro, Elena; Hazell, Steven; Jafar, Maysam; Eeles, Rosalind

    2014-01-01

    •Endorectal T2W + DW-MRI is potentially useful for prostate cancer screening.•MRI is specific for detecting prostate cancer in men with increased genetic risk.•Detection of prostate cancer in men at genetically low risk with MRI is limited. Endorectal T2W + DW-MRI is potentially useful for prostate cancer screening. MRI is specific for detecting prostate cancer in men with increased genetic risk. Detection of prostate cancer in men at genetically low risk with MRI is limited. Diffusion-weighted (DW)-MRI is invaluable in detecting prostate cancer. We determined its sensitivity and specificity and established interobserver agreement for detecting tumour in men with a family history of prostate cancer stratified by genetic risk. 51 men with a family history of prostate cancer underwent T2-W + DW-endorectal MRI at 3.0 T. Presence of tumour was noted at right and left apex, mid and basal prostate sextants by 2 independent observers, 1 experienced and the other inexperienced in endorectal MRI. Sensitivity and specificity against a 10-core sampling technique (lateral and medial cores at each level considered together) in men with >2× population risk based on 71 SNP analysis versus those with lower genetic risk scores was established. Interobserver agreement was determined at a subject level. Biopsies indicated cancer in 28 sextants in 13/51 men; 32 of 51 men had twice the population risk (>0.25) based on 71 SNP profiling. Sensitivity/specificity per-subject for patients was 90.0%/86.4% (high-risk) vs. 66.7%/100% (low-risk, observer 1) and 60.0%/86.3% (high-risk) vs. 33.3%/93.8% (low-risk, observer 2) with moderate overall inter-observer agreement (kappa = 0.42). Regional sensitivities/specificities for high-risk vs. low-risk for observer 1 apex 72.2%/100% [33.3%/100%], mid 100%/93.1% [100%/97.3%], base 16.7%/98.3% [0%/100%] and for observer 2 apex 36.4%/98.1% [0%/100%], mid 28.6%/96.5% [100%/100%], base 20%/100% [0%/97.3%] were poorer as they failed to detect

  14. Height, selected genetic markers and prostate cancer risk

    DEFF Research Database (Denmark)

    Lophatananon, Artitaya; Stewart-Brown, Sarah; Kote-Jarai, Zsofia

    2017-01-01

    BACKGROUND: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer. METHODS: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases ...

  15. Height, selected genetic markers and prostate cancer risk

    DEFF Research Database (Denmark)

    Lophatananon, Artitaya; Stewart-Brown, Sarah; Kote-Jarai, Zsofia

    2017-01-01

    Background:Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.Methods:We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and...

  16. Strong genetic differentiation among east Atlantic populations of the sword razor shell ( Ensis siliqua) assessed with mtDNA and RAPD markers

    Science.gov (United States)

    Arias, Alberto; Fernández-Moreno, Mercedes; Fernández-Tajes, Juan; Gaspar, Miguel B.; Méndez, Josefina

    2011-03-01

    The sword razor shell Ensis siliqua (Linnaeus, 1758) is a bivalve with a high commercial value being appreciated in fresh and processed markets. However, the genetic studies carried out in populations of E. siliqua are scarce. In this work, the genetic variability and differentiation of the sword razor shell was assessed using PCR-RFLPs of a fragment of the 16S rRNA mitochondrial gene and random amplified polymorphic loci (RAPD) in nine localities from Ireland, Spain, and Portugal. In the 314 individuals examined for the mitochondrial fragment, 12 composite haplotypes were observed; meanwhile, a unique phenotype was observed for each of the 242 individuals analyzed with 61 RAPD loci. Two of the mitochondrial composite haplotypes accounted for the majority of individuals (89.81%) and showed a remarkably disjoint distribution between Irish and Iberian samples, with the exception of Aveiro which exhibited as the most frequent haplotype the same found in Ireland. The level of variability observed for each sample was generally correlated with both types of markers and the results obtained suggest the existence of a strong population differentiation between Irish and Iberian localities, except for the Portuguese sample from Aveiro which is surprisingly closer to Irish individuals, although it is probably highly differentiated.

  17. The Geographic Distribution of Saccharomyces cerevisiae Isolates within three Italian Neighboring Winemaking Regions Reveals Strong Differences in Yeast Abundance, Genetic Diversity and Industrial Strain Dissemination

    Directory of Open Access Journals (Sweden)

    Alessia Viel

    2017-08-01

    Full Text Available In recent years the interest for natural fermentations has been re-evaluated in terms of increasing the wine terroir and managing more sustainable winemaking practices. Therefore, the level of yeast genetic variability and the abundance of Saccharomyces cerevisiae native populations in vineyard are becoming more and more crucial at both ecological and technological level. Among the factors that can influence the strain diversity, the commercial starter release that accidentally occur in the environment around the winery, has to be considered. In this study we led a wide scale investigation of S. cerevisiae genetic diversity and population structure in the vineyards of three neighboring winemaking regions of Protected Appellation of Origin, in North-East of Italy. Combining mtDNA RFLP and microsatellite markers analyses we evaluated 634 grape samples collected over 3 years. We could detect major differences in the presence of S. cerevisiae yeasts, according to the winemaking region. The population structures revealed specificities of yeast microbiota at vineyard scale, with a relative Appellation of Origin area homogeneity, and transition zones suggesting a geographic differentiation. Surprisingly, we found a widespread industrial yeast dissemination that was very high in the areas where the native yeast abundance was low. Although geographical distance is a key element involved in strain distribution, the high presence of industrial strains in vineyard reduced the differences between populations. This finding indicates that industrial yeast diffusion it is a real emergency and their presence strongly interferes with the natural yeast microbiota.

  18. Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

    Science.gov (United States)

    Cheng, Yue; Yu, Chengxiao; Huang, Mingtao; Du, Fangzhi; Song, Ci; Ma, Zijian; Zhai, Xiangjun; Yang, Yuan; Liu, Jibin; Bei, Jin-Xin; Jia, Weihua; Jin, Guangfu; Li, Shengping; Zhou, Weiping; Liu, Jianjun; Dai, Juncheng; Hu, Zhibin

    2017-10-01

    Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk. Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk. We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups. Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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

  20. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

    DEFF Research Database (Denmark)

    Muranen, Taru A; Greco, Dario; Blomqvist, Carl

    2017-01-01

    PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion...

  1. Prediction of breast cancer risk based on profiling with common genetic variants

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Pharoah, Paul D P; Michailidou, Kyriaki

    2015-01-01

    BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. M...

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

    DEFF Research Database (Denmark)

    Robinson, Elise B; St Pourcain, Beate; Anttila, Verneri

    2016-01-01

    Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we...

  3. Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk

    DEFF Research Database (Denmark)

    Rudolph, Anja; Hein, Rebecca; Lindström, Sara

    2013-01-01

    Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case...

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

    NARCIS (Netherlands)

    Pertry, I.; Nothegger, C.; Sweet, J.; Kuiper, H.A.; Davies, H.; Iserentant, D.; Hull, R.; Mezzetti, B.; Messens, K.; Loose, De M.; Oliveira, de D.; Burssens, S.; Gheysen, G.; Tzotzos, G.

    2014-01-01

    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

  5. Prediction of breast cancer risk based on profiling with common genetic variants

    NARCIS (Netherlands)

    N. Mavaddat (Nasim); P.D.P. Pharoah (Paul); K. Michailidou (Kyriaki); J.P. Tyrer (Jonathan); M.N. Brook (Mark N.); M.K. Bolla (Manjeet); Q. Wang (Qing); J. Dennis (Joe); A.M. Dunning (Alison); M. Shah (Mitul); R.N. Luben (Robert); J. Brown (Judith); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune F.); H. Flyger (Henrik); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mikael); J. Peto (Julian); I. dos Santos Silva (Isabel); F. Dudbridge (Frank); N. Johnson (Nichola); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Verhoef; E.J. Rutgers (Emiel J.); A.J. Swerdlow (Anthony ); A. Ashworth (Alan); N. Orr (Nick); M. Schoemaker (Minouk); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); L.A. Brinton (Louise); J. Lissowska (Jolanta); F.J. Couch (Fergus); J.E. Olson (Janet); C. Vachon (Celine); V.S. Pankratz (Shane); D. Lambrechts (Diether); H. Wildiers (Hans); C. van Ongeval (Chantal); E. van Limbergen (Erik); V. Kristensen (Vessela); G. Grenaker Alnæs (Grethe); S. Nord (Silje); A.-L. Borresen-Dale (Anne-Lise); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); P.A. Fasching (Peter); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); A. Trentham-Dietz (Amy); P. Newcomb (Polly); L. Titus (Linda); K.M. Egan (Kathleen M.); D. Hunter (David); S. Lindstrom (Stephen); R. Tamimi (Rulla); P. Kraft (Peter); N. Rahman (Nazneen); C. Turnbull (Clare); A. Renwick (Anthony); S. Seal (Sheila); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); J. Benítez (Javier); M.P. Zamora (Pilar); J.I. Arias Pérez (José Ignacio); P. Menéndez (Primitiva); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); T. Dörk (Thilo); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); A. Ziogas (Argyrios); L. Bernstein (Leslie); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); E.K. Khusnutdinova (Elza); M. Bermisheva (Marina); D. Prokofyeva (Darya); Z. Takhirova (Zalina); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Sutter (Christian); R. Yang (Rongxi); P. Schürmann (Peter); M. Bremer (Michael); H. Christiansen (Hans); T.-W. Park-Simon; P. Hillemanns (Peter); P. Guénel (Pascal); T. Truong (Thérèse); F. Menegaux (Florence); M. Sanchez (Marie); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); V. Pensotti (Valeria); J. Hopper (John); H. Tsimiklis (Helen); C. Apicella (Carmel); M.C. Southey (Melissa); H. Brauch (Hiltrud); T. Brüning (Thomas); Y.-D. Ko (Yon-Dschun); A.J. Sigurdson (Alice); M.M. Doody (Michele M.); U. Hamann (Ute); D. Torres (Diana); H.U. Ulmer (Hans); A. Försti (Asta); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A. Marie Mulligan (Anna); G. Chenevix-Trench (Georgia); R. Balleine (Rosemary); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); A. Lindblom (Annika); S. Margolin (Sara); C.A. Haiman (Christopher); B.E. Henderson (Brian); F. Schumacher (Fredrick); L. Le Marchand (Loic); U. Eilber (Ursula); S. Wang-Gohrke (Shan); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); A.M.W. van den Ouweland (Ans); L.B. Koppert (Lisa); J. Carpenter (Jane); C. Clarke (Christine); R.J. Scott (Rodney J.); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); H. Brenner (Hermann); V. Arndt (Volker); C. Stegmaier (Christa); A. Karina Dieffenbach (Aida); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); K. Offit (Kenneth); J. Vijai (Joseph); M. Robson (Mark); R. Rau-Murthy (Rohini); M. Dwek (Miriam); R. Swann (Ruth); K. Annie Perkins (Katherine); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); D. Eccles (Diana); W. Tapper (William); M. Rafiq (Meena); E.M. John (Esther M.); A.S. Whittemore (Alice); S. Slager (Susan); D. Yannoukakos (Drakoulis); A.E. Toland (Amanda); S. Yao (Song); W. Zheng (Wei); S.L. Halverson (Sandra L.); A. González-Neira (Anna); G. Pita (G.); M. Rosario Alonso; N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); S. Healey (Sue); J. Simard (Jacques); P. Hall (Per); D.F. Easton (Douglas); M. García-Closas (Montserrat)

    2015-01-01

    textabstractBackground: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is

  6. Genetic variation in adipokine genes and risk of colorectal cancer

    Czech Academy of Sciences Publication Activity Database

    Pechlivanis, S.; Bermejo, J. L.; Pardini, Barbara; Naccarati, Alessio; Vodičková, Ludmila; Novotný, J.; Hemminki, K.; Vodička, Pavel; Försti, A.

    2009-01-01

    Roč. 160, č. 6 (2009), s. 933-940 ISSN 0804-4643 R&D Projects: GA ČR GA310/07/1430; GA MZd NR8563 Grant - others:EU(SE) LSHC-CT-2004-503465 Institutional research plan: CEZ:AV0Z50390512 Keywords : colorectal cancer * diabetes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.539, year: 2009

  7. Personalized medicine: Genetic risk prediction of drug response.

    Science.gov (United States)

    Zhang, Ge; Nebert, Daniel W

    2017-07-01

    Pharmacogenomics (PGx), a substantial component of "personalized medicine", seeks to understand each individual's genetic composition to optimize drug therapy -- maximizing beneficial drug response, while minimizing adverse drug reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits -- influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance -- thus having limited predictive power and clinical utility. Copyright © 2017 Elsevier Inc. All

  8. Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study.

    Science.gov (United States)

    Seyednasrollah, Fatemeh; Mäkelä, Johanna; Pitkänen, Niina; Juonala, Markus; Hutri-Kähönen, Nina; Lehtimäki, Terho; Viikari, Jorma; Kelly, Tanika; Li, Changwei; Bazzano, Lydia; Elo, Laura L; Raitakari, Olli T

    2017-06-01

    Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods. A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744, P obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity. © 2017 American Heart Association, Inc.

  9. Genetic risk scores and family history as predictors of schizophrenia in Nordic registers

    DEFF Research Database (Denmark)

    Lu, Y.; Pouget, J. G.; Andreassen, O. A.

    2017-01-01

    Background: Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk...... through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes. Results...

  10. Risk-based in situ bioremediation design using a noisy genetic algorithm

    Science.gov (United States)

    Smalley, J. Bryan; Minsker, Barbara S.; Goldberg, David E.

    2000-10-01

    Risk-based corrective action (RBCA) is rapidly becoming the method of choice for remediating contaminated groundwater. In this paper, a management model is presented that simultaneously predicts risk and proposes cost-effective options for reducing risk to acceptable levels under conditions of uncertainty. The model combines a noisy genetic algorithm with a numerical fate and transport model and an exposure and risk assessment model. The noisy genetic algorithm uses sampling from parameter distributions to assess the performance of candidate designs. Results from an application to a site from the literature show that the noisy genetic algorithm is capable of identifying highly reliable designs from a small number of samples, a significant advantage for computationally intensive groundwater management models. For the site considered, time-dependent costs associated with monitoring and the remedial system were significant, illustrating the potential importance of allowing variable cleanup lengths and a realistic cost function.

  11. Risks associated with genetic testing: health insurance discrimination or simply business as usual?

    Science.gov (United States)

    Steinberg, K K

    2000-01-01

    Doctors can test patients for mutations that put them at high risk for hereditary forms of such diseases as breast and ovarian cancer. Even though the opportunities for disease prevention using genetic testing will increase with time, the risks of testing, which include insurance loss and employment discrimination, currently make testing problematic. Some have proposed making use of genetic information in health insurance underwriting illegal. But in the current system of risk-based underwriting, it is hard to imagine that insurance companies will willingly forego access to a growing body of information on risk. If the American public chooses to limit the use of genetic information, a reassessment of current laws or methods of paying for health care will be needed.

  12. Psychological factors associated with emotional responses to receiving genetic risk information.

    Science.gov (United States)

    Bennett, Paul; Wilkinson, Clare; Turner, Jim; Brain, Kate; Edwards, Rhiannon Tudor; Griffith, Gethin; France, Barbara; Gray, Jonathon

    2008-06-01

    This study identified levels of distress, and predictors of levels of distress, in women undergoing assessment for genetic risk of breast/ovarian cancer based on their family history. It comprised a cohort study following 154 women who completed questionnaires at entry into a cancer genetic assessment programme and following risk provision. Independent significant associates of anxiety following risk provision were age, neuroticism, feeling hopeless about developing cancer, a perceived lack of control over developing cancer, lack of a social confidant, and a coping response involving acceptance/resignation. Depression was associated with age, neuroticism, feeling hopeless about developing cancer, lack of social confidant, and a coping response involving acceptance/resignation. To avoid high levels of psychological morbidity in future cohorts undergoing cancer genetic risk assessment, information should be given that emphasises that some degree of control over health outcomes through behaviour change or increased surveillance is possible.

  13. Ecological Risk Assessment of Genetically Modified Higher Plants (GMHP)

    DEFF Research Database (Denmark)

    Kjær, C.; Damgaard, C.; Kjellsson, G.

    assessment of GM plants when application for placing on the market is made. It is our hope that both the scientific community, the biotechnological industry and the regulatory bodies will participate in the process of improving the present draft, so that it can develop into a useful tool for both...... and establishment of the modified plant in natural habitats; risk of introgression of the inserted or modified traits to other plant species; and the risk of adverse effects on non-target organisms. The guidance paper considers only aspects of ecological risk assessment. Possible risks to human health, livestock...... for reproduction of the GMHP B. Identification of possible effects on non-target organisms C. Detection of potential hybridisation, and assessment of the selective force acting on the inserted gene in a natural plant population Tier III. Laboratory measurements and small scale trials on the GMHP A. Test of changes...

  14. Stress and Coping in Genetic Testing for Cancer Risk

    National Research Council Canada - National Science Library

    Coyne, James

    1997-01-01

    .... In the absence of a large body of relevant prior research, we are faced with an urgent need for basic descriptive data concerning women at high-risk for early onset breast cancer and their families...

  15. Genetically elevated bilirubin and risk of ischaemic heart disease

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  16. Prostate cancer screening using risk stratification based on a multi-state model of genetic variants.

    Science.gov (United States)

    Yen, Amy Ming-Fang; Auvinen, Anssi; Schleutker, Johanna; Wu, Yi-Ying; Fann, Jean Ching-Yuan; Tammela, Teuvo; Chen, Sam Li-Sheng; Chiu, Sherry Yueh-Hsia; Chen, Hsiu-Hsi

    2015-06-01

    Risk-stratified screening for prostate cancer (PCa) with prostate-specific antigen (PSA) testing incorporating genetic variants has received some attention but has been scarcely investigated. We developed a model to stratify the Finnish population by different risk profiles related to genetic variants to optimize the screening policy. Data from the Finnish randomized controlled trial on screening for PCa with PSA testing were used to estimate a six-state Markov model of disease progression. Blood samples from Finnish men were used to assess the risk of PCa related to three genetic variants (rs4242382, rs138213197, and rs200331695). A risk score-based approach combined with a series of computer simulation models was applied to optimize individual screening policies. The 10-year risk of having progressive prostate cancer detected ranged from 43% in the top 5% risk group to approximately 11% in the bottom half of the population. Using the median group, with screening every four years beginning at 55 years-old, as the reference group, the recommended age beginning screening was approximately 47 years-old for the top 5% risk group and 55 years-old for those in the lower 60% risk group. The recommended interscreening interval has been shortened for individuals in the high risk group. The increased availability of genomic information allows the proposed multistate model to be more discriminating with respect to risk stratification and the suggested screening policy, particularly for the lowest risk groups-. -- A multi-state genetic variant-based model was developed for further application to population risk stratification to optimize the interscreening interval and the age at which to begin screening for PSA. A small sub-group of the population is likely to benefit from more intensive screening with early start and short interval, while half of the population is unlikely to benefit from such protocol (compared with four-year interval after age 55 years). © 2015 Wiley

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

    Science.gov (United States)

    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

  18. Risk assessment: the importance of genetic polymorphisms in man

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E.; Loft, S H; Autrup, H

    2001-01-01

    of 2. Some polymorphisms are effect modifiers, i.e. without exposure they have no consequence and the effect of exposure can appear independent of the genotype. Genetic polymorphisms in metabolism of environmental toxicants plays a significant role in exposures to traffic generated air pollution...... in Copenhagen, revealing statistically significant higher levels of chromosomal aberrations in non-smoking bus drivers with glutathion-S-transferase M1, GSTM1 null and N-acetyltransferase 2, NAT2 slow genotypes. Combined with cohort studies showing positive associations between high chromosomal levels...

  19. Risks assessment - role of pre-existing genetic variation

    International Nuclear Information System (INIS)

    Unrau, P.; Doerffer, K.

    1996-01-01

    Previously published research on the epidemiology and molecular basis of genetic or congenital diseases and their occurrence in certain 'ethnic' or isolated populations is discussed to show the significance of consanguinity and 'ethnicity' as contributing factors. A statistical study aiming to correlate malformations with absolutely any environmental factor may miss the significance of defects in a gene pool. This consideration has an obvious significance for the nuclear industry. For example, carriers of Fanconi's anemia appear to have an increased tendency to develop acute myelogenous leukemia. The authors indicate the difficulty in finding a definite molecular basis even for simple Mendelian monogenic disorders such as Tay-Sachs disease. 12 refs., 4 tabs

  20. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study

    Science.gov (United States)

    Muniz Terrera, Graciela; Keage, Hannah; Rahkonen, Terhi; Oinas, Minna; Matthews, Fiona E.; Cunningham, Colm; Polvikoski, Tuomo; Sulkava, Raimo; MacLullich, Alasdair M. J.; Brayne, Carol

    2012-01-01

    .1–3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2–6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia. PMID:22879644

  1. Genetic and environmental-genetic interaction rules for the myopia based on a family exposed to risk from a myopic environment.

    Science.gov (United States)

    Wenbo, Li; Congxia, Bai; Hui, Liu

    2017-08-30

    To quantitatively assess the role of heredity and environmental factors in myopia based on the family with enough exposed to risk from myopic environment for establishment of environmental and genetic index (EGI). A pedigree analysis unit was defined as one child (university student), father, and mother. Information pertaining to visual acuity, experience in participating in the college entrance examination in mainland of China (regarded as a strong environmental risk for myopia), and occupation for pedigree analysis units were obtained. The difference between effect of both genetic and environmental factors (myopia prevalence in children with two myopic parents) and environmental factors (myopia prevalence in children of whom neither parent was myopic) was defined as the EGI. Multiple regression analysis was performed for 114 pedigree using diopters of father, mother, average diopters in parents, maximum and minimum diopters in father and mother as variables. A total of 353 farmers and 162 farmer families were used as a control group. A distinct difference in myopia rate (96.2% versus 57.7%) was observed for children from parents with myopia and parents without myopia (EGI=0.385). The maximum diopter was included to regression equation which was statistically significant. The prevalence of myopia was 9.9% in the farmer. The prevalence in children is similar between the farmer and other families. A new genetic rule that myopia in children was directly related with maximum diopters in father and mother may be suggested. Environmental factors may play a leading role in the formation of myopia. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women.

    Science.gov (United States)

    Sarnowski, Chloé; Kavousi, Maryam; Isaacs, Steve; Demerath, Ellen W; Broer, Linda; Muka, Taulant; Franco, Oscar H; Ikram, Mohammad Arfan; Uitterlinden, André; Franceschini, Nora; Lunetta, Kathryn L; Murabito, Joanne M

    2018-04-01

    To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data. Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopause is associated with increased cardiovascular disease risk, it is reasonable to ask whether the risk is shared by men carrying the alleles, despite not experiencing menopause. We estimated the hazard ratio for the score for time to first cardiovascular event. To investigate the possible genetic pleiotropy between age-at-natural menopause and cardiovascular disease, we performed cross-trait linkage disequilibrium score regressions between age-at-natural menopause and cardiovascular disease and risk factors using genome-wide association studies. Twenty-two thousand five hundred and sixty-eight cardiovascular disease-free participants at baseline were analyzed (9,808 men, 12,760 women). Each additional unit of the genetic propensity to earlier age-at-natural menopause increased the hazard of both cardiovascular disease and cardiac death in women (cardiovascular disease: hazard ratio 1.10 [1.04-1.16], P = 9.7 × 10; cardiac death: 1.12 [1.02-1.24], P = 0.03), whereas no effect was observed for either outcome in men (hazard ratio 0.99 [0.95-1.04], P = 0.71; 1.05 [0.94-1.16], P = 0.34). We found significant negative genetic correlations in women, but not men, between age-at-natural menopause and cardiovascular disease and risk factors. Genetic variants associated with earlier age-at-natural menopause are associated with increased cardiovascular disease risk in women, but not men, suggesting sex-specific genetic effects on cardiovascular disease risk.

  3. Differential Effects of Estrogen and Progesterone on Genetic and Environmental Risk for Emotional Eating in Women

    Science.gov (United States)

    Klump, Kelly L.; O’Connor, Shannon M.; Hildebrandt, Britny A.; Keel, Pamela K.; Neale, Michael; Sisk, Cheryl L.; Boker, Steven; Burt, S. Alexandra

    2016-01-01

    Recent data show shifts in genetic and environmental influences on emotional eating across the menstrual cycle, with significant shared environmental influences during pre-ovulation, and primarily genetic effects during post-ovulation. Factors driving differential effects are unknown, although increased estradiol during pre-ovulation and increased progesterone during post-ovulation are thought to play a role. We indirectly investigated this possibility by examining whether overall levels of estradiol and progesterone differentially impact genetic and environmental risk for emotional eating in adult female twins (N = 571) drawn from the MSU Twin Registry. Emotional eating, estradiol levels, and progesterone levels were assessed daily and then averaged to create aggregate measures for analysis. As predicted, shared environmental influences were significantly greater in twins with high estradiol levels, whereas additive genetic effects increased substantially across low versus high progesterone groups. Results highlight significant and differential effects of ovarian hormones on etiologic risk for emotional eating in adulthood. PMID:27747142

  4. Structure of genetic and environmental risk factors for dimensional representations of DSM–IV anxiety disorders

    Science.gov (United States)

    Tambs, Kristian; Czajkowsky, Nikolai; Røysamb, Espen; Neale, Michael C.; Reichborn-Kjennerud, Ted; Aggen, Steven H.; Harris, Jennifer R.; Ørstavik, Ragnhild E.; Kendler, Kenneth S.

    2010-01-01

    Background Twin data permit decomposition of comorbidity into genetically and environmentally derived correlations. No previous twin study includes all major forms of anxiety disorder. Aims To estimate the degree to which genetic and environmental risk factors are shared rather than unique to dimensionally scored panic disorder, generalised anxiety disorder, phobias, obsessive–compulsive disorder and post-traumatic stress disorder. Method Data obtained from 2801 young-adult Norwegian twins by means of the Composite International Diagnostic Interview were analysed with the Mx program. Results A multivariate common factor model fitted best. The latent liability to all anxiety disorders was substantially more heritable (54%) than the individual disorders (23% to 40%). Most of the genetic effect was common to the disorders. Genes contributed just over 50% to the covariance between liabilities. Conclusions The five anxiety disorders all share genetic and environmental risk factors. This has implications for the revision of the anxiety disorder section in DSM–V. PMID:19794197

  5. Use of doubling doses for the estimation of genetic risks

    International Nuclear Information System (INIS)

    Searle, A.G.

    1977-01-01

    Doubling dose estimates derived from radiation experiments in mice are proving of great value for the assessment of genetic hazards to man from extra radiation exposure because they allow the latest information on mutation frequencies and the incidence of genetic disease in man to be used in the assessment process. The similarity in spectra of 'spontaneous' and induced mutations increases coincidence in the validity of this approach. Data on rates of induction of dominant and recessive mutations, translocations and X-chromosome loss are used to derive doubling doses for chronic exposures to both low and high-LET radiations. Values for γ and X-rays, derived from both male and female germ-cells, fall inside a fairly small range and it is felt that the use of an overall figure of 100 rads is justifiable for protection purposes. Values for neutrons and α-particles, obtained from male germ-cells, varied according to neutron energy etc. but clustered around a value of 5 rads for fission neutrons

  6. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

    DEFF Research Database (Denmark)

    Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki

    2016-01-01

    PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D suscept...

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

    Science.gov (United States)

    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. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Comparative analyses of genetic risk prediction methods reveal ...

    Indian Academy of Sciences (India)

    2015-03-12

    Mar 12, 2015 ... where it is related to modern lifestyle with additional com- plication due to rising incidence of type 2 diabetes melli- tus (DM) and obesity (Angulo and ..... is rapidly becoming a health burden in western and develop- ing countries. In this study we defined a model of disease risk score prediction for different ...

  9. Risk Management of the Natural Gas Consumption using Genetic Algorithms

    Czech Academy of Sciences Publication Activity Database

    Pelikán, Emil; Šimůnek, Milan

    2005-01-01

    Roč. 15, - (2005), s. 425-436 ISSN 1210-0552 R&D Projects: GA AV ČR 1ET400300513 Institutional research plan: CEZ:AV0Z10300504 Keywords : forecasting * risk-management * energy consumption Subject RIV: BB - Applied Statistics, Operational Research

  10. Interaction between 5 genetic variants and allergy in glioma risk

    DEFF Research Database (Denmark)

    Schoemaker, Minouk J; Robertson, Lindsay; Wigertz, Annette

    2010-01-01

    .047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development......., CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden......, and the United Kingdom (2000-2004) were used, totaling 1,029 cases and 1,668 controls. Risk was inversely associated with asthma, hay fever, eczema, and "any allergy," significantly for each factor except asthma, and was significantly positively associated with number of risk alleles for each of the 5 single...

  11. Germline genetic variants with implications for disease risk and therapeutic outcomes.

    Science.gov (United States)

    Pasternak, Amy L; Ward, Kristen M; Luzum, Jasmine A; Ellingrod, Vicki L; Hertz, Daniel L

    2017-10-01

    Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care. Copyright © 2017 the American Physiological Society.

  12. Sex differences in genetic and environmental risk factors for irrational fears and phobias.

    Science.gov (United States)

    Kendler, K S; Jacobson, K C; Myers, J; Prescott, C A

    2002-02-01

    For irrational fears and their associated phobias, epidemiological studies suggest sex differences in prevalence and twin studies report significant genetic effects. How does sex impact on the familial transmission of liability to fears and phobias? In personal interviews with over 3000 complete pairs (of whom 1058 were opposite-sex dizygotic pairs), ascertained from a population-based registry, we assessed the lifetime prevalence of five phobias and their associated irrational fears analysed using a multiple threshold model. Twin resemblance was assessed by polychoric correlations and biometrical model-fitting incorporating sex-specific effects. For agoraphobia, situational and blood/injury fear/phobia, the best fit model suggested equal heritability in males and females and genetic correlations between the sexes of less than +0.50. For animal fear/phobias by contrast, the best fit model suggested equal heritability in males and females and a genetic correlation of unity. No evidence was found for an impact of family environment on liability to these fears or phobias. For social phobias, twin resemblance in males was explained by genetic factors and in females by familial-environmental factors. The impact of sex on genetic risk may differ meaningfully across phobia subtypes. Sex-specific genetic risk factors may exist for agoraphobia, social, situational and blood-injury phobias but not for animal fear/phobia. These results should be interpreted in the context of the limited power of twin studies, even with large sample sizes, to resolve sex-specific genetic effects.

  13. Genetic risk scores link body fat distribution with specific cardiometabolic profiles

    DEFF Research Database (Denmark)

    Svendstrup, Mathilde; Sandholt, Camilla H; Andersson Galijatovic, Ehm Astrid

    2016-01-01

    OBJECTIVE: Forty-nine known single nucleotide polymorphisms (SNPs) associating with body mass index (BMI)-adjusted waist-hip-ratio (WHR) (WHRadjBMI) were recently suggested to cluster into three groups with different associations to cardiometabolic traits. Genetic risk scores of the clusters...... on the risk of incident diabetes and associations with detailed cardiometabolic phenotypes were tested. METHODS: In a prospective study of 6,121 Inter99 individuals, the risk of incident diabetes using Cox proportional hazards regression was evaluated. Using linear regession, the associations between genetic...... risk scores and anthropometry and blood samples at fasting and during an oral glucose tolerance test were tested. Analyses were adjusted for age, sex, and BMI. RESULTS: Cluster 1 associated with an increased risk of diabetes (HR = 1.05, P = 2.74 × 10(-) (4) ) and with a poor metabolic profile...

  14. Risk assesment in the context of EC directives on genetically modified organisms

    International Nuclear Information System (INIS)

    Meer, P.J. van der

    1992-01-01

    The introduction of these new molecular technologies initiated an international discussion on the safety in biotechnology. In 1974 one of the pioneers of this new technology, Paul Berg, expressed his view on the potential risks of recombinant DNA applications in the famous 'Berg letter', leading to a self-imposed moratorium on certain experiments. Following the Berg letter and the Asilomar convention, much international attention has been given to the question of safety in biotechnology. This attention resulted in hundreds of documents, research programmes, guidelines and regulations. This resulted, among others, in two EC Directives on genetically modified organisms: the EC Directive 90/219/EEC on the contained use of genetically modified micro-organisms, and Directive 90/220/EEC on the release of genetically modified organisms. These directives lay down a system for harmonization of risk assessment and risk management with regard to the safety for human health and the environment

  15. Prediction of individual genetic risk to prostate cancer using a polygenic score

    DEFF Research Database (Denmark)

    Szulkin, Robert; Whitington, Thomas; Eklund, Martin

    2015-01-01

    BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate...... prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS...... regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction....

  16. Strong correlation between cross-amplification success and genetic distance across all members of 'True Salamanders' (Amphibia: Salamandridae) revealed by Salamandra salamandra-specific microsatellite loci.

    Science.gov (United States)

    Hendrix, Ralf; Susanne Hauswaldt, J; Veith, Michael; Steinfartz, Sebastian

    2010-11-01

    The unpredictable and low cross-amplification success of microsatellite loci tested for congeneric amphibian species has mainly been explained by the size and complexity of amphibian genomes, but also by taxonomy that is inconsistent with phylogenetic relationships among taxa. Here, we tested whether the cross-amplification success of nine new and 11 published microsatellite loci cloned for an amphibian source species, the fire salamander (Salamandra salamandra), correlated with the genetic distance across all members of True Salamanders (genera Chioglossa, Lyciasalamandra, Mertensiella and Salamandra that form a monophyletic clade within the family of Salamandridae) serving as target species. Cross-amplification success varied strongly among the species and showed a highly significant negative relationship with genetic distance and amplification success. Even though lineages of S. salamandra and Lyciasalamndra have separated more than 30 Ma, a within genus amplification success rate of 65% was achieved for species of Lyciasalamandra thus demonstrating that an efficient cross-species amplification of microsatellite loci in amphibians is feasible even across large evolutionary distances. A decrease in genome size, on the other hand, paralleled also a decrease in amplified loci and therefore contradicted previous results and expectations that amplification success should increase with a decrease in genome size. However, in line with other studies, our comprehensive dataset clearly shows that cross-amplification success of microsatellite loci is well explained by phylogenetic divergence between species. As taxonomic classifications on the species and genus level do not necessarily mirror phylogenetic divergence between species, the pure belonging of species to the same taxonomic units (i.e. species or genus) might be less useful to predict cross-amplification success of microsatellite loci between such species. © 2010 Blackwell Publishing Ltd.

  17. Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

    Science.gov (United States)

    Liu, Xinyang; Hildebrandt, Andrea; Recio, Guillermo; Sommer, Werner; Cai, Xinxia; Wilhelm, Oliver

    2017-01-01

    Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT) Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN), when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account or not. These

  18. Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

    Directory of Open Access Journals (Sweden)

    Xinyang Liu

    2017-08-01

    Full Text Available Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN, when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account

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

    Directory of Open Access Journals (Sweden)

    Carly A Conran

    2016-01-01

    Full Text Available 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 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 of the number of risk-associated SNPs used in the calculation.

  20. Interaction between common breast cancer susceptibility variants, genetic ancestry, and nongenetic risk factors in Hispanic women.

    Science.gov (United States)

    Fejerman, Laura; Stern, Mariana C; John, Esther M; Torres-Mejía, Gabriela; Hines, Lisa M; Wolff, Roger K; Baumgartner, Kathy B; Giuliano, Anna R; Ziv, Elad; Pérez-Stable, Eliseo J; Slattery, Martha L

    2015-11-01

    Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified SNPs among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population. We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions. We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele OR: 0.94 (95% confidence intervals, 0.74-1.20), 1.20 (0.94-1.53), and 1.49 (1.28-1.75) for current, former, and never hormone therapy users, respectively, Pinteraction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72-1.42), 1.19 (0.98-1.45), and 1.69 (1.26-2.26) for never, 12 months breastfeeding, respectively, Pinteraction 0.014]. The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women. These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and nongenetic risk factors and their contribution to breast cancer risk. ©2015 American Association for Cancer Research.

  1. Portrayal of genetic risk for breast cancer in ethnic and non-ethnic newspapers.

    Science.gov (United States)

    Donelle, L; Hoffman-Goetz, L; Clarke, J N

    2004-01-01

    There has been enormous attention paid to the genetics of breast cancer in this era of genomic medicine. A great deal of the interest has been generated through discourse in the public mass media. However, genetic risk is a probabilistic concept and one that requires adequate numeracy skills. The purpose of this qualitative content analysis was to describe and evaluate the portrayal of genetic risk for breast cancer in mass print media. Mass print newspapers targeting high (Ashkenazi Jews) and low (general Canadian population) genetic risk audiences and published at least monthly, available in English and accessible through public archives at the National Library of Canada, were identified and hand searched for articles on breast cancer. Approximately 47% of breast cancer articles in 6 Jewish newspapers and published between 1996-2000 identified genetics in the title, first or last paragraph compared with 17% of 145 articles in 6 provincial newspapers published in 2000. The description of breast cancer risk was equally problematic in print media targeting high and low risk audiences. Statistics were presented in complex and contradictory ways, with, for example, the confounding of individual and population based risk estimates. Inconsistent messages about the value of genetic screening for breast cancer characterized articles in both ethnic and non-ethnic newspapers. Deciphering the information into a comprehensible form is likely challenging, particularly in light of widespread numeric-literacy limitations. The publication of discrepant research findings and the perplexing statistical information consequently brought into question the credibility of the scientific process and the recommendations of health care professionals.

  2. Accuracy of predicting the genetic risk of disease using a genome-wide approach.

    Directory of Open Access Journals (Sweden)

    Hans D Daetwyler

    Full Text Available The prediction of the genetic disease risk of an individual is a powerful public health tool. While predicting risk has been successful in diseases which follow simple Mendelian inheritance, it has proven challenging in complex diseases for which a large number of loci contribute to the genetic variance. The large numbers of single nucleotide polymorphisms now available provide new opportunities for predicting genetic risk of complex diseases with high accuracy.We have derived simple deterministic formulae to predict the accuracy of predicted genetic risk from population or case control studies using a genome-wide approach and assuming a dichotomous disease phenotype with an underlying continuous liability. We show that the prediction equations are special cases of the more general problem of predicting the accuracy of estimates of genetic values of a continuous phenotype. Our predictive equations are responsive to all parameters that affect accuracy and they are independent of allele frequency and effect distributions. Deterministic prediction errors when tested by simulation were generally small. The common link among the expressions for accuracy is that they are best summarized as the product of the ratio of number of phenotypic records per number of risk loci and the observed heritability.This study advances the understanding of the relative power of case control and population studies of disease. The predictions represent an upper bound of accuracy which may be achievable with improved effect estimation methods. The formulae derived will help researchers determine an appropriate sample size to attain a certain accuracy when predicting genetic risk.

  3. Genetic regulation of serum phytosterol levels and risk of coronary artery disease.

    Science.gov (United States)

    Teupser, Daniel; Baber, Ronny; Ceglarek, Uta; Scholz, Markus; Illig, Thomas; Gieger, Christian; Holdt, Lesca M; Leichtle, Alexander; Greiser, Karin H; Huster, Dominik; Linsel-Nitschke, Patrick; Schäfer, Arne; Braund, Peter S; Tiret, Laurence; Stark, Klaus; Raaz-Schrauder, Dorette; Fiedler, Georg M; Wilfert, Wolfgang; Beutner, Frank; Gielen, Stephan; Grosshennig, Anika; König, Inke R; Lichtner, Peter; Heid, Iris M; Kluttig, Alexander; El Mokhtari, Nour E; Rubin, Diana; Ekici, Arif B; Reis, André; Garlichs, Christoph D; Hall, Alistair S; Matthes, Gert; Wittekind, Christian; Hengstenberg, Christian; Cambien, Francois; Schreiber, Stefan; Werdan, Karl; Meitinger, Thomas; Loeffler, Markus; Samani, Nilesh J; Erdmann, Jeanette; Wichmann, H-Erich; Schunkert, Heribert; Thiery, Joachim

    2010-08-01

    Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)). Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

  4. Risk adjustment model of credit life insurance using a genetic algorithm

    Science.gov (United States)

    Saputra, A.; Sukono; Rusyaman, E.

    2018-03-01

    In managing the risk of credit life insurance, insurance company should acknowledge the character of the risks to predict future losses. Risk characteristics can be learned in a claim distribution model. There are two standard approaches in designing the distribution model of claims over the insurance period i.e, collective risk model and individual risk model. In the collective risk model, the claim arises when risk occurs is called individual claim, accumulation of individual claim during a period of insurance is called an aggregate claim. The aggregate claim model may be formed by large model and a number of individual claims. How the measurement of insurance risk with the premium model approach and whether this approach is appropriate for estimating the potential losses occur in the future. In order to solve the problem Genetic Algorithm with Roulette Wheel Selection is used.

  5. Genetic ancestry modifies the association between genetic risk variants and breast cancer risk among Hispanic and non-Hispanic white women.

    Science.gov (United States)

    Fejerman, Laura; Stern, Mariana C; Ziv, Elad; John, Esther M; Torres-Mejia, Gabriela; Hines, Lisa M; Wolff, Roger; Wang, Wei; Baumgartner, Kathy B; Giuliano, Anna R; Slattery, Martha L

    2013-08-01

    Hispanic women in the USA have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case-control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1 and rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 [95% confidence interval (CI) = 0.50-1.15] for low IA ancestry and 1.38 (95% CI = 1.04-1.82) for high IA ancestry (P interaction 0.02). The ORs for association at RELN were 0.87 (95% CI = 0.59-1.29) and 1.69 (95% CI = 1.04-2.73), respectively (P interaction 0.03). At the TLR1 locus, the ORs for women homozygous for the rare allele were 0.74 (95% CI = 0.42-1.31) and 1.73 (95% CI = 1.19-2.52) (P interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of 3 of the 10 previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.

  6. Prediction of Adult Dyslipidemia Using Genetic and Childhood Clinical Risk Factors: The Cardiovascular Risk in Young Finns Study.

    Science.gov (United States)

    Nuotio, Joel; Pitkänen, Niina; Magnussen, Costan G; Buscot, Marie-Jeanne; Venäläinen, Mikko S; Elo, Laura L; Jokinen, Eero; Laitinen, Tomi; Taittonen, Leena; Hutri-Kähönen, Nina; Lyytikäinen, Leo-Pekka; Lehtimäki, Terho; Viikari, Jorma S; Juonala, Markus; Raitakari, Olli T

    2017-06-01

    Dyslipidemia is a major modifiable risk factor for cardiovascular disease. We examined whether the addition of novel single-nucleotide polymorphisms for blood lipid levels enhances the prediction of adult dyslipidemia in comparison to childhood lipid measures. Two thousand four hundred and twenty-two participants of the Cardiovascular Risk in Young Finns Study who had participated in 2 surveys held during childhood (in 1980 when aged 3-18 years and in 1986) and at least once in a follow-up study in adulthood (2001, 2007, and 2011) were included. We examined whether inclusion of a lipid-specific weighted genetic risk score based on 58 single-nucleotide polymorphisms for low-density lipoprotein cholesterol, 71 single-nucleotide polymorphisms for high-density lipoprotein cholesterol, and 40 single-nucleotide polymorphisms for triglycerides improved the prediction of adult dyslipidemia compared with clinical childhood risk factors. Adjusting for age, sex, body mass index, physical activity, and smoking in childhood, childhood lipid levels, and weighted genetic risk scores were associated with an increased risk of adult dyslipidemia for all lipids. Risk assessment based on 2 childhood lipid measures and the lipid-specific weighted genetic risk scores improved the accuracy of predicting adult dyslipidemia compared with the approach using only childhood lipid measures for low-density lipoprotein cholesterol (area under the receiver-operating characteristic curve 0.806 versus 0.811; P =0.01) and triglycerides (area under the receiver-operating characteristic curve 0.740 versus area under the receiver-operating characteristic curve 0.758; P dyslipidemia in adulthood. © 2017 American Heart Association, Inc.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2016-01-01

    This paper addresses practical and ethical considerations regarding genetic tests to predict performance and/or risk of exercise-related injury or illness. Various people might wish to conduct sport-related genetic tests for a variety of reasons. For example, an individual might seek personal genetic information to help guide their own sport participation. A sports coach might wish to test young athletes to aid team selection or individualize training. A physician might want to predict the risk of injury or illness in athletes and advise regarding selection or preventative measures. An insurance company might seek to estimate the risk of career-threatening injury for athletes based partly on genetic information. Whilst this information is, in part, encoded in our DNA sequence, the available tests allow generally only a poor prediction of the aforementioned variables. In other words, the current genetic tests and analysis methods are not powerful enough to inform important decisions in sport to a substantial degree. It is particularly disappointing that more than half of the commercially available genetic tests related to exercise and sport do not appear to identify publicly the genetic variants they assess, making scrutiny by academic scholars and consumers (or their representatives) impossible. There are also challenging ethical issues to consider. For example, the imposition of genetic tests on individuals (especially young people) by third parties is potentially susceptible to abuse. Scientists and practitioners should understand the limitations of the tests currently available, the ethical concerns and the importance of counselling before and after testing so that they are only used in a responsible manner. © 2016 S. Karger AG, Basel.

  9. Changes in genetic risk for emotional eating across the menstrual cycle: a longitudinal study.

    Science.gov (United States)

    Klump, K L; Hildebrandt, B A; O'Connor, S M; Keel, P K; Neale, M; Sisk, C L; Boker, S; Burt, S A

    2015-11-01

    Previous studies have shown significant within-person changes in binge eating and emotional eating across the menstrual cycle, with substantial increases in both phenotypes during post-ovulation. Increases in both estradiol and progesterone levels appear to account for these changes in phenotypic risk, possibly via increases in genetic effects. However, to date, no study has examined changes in genetic risk for binge phenotypes (or any other phenotype) across the menstrual cycle. The goal of the present study was to examine within-person changes in genetic risk for emotional eating scores across the menstrual cycle. Participants were 230 female twin pairs (460 twins) from the Michigan State University Twin Registry who completed daily measures of emotional eating for 45 consecutive days. Menstrual cycle phase was coded based on dates of menstrual bleeding and daily ovarian hormone levels. Findings revealed important shifts in genetic and environmental influences, where estimates of genetic influences were two times higher in post- as compared with pre-ovulation. Surprisingly, pre-ovulation was marked by a predominance of environmental influences, including shared environmental effects which have not been previously detected for binge eating phenotypes in adulthood. Our study was the first to examine within-person shifts in genetic and environmental influences on a behavioral phenotype across the menstrual cycle. Results highlight a potentially critical role for these shifts in risk for emotional eating across the menstrual cycle and underscore the need for additional, large-scale studies to identify the genetic and environmental factors contributing to menstrual cycle effects.

  10. The role of genetics in stroke risk factors; the discussion of two rare genetic syndroms associated with stroke and review of the literature

    Directory of Open Access Journals (Sweden)

    Eda Kılıç Çoban

    2015-09-01

    Full Text Available Stroke is defined as a focal or at times global neurological impairment of sudden onset, that lasts more than 24 hours or that leads to death. The nonmodifiable risk factors for stroke include age, race, gender and acquired risk factors include smoking, hypertension, diabetes and obesity. Previous studies have shown that these mentioned risk factors might be responsible for approximately 50% of patients presenting stroke. However for the remaining half of the stroke patients no risk factors could be detected and genetics might be responsible for this group. In this manuscript we would like to present 2 cases who were being followed-up with the rare genetic syndromes as Marfan syndrome and Robinow syndrome respectively. These patients presented to our clinic with stroke and no identifiable risk factors other than these genetic syndromes could be detected. By this case-series we would like to further discuss the relationship between genetic syndromes and stroke.

  11. The media and genetically modified foods: evidence in support of social amplification of risk.

    Science.gov (United States)

    Frewer, Lynn J; Miles, Susan; Marsh, Roy

    2002-08-01

    Empirical examinations of the "social amplification of risk" framework are rare, partly because of the difficulties in predicting when conditions likely to result in amplification effects will occur. This means that it is difficult to examine changes in risk perception that are contemporaneous with increases and/or decreases in social or media discussion of the risks associated with a particular risk event. However, the collection of attitude data before, during, and after the increased reporting of the risks of genetically modified food in the United Kingdom (spring 1999) has demonstrated that people's risk perceptions do increase and decrease in line with what might be expected upon examination of the amplification and attenuation mechanisms integral to the framework. Perceptions of benefit, however, appeared to be permanently depressed by negative reporting about genetically modified food. Trust in regulatory institutions with responsibility for protecting the public was not affected. It was concluded that the social amplification of risk framework is a useful framework for beginning to explain the potential impact on risk perceptions of a risk event, particularly if that risk event is presented to the public as a new hazard occurring in a crisis context.

  12. Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review.

    Directory of Open Access Journals (Sweden)

    Lijun Jing

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

  13. Effect of Alzheimer disease genetic risk disclosure on dietary supplement use.

    Science.gov (United States)

    Vernarelli, Jacqueline A; Roberts, J Scott; Hiraki, Susan; Chen, Clara A; Cupples, L Adrienne; Green, Robert C

    2010-05-01

    Genetic susceptibility testing for Alzheimer disease (AD) with APOE genotype disclosure is not recommended for clinical use but is available through direct-to-consumer (DTC) genetic testing companies. Little is known about whether APOE genotype disclosure would actually prompt changes in nutrition behaviors among at-risk individuals. We studied the effect of APOE genotype disclosure for AD risk assessment on dietary supplement use in adults with a family history of AD. As part of a secondary analysis of data from the second Risk Evaluation and Education for Alzheimer's Disease Study, we examined the effect of genotype disclosure on health-behavior changes among 272 unaffected first-degree relatives of persons with AD. Overall, 16% of all participants reported a change in dietary supplement use after AD risk assessment. Participants who learned that they had at least one copy of the risk-increasing epsilon4 allele (epsilon4+) had 4.75 times the odds of reporting a change in dietary supplement use than did their counterparts who had an absence of the risk-increasing epsilon4 allele (epsilon4-) (95% CI: 2.23, 10.10; P exercise, or medications. In this sample of first-degree relatives receiving genetic susceptibility testing for AD, an APOE epsilon4+ genotype status was positively associated with dietary supplement use after risk disclosure. Such changes occurred despite the absence of evidence that supplement use reduces the risk of AD. Given the expansion of DTC genetic tests, this study highlights the need for future studies in disease risk communication.

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

    Science.gov (United States)

    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 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 pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses. PMID:24559379

  15. Genetics University of Toronto Thrombophilia Study in Women (GUTTSI: genetic and other risk factors for venous thromboembolism in women

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    Evrovski Jovan

    2001-05-01

    Full Text Available Abstract Background Women may be at increased risk for venous thromboembolism (VTE as compared with men. We studied the effects of genetic and biochemical markers of thrombophilia in women, in conjunction with other established risk factors for VTE. Method The present retrospective case-control study was conducted in a thrombosis treatment programme at a large Toronto hospital. The cases were 129 women aged 16-79 years with objectively confirmed VTE. Age-matched control individuals were women who were free of venous thrombosis. Neither cases nor control individuals had known cardiovascular disease. Participants were interviewed regarding personal risk factors for VTE, including smoking, history of malignancy, pregnancy, and oestrogen or oral contraceptive use. Blood specimens were analyzed for common single nucleotide polymorphisms of prothrombin, factor V and methylenetetrahydrofolate reductase (MTHFR; C677T, A1298C and T1317C, and the A66G polymorphism for methionine synthase reductase (MTRR.Fasting plasma homocysteine was also analyzed. Results Women with VTE were significantly more likely than female control individuals to carry the prothrombin polymorphism and the factor V polymorphism, or to have fasting hyperhomocysteinaemia. Homozygosity for the C677T MTHFR gene was not a significant risk factor for VTE, or were the A1298C or T1317C MTHFR homozygous variants. Also, the A66G MTRR homozygous state did not confer an increased risk for VTE. Conclusion Prothrombin and factor V polymorphisms increased the risk for VTE in women, independent from other established risk factors. Although hyperhomocysteinaemia also heightens this risk, common polymorphisms in two genes that are responsible for homocysteine remethylation do not. These findings are consistent with previous studies that included both men and women.

  16. The association between a genetic risk score for allergy and the risk of developing allergies in childhood-Results of the WHISTLER cohort

    NARCIS (Netherlands)

    Arabkhazaeli, Ali; Ahmadizar, Fariba; Leusink, Maarten; Arets, Hubertus G. M.; Raaijmakers, Jan A. M.; Uiterwaal, Cuno S. P. M.; van der Ent, Cornelis K.; Maitland-van der Zee, Anke-Hilse; Vijverberg, Susanne J. H.

    2018-01-01

    Several genetic variants have been associated with the susceptibility to allergic disease in adults, but it remains unclear whether these genetic variants are also associated with the onset of allergic disease early in life. The aim of this study was to develop a genetic risk score (GRS) for allergy

  17. The association between a genetic risk score for allergy and the risk of developing allergies in childhood-Results of the WHISTLER cohort

    NARCIS (Netherlands)

    Arabkhazaeli, Ali; Ahmadizar, Fariba; Leusink, Maarten; Arets, Hubertus G. M.; Raaijmakers, Jan A. M.; Uiterwaal, Cuno S. P. M.; van der Ent, Cornelis K.; Maitland-van der Zee, Anke-Hilse; Vijverberg, Susanne J. H.

    2018-01-01

    Background: Several genetic variants have been associated with the susceptibility to allergic disease in adults, but it remains unclear whether these genetic variants are also associated with the onset of allergic disease early in life. The aim of this study was to develop a genetic risk score (GRS)

  18. Genetic and environmental influences on cardiovascular disease risk factors: a study of Chinese twin children and adolescents.

    Science.gov (United States)

    Ji, Fuling; Ning, Feng; Duan, Haiping; Kaprio, Jaakko; Zhang, Dongfeng; Zhang, Dong; Wang, Shaojie; Qiao, Qing; Sun, Jianping; Liang, Jiwei; Pang, Zengchang; Silventoinen, Karri

    2014-04-01

    We evaluated the genetic and environmental contributions to metabolic cardiovascular risk factors and their mutual associations. Eight metabolic factors (body mass index, waist circumference, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, total serum cholesterol, serum triglycerides, and serum uric acid) were measured in 508 twin pairs aged 8-17 years from the Qingdao Twin Registry, China. Linear structural equation models were used to estimate the heritability of these traits, as well as the genetic and environmental correlations between them. Among boys, body mass index and uric acid showed consistently high heritability (0.49-0.81), whereas other traits showed moderate to high common environmental variance (0.37-0.73) in children (8-12 years) and adolescents (13-17 years) except total cholesterol. For girls, moderate to high heritability (0.39-0.75) were obtained for six metabolic traits in children, while only two traits showed high heritability and others mostly medium to large common environmental variance in adolescents. Genetic correlations between the traits were strong in both boys and girls in children (r g = 0.64-0.99 between body mass index and diastolic blood pressure; r g = 0.71-1.00 between body mass index and waist circumference), but decreased for adolescent girls (r g = 0.51 between body mass index and waist-to-hip ratio; r g = 0.55 between body mass index and uric acid; r g = 0.61 between body mass index and systolic blood pressure). The effect of genetic factors on most metabolic traits decreased from childhood to adolescence. Both common genetic and specific environmental factors influence the mutual associations among most of the metabolic traits.

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

    International Nuclear Information System (INIS)

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

    2007-01-01

    The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population. We used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1, GSTT1, GSTP1 Ile 105 Val, EPHX1 Tyr 113 His and EPHX1 His 139 Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression. A higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2 nd quartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of the EPHX1 codon 113 polymorphism. An association was also observed for the EPHX1 codon 113 polymorphism in the low-risk adenomas, although not as obvious. Although, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma

  20. Simulated Annealing Genetic Algorithm Based Schedule Risk Management of IT Outsourcing Project

    Directory of Open Access Journals (Sweden)

    Fuqiang Lu

    2017-01-01

    Full Text Available IT outsourcing is an effective way to enhance the core competitiveness for many enterprises. But the schedule risk of IT outsourcing project may cause enormous economic loss to enterprise. In this paper, the Distributed Decision Making (DDM theory and the principal-agent theory are used to build a model for schedule risk management of IT outsourcing project. In addition, a hybrid algorithm combining simulated annealing (SA and genetic algorithm (GA is designed, namely, simulated annealing genetic algorithm (SAGA. The effect of the proposed model on the schedule risk management problem is analyzed in the simulation experiment. Meanwhile, the simulation results of the three algorithms GA, SA, and SAGA show that SAGA is the most superior one to the other two algorithms in terms of stability and convergence. Consequently, this paper provides the scientific quantitative proposal for the decision maker who needs to manage the schedule risk of IT outsourcing project.

  1. Observationally and Genetically High YKL-40 and Risk of Venous Thromboembolism in the General Population

    DEFF Research Database (Denmark)

    Kjaergaard, Alisa D; Johansen, Julia S; Bojesen, Stig E

    2016-01-01

    OBJECTIVE: High baseline YKL-40 is associated with later development of ischemic stroke, but not with myocardial infarction. Whether high YKL-40 levels are associated with increased risk of venous thromboembolism is presently unknown. We tested the hypothesis that observationally and genetically...... high YKL-40 is associated with increased risk of venous thromboembolism in the general population. APPROACH AND RESULTS: Cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (N=21 647) and CHI3L1 rs4950928 genotype (N...... levels, but not with risk of venous thromboembolism. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for pulmonary embolism of 1.17 (1.00-1.38) and a genetic odds ratio of 0.97 (0.76-1.23). Corresponding risk estimates were 1.28 (1.12-1.47) observationally...

  2. Lifestyle modifies obesity-associated risk of cardiovascular disease in a genetically homogeneous population

    DEFF Research Database (Denmark)

    Jørgensen, Marit E; Borch-Johnsen, Knut; Bjerregaard, Peter

    2006-01-01

    BACKGROUND: The association between obesity and cardiovascular disease risk differs across populations. Whether such differences in obesity-related risk factors exist within population groups of the same genetic origin but with differences in lifestyle remains to be determined. OBJECTIVE: The aim...... was to analyze whether obesity was associated with the same degree of metabolic disturbances in 2 groups of genetically homogeneous Inuit who were exposed to considerable differences in lifestyle. DESIGN: We studied obesity and cardiovascular disease risk factors in a cross-sectional population survey of 2311...... groups of Inuit living in Greenland and Inuit migrants living in Denmark. The findings indicate that lifestyle factors modify the cardiovascular disease risk associated with obesity....

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

    Science.gov (United States)

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

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

    Science.gov (United States)

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

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

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

    Science.gov (United States)

    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.

  6. Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts

    Science.gov (United States)

    Hughes, Maria F.; Saarela, Olli; Stritzke, Jan; Kee, Frank; Silander, Kaisa; Klopp, Norman; Kontto, Jukka; Karvanen, Juha; Willenborg, Christina; Salomaa, Veikko; Virtamo, Jarmo; Amouyel, Phillippe; Arveiler, Dominique; Ferrières, Jean; Wiklund, Per-Gunner; Baumert, Jens; Thorand, Barbara; Diemert, Patrick; Trégouët, David-Alexandre; Hengstenberg, Christian; Peters, Annette; Evans, Alun; Koenig, Wolfgang; Erdmann, Jeanette; Samani, Nilesh J.

    2012-01-01

    Background More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men. PMID:22848412

  7. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

    DEFF Research Database (Denmark)

    Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti

    2011-01-01

    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...... 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...

  8. Omega-3 fatty acids and the genetic risk of early onset acute coronary syndrome.

    Science.gov (United States)

    Leung Yinko, S S L; Thanassoulis, G; Stark, K D; Avgil Tsadok, M; Engert, J C; Pilote, L

    2014-11-01

    Recent gene-environment interaction studies suggest that diet may influence an individual's genetic predisposition to cardiovascular risk. We evaluated whether omega-3 fatty acid intake may influence the risk for acute coronary syndrome (ACS) conferred by genetic polymorphisms among patients with early onset ACS. Our population consisted of 705 patients of white European descent enrolled in GENESIS-PRAXY, a multicenter cohort study of patients aged 18-55 years and hospitalized with ACS. We used a case-only design to investigate interactions between the omega-3 index (a validated biomarker of omega-3 fatty acid intake) and 30 single nucleotide polymorphisms (SNPs) robustly associated with ACS. We used logistic regression to assess the interaction between each SNP and the omega-3 index. Interaction was also assessed between the omega-3 index and a genetic risk score generated from the 30 SNPs. All models were adjusted for age and sex. An interaction for increased ACS risk was found between carriers of the chromosome 9p21 variant rs4977574 and low omega-3 index (OR 1.57, 95% CI 1.07-2.32, p = 0.02), but this was not significant after correction for multiple testing. Similar results were obtained in the adjusted model (OR 1.55, 95% CI 1.05-2.29, p = 0.03). We did not observe any interaction between the genetic risk score or any of the other SNPs and the omega-3 index. Our results suggest that omega-3 fatty acid intake may modify the genetic risk conferred by chromosome 9p21 variation in the development of early onset ACS and requires independent replication. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Populations genetically rifting within a complex geological system: The case of strong structure and low genetic diversity in the migratory freshwater catfish,Bagrus docmak,in East Africa.

    Science.gov (United States)

    Basiita, Rose Komugisha; Zenger, Kyall Richard; Jerry, Dean Robert

    2017-08-01

    The complex geological history of East Africa has been a driving factor in the rapid evolution of teleost biodiversity. While there is some understanding of how macroevolutionary drivers have shaped teleost speciation in East Africa, there is a paucity of research into how the same biogeographical factors have affected microevolutionary processes within lakes and rivers. To address this deficiency, population genetic diversity, demography, and structure were investigated in a widely distributed and migratory (potamodromous) African teleost species, Ssemutundu ( Bagrus docmak ). Samples were acquired from five geographical locations in East Africa within two major drainage basins; the Albertine Rift and Lake Victoria Basin. Individuals ( N  = 175) were genotyped at 12 microsatellite loci and 93 individuals sequenced at the mitochondrial DNA control region. Results suggested populations from Lakes Edward and Victoria had undergone a severe historic bottleneck resulting in very low nucleotide diversity (π = 0.004 and 0.006, respectively) and negatively significant Fu values (-3.769 and -5.049; p  < .05). Heterozygosity deficiencies and restricted effective population size ( N eLD ) suggested contemporary exposure of these populations to stress, consistent with reports of the species decline in the East African Region. High genetic structuring between drainages was detected at both historical (ɸ ST  = 0.62 for mtDNA; p  < .001) and contemporary (microsatellite F ST  = 0.460; p  < .001) levels. Patterns of low genetic diversity and strong population structure revealed are consistent with speciation patterns that have been linked to the complex biogeography of East Africa, suggesting that these biogeographical features have operated as both macro- and micro-evolutionary forces in the formation of the East African teleost fauna.

  10. Belief and disbelief in the existence of genetic risk factors for suicide: cross-cultural comparisons.

    Science.gov (United States)

    Voracek, Martin

    2007-12-01

    There is evidence for widespread disbelief in the genetics of suicide, despite recent research progress in this area and convergent evidence supporting a role for genetic factors. This study analyzed the beliefs held in 8 samples (total N = 1224) of various types (psychology, medical, and various undergraduates, psychology graduates, and the general population) from 6 countries located on 3 continents (Austria, Canada, Malaysia, Romania, United Kingdom, and the USA). Endorsement rates for the existence of genetic risk factors for suicide ranged from 26% and 30% (Austrian psychology undergraduates and general population) to around 50% (psychology undergraduates in the USA and United Kingdom). In the 8 samples, respondents' sex, age, religiosity, political orientation, and other demographic variables were, for the most part, unrelated, but overall knowledge about suicide throughout was related positively to endorsement rates. Consistent with previous research, across a considerable variety of sample types and cultural settings there was no evidence for a clear majority believing in genetic bases for suicide.

  11. Reaching high-risk underserved individuals for cancer genetic counseling by video-teleconferencing.

    Science.gov (United States)

    Mette, Lindsey A; Saldívar, Anna Maria Pulido; Poullard, Natalie E; Torres, Ivette C; Seth, Sarah G; Pollock, Brad H; Tomlinson, Gail E

    2016-04-01

    Breast and colorectal cancers are common cancers for which genetic risk assessment and counseling are available. However, these services are often limited to metropolitan areas and are not readily accessible to underserved populations. Moreover, ethnic and racial disparities present additional obstacles to identifying and screening high-risk individuals and have a bearing on treatment outcomes. To provide cancer genetic risk assessment and counseling through telemedicine to the remote, underserved primarily Hispanic population of the Texas-Mexico border region. Program participants were mailed a questionnaire to assess their satisfaction with the program so that we could determine the acceptability of video-teleconferencing for cancer risk assessment. The overall level of satisfaction with the program was very high, demonstrating the acceptability of a cancer genetic risk assessment program that relied on telemedicine to reach and underserved minority community. Delivery model requires the availability of and access to communication technologies; trained staff are needed at remote sites for sample collection and patient handling. Video-teleconferencing is an acceptable method of providing cancer risk assessment in a remote, underserved population. ©2016 Frontline Medical Communications.

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

    Science.gov (United States)

    LaSalle, Janine M

    2013-07-01

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

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2014-08-01

    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. 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. 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). 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.

  15. Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study.

    Science.gov (United States)

    Walder, Deborah J; Faraone, Stephen V; Glatt, Stephen J; Tsuang, Ming T; Seidman, Larry J

    2014-08-01

    The familial ("genetic") high-risk (FHR) paradigm enables assessment of individuals at risk for schizophrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both biological and environmental factors within a FHR study of adolescents. We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Participants assessed between 1998 and 2007 (ages 13-25) included 40 (20F/20M) adolescents at FHR for schizophrenia (FHRs) and 55 (31F/24M) community controls. 'Genetic load' indexed number of affected family members relative to pedigree size. PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genetic liability was significantly associated with PHI and family expressiveness. Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed 'polygenic neurodevelopmental diathesis-stress model' whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    Background: Previous studies suggest that the X-ray repair cross-complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. Objectives:This meta-analysis aimed to ...

  17. Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma

    DEFF Research Database (Denmark)

    Calışkan, Minal; Bochkov, Yury A; Kreiner-Møller, Eskil

    2013-01-01

    Background Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospe...

  18. Genetic Factors Underlying the Risk of Thalidomide-Related Neuropathy in Patients With Multiple Myeloma

    NARCIS (Netherlands)

    Johnson, David C.; Corthals, Sophie L.; Walker, Brian A.; Ross, Fiona M.; Gregory, Walter M.; Dickens, Nicholas J.; Lokhorst, Henk M.; Goldschmidt, Hartmut; Davies, Faith E.; Durie, Brian G. M.; Van Ness, Brian; Child, J. Anthony; Sonneveld, Pieter; Morgan, Gareth J.

    2011-01-01

    Purpose To indentify genetic variation that can modulate and predict the risk of developing thalidomide-related peripheral neuropathy (TrPN). Patients and Methods We analyzed DNA from 1,495 patients with multiple myeloma. Using a custom-built single nucleotide polymorphism (SNP) array, we tested the

  19. The assessment of genetic risk of breast cancer : a set of GP guidelines

    NARCIS (Netherlands)

    de Bock, GH; Vlieland, TPMV; Hageman, GCHA; Oosterwijk, JC; Springer, MP; Kievit, J

    Background. Assessing a genetic risk for developing breast cancer is not an easy task for a GP. Current expert guidelines for referring and counselling women with a family history positive for breast cancer are complex and difficult to apply in general practice, and have only two strategies (to

  20. Genetic, behavioral, and sociodemographic risk factors for second eye progression in age-related macular degeneration

    NARCIS (Netherlands)

    Lechanteur, Y.T.; van de Ven, J.P.; Smailhodzic, D.; Boon, C.J.F.; Klevering, B.J.; Fauser, S.; Groenewoud, J.M.; Wilt, G.J. van der; Hollander, A.I. den; Hoyng, C.B.

    2012-01-01

    PURPOSE: This study was conducted to investigate the correlation of genetic, sociodemographic, and behavioral risk factors with second eye progression to end-stage AMD. METHODS: One hundred and eight patients with end-stage AMD in one or both eyes were included in a retrospective time-to-event

  1. Sudden infant death syndrome, childhood thrombosis, and presence of genetic risk factors for thrombosis

    DEFF Research Database (Denmark)

    Larsen, TB; Nørgaard-Pedersen, B; Lundemose, JB

    2000-01-01

    . The vulnerability of the infant brain stem to ischemia has been suggested to be a conceivable cause of sudden infant death syndrome. This is compatible with a hypothesis that genetic risk factors for cerebral thrombosis could cause microinfarction in the brain stem during the first month of life, affecting vital...

  2. Molecular genetic features and risk assessment in a series of 30 ...

    African Journals Online (AJOL)

    Background: The objective of the study was to investigate the relationship between molecular genetic features and the standard criteria of risk assessment in patients affected by gastrointestinal stromal tumours (GISTs). Methods: A review was conducted of a series of 30 patients, with a mean age of 67 years, who underwent ...

  3. Genetic variation in the ADIPOQ gene, adiponectin concentrations and risk of colorectal cancer

    DEFF Research Database (Denmark)

    Nimptsch, Katharina; Song, Mingyang; Aleksandrova, Krasimira

    2017-01-01

    analyses (pooled OR per score-unit unit 0.97, 95% CI 0.91, 1.04). Genetically determined twofold higher adiponectin was not significantly associated with risk of colorectal cancer using the ADIPOQ allele score as instrumental variable (pooled OR 0.73, 95% CI 0.40, 1.34). In a summary instrumental variable...

  4. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

    NARCIS (Netherlands)

    S. Reppe (Sjur); Y. Wang (Yunpeng); W.K. Thompson (Wesley K.); L.K. McEvoy (Linda K.); N.J. Schork (Nicholas); V. Zuber (Verena); M. Leblanc (Marissa); F. Bettella (Francesco); I.G. Mills (Ian G.); R.S. Desikan (Rahul S.); S. Djurovic (Srdjan); K.M. Gautvik (Kaare); A.M. Dale (Anders); O.A. Andreassen (Ole); K. Estrada Gil (Karol); U. Styrkarsdottir (Unnur); E. Evangelou (Evangelos); Y.-H. Hsu (Yi-Hsiang); E.L. Duncan (Emma); E.E. Ntzani (Evangelia); L. Oei (Ling); O.M.E. Albagha (Omar M.); N. Amin (Najaf); J.P. Kemp (John); D.L. Koller (Daniel); G. Li (Guo); C.-T. Liu (Ching-Ti); R.L. Minster (Ryan); A. Moayyeri (Alireza); L. Vandenput (Liesbeth); D. Willner (Dana); S.-M. Xiao (Su-Mei); L.M. Yerges-Armstrong (Laura); H.-F. Zheng (Hou-Feng); N. Alonso (Nerea); J. Eriksson (Joel); C.M. Kammerer (Candace); S. Kaptoge (Stephen); P.J. Leo (Paul); G. Thorleifsson (Gudmar); S.G. Wilson (Scott); J.F. Wilson (James F); V. Aalto (Ville); M. Alen (Markku); A.K. Aragaki (Aaron); T. Aspelund (Thor); J.R. Center (Jacqueline); Z. Dailiana (Zoe); C. Duggan; M. Garcia (Melissa); N. Garcia-Giralt (Natàlia); S. Giroux (Sylvie); G. Hallmans (Göran); L.J. Hocking (Lynne); L.B. Husted (Lise Bjerre); K. Jameson (Karen); R. Khusainova (Rita); G.S. Kim (Ghi Su); C. Kooperberg (Charles); T. Koromila (Theodora); M. Kruk (Marcin); M. Laaksonen (Marika); A.Z. Lacroix (Andrea Z.); S.H. Lee (Seung Hun); P.C. Leung (Ping C.); J.R. Lewis (Joshua); L. Masi (Laura); S. Mencej-Bedrac (Simona); T.V. Nguyen (Tuan); X. Nogues (Xavier); M.S. Patel (Millan); J. Prezelj (Janez); L.M. Rose (Lynda); S. Scollen (Serena); K. Siggeirsdottir (Kristin); G.D. Smith; O. Svensson (Olle); S. Trompet (Stella); O. Trummer (Olivia); N.M. van Schoor (Natasja); J. Woo (Jean); K. Zhu (Kun); S. Balcells (Susana); M.L. Brandi; B.M. Buckley (Brendan M.); S. Cheng (Sulin); C. Christiansen; C. Cooper (Charles); G.V. Dedoussis (George); I. Ford (Ian); M. Frost (Morten); D. Goltzman (David); J. González-Macías (Jesús); M. Kähönen (Mika); M. Karlsson (Magnus); E.K. Khusnutdinova (Elza); J.-M. Koh (Jung-Min); P. Kollia (Panagoula); B.L. Langdahl (Bente); W.D. Leslie (William D.); P. Lips (Paul); O. Ljunggren (Östen); R. Lorenc (Roman); J. Marc (Janja); D. Mellström (Dan); B. Obermayer-Pietsch (Barbara); D. Olmos (David); U. Pettersson-Kymmer (Ulrika); D.M. Reid (David); J.A. Riancho (José); P.M. Ridker (Paul); M.F. Rousseau (Francois); P.E. Slagboom (Eline); N.L.S. Tang (Nelson L.S.); R. Urreizti (Roser); W. Van Hul (Wim); J. Viikari (Jorma); M.T. Zarrabeitia (María); Y.S. Aulchenko (Yurii); M.C. Castaño Betancourt (Martha); E. Grundberg (Elin); L. Herrera (Lizbeth); T. Ingvarsson (Torvaldur); H. Johannsdottir (Hrefna); T. Kwan (Tony); R. Li (Rui); R.N. Luben (Robert); M.C. Medina-Gomez (Carolina); S.T. Palsson (Stefan Th); J.I. Rotter (Jerome I.); G. Sigurdsson (Gunnar); J.B.J. van Meurs (Joyce); D.J. Verlaan (Dominique); F.M. Williams (Frances); A.R. Wood (Andrew); Y. Zhou (Yanhua); T. Pastinen (Tomi); S. Raychaudhuri (Soumya); J.A. Cauley (Jane); D.I. Chasman (Daniel); G.R. Clark (Graeme); S.R. Cummings (Steven R.); P. Danoy (Patrick); E.M. Dennison (Elaine); R. Eastell (Richard); J.A. Eisman (John); V. Gudnason (Vilmundur); A. Hofman (Albert); R.D. Jackson (Rebecca); G. Jones (Graeme); J.W. Jukema (Jan Wouter); K.T. Khaw; T. Lehtimäki (Terho); Y. Liu (YongMei); M. Lorentzon (Mattias); E. McCloskey (Eugene); B.D. Mitchell (Braxton); K. Nandakumar (Kannabiran); G.C. Nicholson (Geoffrey); B.A. Oostra (Ben); M. Peacock (Munro); H.A.P. Pols (Huib); R.L. Prince (Richard); O. Raitakari (Olli); I.R. Reid (Ian); J. Robbins (John); P.N. Sambrook (Philip); P.C. Sham (Pak Chung); A.R. Shuldiner (Alan); F.A. Tylavsky (Frances); C.M. van Duijn (Cornelia); N.J. Wareham (Nicholas J.); L.A. Cupples (Adrienne); M.J. Econs (Michael); D.M. Evans (David); T.B. Harris (Tamara B.); A.W.C. Kung (Annie Wai Chee); B.M. Psaty (Bruce); J. Reeve (Jonathan); T.D. Spector (Timothy); E.A. Streeten (Elizabeth); M.C. Zillikens (Carola); U. Thorsteinsdottir (Unnur); C. Ohlsson (Claes); D. Karasik (David); J.B. Richards (Brent); M.A. Brown (Matthew); J-A. Zwart (John-Anker); A.G. Uitterlinden (André); S.H. Ralston (Stuart); J.P.A. Ioannidis (John P.A.); D.P. Kiel (Douglas P.); F. Rivadeneira Ramirez (Fernando)

    2015-01-01

    textabstractBone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown.

  5. Autism risk assessment in siblings of affected children using sex-specific genetic scores

    Directory of Open Access Journals (Sweden)

    Carayol Jerome

    2011-10-01

    Full Text Available Abstract Background The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system. Methods SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE repository. A reproducibility index (RI was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism. Results We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 × 10-6 and 1.9 × 10-5, respectively. Conclusions Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of

  6. Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

    Science.gov (United States)

    Wen, Wanqing; Shu, Xiao-Ou; Guo, Xingyi; Cai, Qiuyin; Long, Jirong; Bolla, Manjeet K; Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Gao, Yu-Tang; Zheng, Ying; Dunning, Alison M; García-Closas, Montserrat; Brennan, Paul; Chen, Shou-Tung; Choi, Ji-Yeob; Hartman, Mikael; Ito, Hidemi; Lophatananon, Artitaya; Matsuo, Keitaro; Miao, Hui; Muir, Kenneth; Sangrajrang, Suleeporn; Shen, Chen-Yang; Teo, Soo H; Tseng, Chiu-Chen; Wu, Anna H; Yip, Cheng Har; Simard, Jacques; Pharoah, Paul D P; Hall, Per; Kang, Daehee; Xiang, Yongbing; Easton, Douglas F; Zheng, Wei

    2016-12-08

    Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively. Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

  7. The genetic landscape of high-risk neuroblastoma.

    Science.gov (United States)

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

    2013-03-01

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

  8. The genetic landscape of high-risk neuroblastoma

    Science.gov (United States)

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

    2013-01-01

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

  9. Risk of genetic maladaptation due to climate change in three major European tree species.

    Science.gov (United States)

    Frank, Aline; Howe, Glenn T; Sperisen, Christoph; Brang, Peter; Clair, J Bradley St; Schmatz, Dirk R; Heiri, Caroline

    2017-12-01

    Tree populations usually show adaptations to their local environments as a result of natural selection. As climates change, populations can become locally maladapted and decline in fitness. Evaluating the expected degree of genetic maladaptation due to climate change will allow forest managers to assess forest vulnerability, and develop strategies to preserve forest health and productivity. We studied potential genetic maladaptation to future climates in three major European tree species, Norway spruce (Picea abies), silver fir (Abies alba), and European beech (Fagus sylvatica). A common garden experiment was conducted to evaluate the quantitative genetic variation in growth and phenology of seedlings from 77 to 92 native populations of each species from across Switzerland. We used multivariate genecological models to associate population variation with past seed source climates, and to estimate relative risk of maladaptation to current and future climates based on key phenotypic traits and three regional climate projections within the A1B scenario. Current risks from climate change were similar to average risks from current seed transfer practices. For all three climate models, future risks increased in spruce and beech until the end of the century, but remained low in fir. Largest average risks associated with climate projections for the period 2061-2090 were found for spruce seedling height (0.64), and for beech bud break and leaf senescence (0.52 and 0.46). Future risks for spruce were high across Switzerland. However, areas of high risk were also found in drought-prone regions for beech and in the southern Alps for fir. Genetic maladaptation to future climates is likely to become a problem for spruce and beech by the end of this century, but probably not for fir. Consequently, forest management strategies should be adjusted in the study area for spruce and beech to maintain productive and healthy forests in the future. © 2017 John Wiley & Sons Ltd.

  10. Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.

    Science.gov (United States)

    Hanscombe, Ken B; Traylor, Matthew; Hysi, Pirro G; Bevan, Stephen; Dichgans, Martin; Rothwell, Peter M; Worrall, Bradford B; Seshadri, Sudha; Sudlow, Cathie; Williams, Frances M K; Markus, Hugh S; Lewis, Cathryn M

    2015-08-01

    Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype. © 2015 The

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

    Science.gov (United States)

    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…

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

    Directory of Open Access Journals (Sweden)

    Ian C Scott

    Full Text Available 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.

  13. Living alone, receiving help, helplessness, and inactivity are strongly related to risk of undernutrition among older home-dwelling people

    Directory of Open Access Journals (Sweden)

    Tomstad ST

    2012-03-01

    Full Text Available Solveig T Tomstad1, Ulrika Söderhamn2, Geir Arild Espnes3, Olle Söderhamn21Department of Social Work and Health Science, Faculty of Sciences and Technology Management, NTNU, Trondheim, Norway and Centre for Caring Research – Southern Norway, Faculty of Health and Sport Sciences, University of Agder, Grimstad, Norway; 2Centre for Caring Research – Southern Norway, Faculty of Health and Sport Sciences, University of Agder, Grimstad, Norway; 3Research Centre for Health Promotion and Resources HiST-NTNU, Department of Social Work and Health Science, Faculty of Social Sciences and Technology Management, NTNU, Trondheim, NorwayBackground: Being at risk of undernutrition is a global problem among older people. Undernutrition can be considered inadequate nutritional status, characterized by insufficient food intake and weight loss. There is a lack of Norwegian studies focusing on being at risk of undernutrition and self-care ability, sense of coherence, and health-related issues among older home-dwelling people.Aim: To describe the prevalence of being at risk of undernutrition among a group of older home-dwelling individuals in Norway, and to relate the results to reported self-care ability, sense of coherence, perceived health and other health-related issues.Methods: A cross-sectional design was applied. A questionnaire with instruments for nutritional screening, self-care ability, and sense of coherence, and health-related questions was sent to a randomized sample of 450 persons (aged 65+ years in southern Norway. The study group included 158 (35.1% participants. Data were analysed using statistical methods.Results: The results showed that 19% of the participants were at medium risk of undernutrition and 1.3% at high risk. Due to the low response rate it can be expected that the nonparticipants can be at risk of undernutrition. The nutritional at-risk group had lower self-care ability and weaker sense of coherence. Living alone, receiving help

  14. Genetic risk scores and family history as predictors of schizophrenia in Nordic registers.

    Science.gov (United States)

    Lu, Y; Pouget, J G; Andreassen, O A; Djurovic, S; Esko, T; Hultman, C M; Metspalu, A; Milani, L; Werge, T; Sullivan, P F

    2017-09-25

    Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other. We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes. Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility. Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

  15. C-reactive protein, genetically elevated levels and risk of ischemic heart and cerebrovascular disease

    DEFF Research Database (Denmark)

    Zacho, Jeppe; Tybjaerg-Hansen, Anne; Nordestgaard, Børge Grønne

    2009-01-01

    We tested whether genetically elevated levels of C-reactive protein (CRP) cause increased risk of ischemic heart disease and ischemic cerebrovascular disease. Levels of CRP >3mg/L, compared with levels disease and ischemic...... cerebrovascular disease. Genotype combinations of the 4 CRP polymorphisms associated with up to a 64% increase in CRP levels, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations did...... not associate with increased risk of ischemic heart and cerebrovascular disease....

  16. Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population.

    Science.gov (United States)

    Rivu, Sanzana Fareen; Apu, Mohd Nazmul Hasan; Shabnaz, Samia; Nahid, Noor Ahmed; Islam, Md Reazul; Al-Mamun, Mir Md Abdullah; Nahar, Zabun; Rabbi, Sikder Nahidul Islam; Ahmed, Maizbha Uddin; Islam, Mohammad Safiqul; Hasnat, Abul

    2017-08-01

    Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160Ccolorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR=2.58, 95% CI=1.77-3.77, pcolorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (pcolorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR=2.02, 95% CI=1.42-2.87, pcolorectal cancer development in Bangladeshi population. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. A population-based survey in Australia of men's and women's perceptions of genetic risk and predictive genetic testing and implications for primary care.

    Science.gov (United States)

    Taylor, S

    2011-01-01

    Community attitudes research regarding genetic issues is important when contemplating the potential value and utilisation of predictive testing for common diseases in mainstream health services. This article aims to report population-based attitudes and discuss their relevance to integrating genetic services in primary health contexts. Men's and women's attitudes were investigated via population-based omnibus telephone survey in Queensland, Australia. Randomly selected adults (n = 1,230) with a mean age of 48.8 years were interviewed regarding perceptions of genetic determinants of health; benefits of genetic testing that predict 'certain' versus 'probable' future illness; and concern, if any, regarding potential misuse of genetic test information. Most (75%) respondents believed genetic factors significantly influenced health status; 85% regarded genetic testing positively although attitudes varied with age. Risk-based information was less valued than certainty-based information, but women valued risk information significantly more highly than men. Respondents reported 'concern' (44%) and 'no concern' (47%) regarding potential misuse of genetic information. This study contributes important population-based data as most research has involved selected individuals closely impacted by genetic disorders. While community attitudes were positive regarding genetic testing, genetic literacy is important to establish. The nature of gender differences regarding risk perception merits further study and has policy and service implications. Community concern about potential genetic discrimination must be addressed if health benefits of testing are to be maximised. Larger questions remain in scientific, policy, service delivery, and professional practice domains before predictive testing for common disorders is efficacious in mainstream health care. Copyright © 2011 S. Karger AG, Basel.

  18. Communicating genetic risk information for common disorders in the era of genomic medicine.

    Science.gov (United States)

    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.

  19. Genetic and modifying factors that determine the risk of brain tumors

    DEFF Research Database (Denmark)

    Montelli, Terezinha de Cresci Braga; Peraçoli, Maria Terezinha Serrão; Rogatto, Silvia Regina

    2011-01-01

    Some modifying factors may determine the risk of brain tumors. Until now, it could not be attempted to identify people at risk and also to improve significantly disease progression. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. Despite...... of these treatments, the prognosis for patients is poor. In this review, we highlight general aspects concerning genetic alterations in brain tumors, namely astrocytomas, glioblastomas, oligodendrogliomas, medulloblastomas and ependymomas. The influence of these genetic alterations in patients' prognosis is discussed....... Mutagen sensitivity is associated with cancer risk. The convincing studies that linked DNA damages and DNA repair alterations with brain tumors are also described. Another important modifying factor is immunity. General immune response against cancer, tumor microenvironment and immune response, mechanisms...

  20. Adoption and the communication of genetic risk: experiences in Huntington disease.

    Science.gov (United States)

    Bombard, Y; Semaka, A; Hayden, M R

    2012-01-01

    Adoption agencies can use genetic information to determine the eligibility of prospective adoptive parents and to establish a child's suitability for adoption. We describe experiences and implications of communicating genetic risk for Huntington disease (HD) in the context of adoption. A secondary analysis was employed using data collected from a cross-sectional survey (n = 233) and two qualitative studies on the psychosocial effects of predictive testing for HD. We demonstrate several ethical and practical challenges in the search for and communication of genetic information for adoptees and their birth relatives. We also found that concern for adoption discrimination was reported by 13.7% of survey respondents (n = 32). Concerns were higher among tested respondents than those who had not been tested (n = 29 vs n = 3, p = 0.010). However, more respondents were concerned about being discriminated based on their family history (FHx) vs their genetic test results (GTR) (concern based on FHx: n = 18 vs based on GTR: n = 1 vs based on both: n =10). These findings contribute to the limited empirical literature by offering evidence on the experiences and implications of communicating genetic risk information in the context of adoption with reference to HD. © 2011 John Wiley & Sons A/S.

  1. Precision Oncology and Genetic Risk Information: Exploring Patients' Preferences and Responses

    Science.gov (United States)

    Dr. Jada Hamilton is an Assistant Member at Memorial Sloan Kettering Cancer Center, as well as an Assistant Attending Psychologist in the Behavioral Sciences Service, Department of Psychiatry and Behavioral Sciences and in the Clinical Genetics Service, Department of Medicine at Memorial Hospital in New York, New York.  She leads a program of research at the intersection of behavioral science, cancer prevention, and genomics, with the goal of translating advances in genetic and genomic medicine into improved cancer care that is of high quality, aligned with patient preferences, and ultimately improves public health.  Dr. Hamilton is also currently leading a study to assess how patients and their families respond to inherited risk information that is revealed as part of tumor sequencing (funded through a Mentored Research Scholar Grant from the American Cancer Society), as well as studies to evaluate alternative models for offering genetic counseling and testing to patients with cancer, and to examine the effects of novel breast cancer genetic risk feedback on patients’ decision-making, psychological, and behavioral outcomes. Prior to joining the faculty of Memorial Sloan Kettering, Dr. Hamilton received a BA in Genetics and Psychology from Ohio Wesleyan University (2004), an MA and PhD in Social and Health Psychology from Stony Brook University (2006, 2009), and an MPH from the Mailman School of Public Health at Columbia University (2010).  She also completed a postdoctoral fellowship as part of the National Cancer Institute’s Cancer Prevention Fellowship Program.

  2. Relationships between TCF7L2 genetic polymorphisms and polycystic ovary syndrome risk: a meta-analysis.

    Science.gov (United States)

    Shen, Wen-Jing; Li, Tian-Ren; Hu, Yan-Jie; Liu, Hong-Bo; Song, Min

    2014-05-01

    This meta-analysis was performed to evaluate the relationships between genetic polymorphisms in the TCF7L2 gene and polycystic ovary syndrome (PCOS) risk. The PubMed, Centralised Information Service for Complementary Medicine (CISCOM), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Google Scholar, EBSCO, Cochrane Library, and Common Biorepository Model (CBM) databases were searched for relevant articles published before November 1st, 2013, without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The relationships were evaluated by calculating the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). Seven case-control studies with a total 2458 PCOS patients and 5109 healthy subjects' met our inclusion criteria for qualitative data analysis. Two common polymorphisms (rs7903146 C→T and rs12255372 G→T) in the TCF7L2 gene were assessed. The results of our meta-analysis suggested that TCF7L2 genetic polymorphisms might be strongly correlated with an increased risk of PCOS (allele model, OR=1.33, 95% CI=1.15-1.54, P<0.001; dominant model, OR=1.40, 95% CI=1.12-1.75, P=0.003), especially for the rs7903146 C→T polymorphism. A subgroup analysis was done to investigate the effect of ethnicity on an individual's risk of PCOS. Our results revealed positive significant correlations between TCF7L2 genetic polymorphisms and an increased risk of PCOS among Caucasians (allele model, OR=1.26, 95% CI=1.08-1.47, P=0.004; dominant model, OR=1.33, 95% CI=1.00-1.76, P=0.046) and Asians (allele model, OR=2.02, 95% CI=1.42-2.89, P<0.001; dominant model, OR=2.02, 95% CI=1.40-2.92, P<0.001), but not among Africans (all P<0.05). Our findings provide convincing evidence that TCF7L2 genetic polymorphisms may contribute to susceptibility to PCOS, especially for the rs7903146 C→T polymorphism among Caucasians and Asians.

  3. Evidence for shared genetic risk between ADHD symptoms and reduced mathematics ability: a twin study.

    Science.gov (United States)

    Greven, Corina U; Kovas, Yulia; Willcutt, Erik G; Petrill, Stephen A; Plomin, Robert

    2014-01-01

    Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. Data came from more than 6,000 twelve-year-old twin pairs from the UK population-representative Twins Early Development Study. Parents rated each twin's behaviour using a DSM-IV-based 18-item questionnaire of inattentive and hyperactive-impulsive ADHD symptoms. Mathematics tests based on the UK National Curriculum were completed by each twin. The twins also completed standardised tests of reading and general cognitive ability. Multivariate twin model fitting was applied. Inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73% respectively). Mathematics ability was moderately heritable (46%). Mathematics ability and inattentiveness showed a significantly greater phenotypic correlation (r(p) = -.26) and genetic correlation (r(A) = -.41) than mathematics ability and hyperactivity-impulsivity (r(p) = -.18; r(A) = -.22). The genetic correlation between inattentiveness and mathematics ability was largely independent from hyperactivity-impulsivity, and was only partially accounted for by genetic influences related to reading and general cognitive ability. Results revealed the novel finding that mathematics ability shows significantly stronger phenotypic and genetic associations with inattentiveness than with hyperactivity-impulsivity. Genetic associations between inattentiveness and mathematics ability could only partially be accounted for by hyperactivity-impulsivity, reading and general cognitive ability. Results suggest that mathematics ability is associated with ADHD symptoms largely because it shares genetic risk factors with inattentiveness, and provide further evidence for considering inattentiveness and hyperactivity-impulsivity separately. DNA markers for ADHD symptoms (especially inattentiveness) may also be candidate risk factors for

  4. Evidence for shared genetic risk between ADHD symptoms and reduced mathematics ability: a twin study

    Science.gov (United States)

    Greven, Corina U.; Kovas, Yulia; Willcutt, Erik G.; Petrill, Stephen A.; Plomin, Robert

    2013-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. Methods Data came from more than 6,000 12-year-old twin pairs from the U.K. population-representative Twins Early Development Study. Parents rated each twin’s behaviour using a DSM-IV-based 18-item questionnaire of inattentive and hyperactive-impulsive ADHD symptoms. Mathematics tests based on the U.K. National Curriculum were completed by each twin. The twins also completed standardised tests of reading and general cognitive ability. Multivariate twin model fitting was applied. Results Inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73%, respectively). Mathematics ability was moderately heritable (46%). Mathematics ability and inattentiveness showed a significantly greater phenotypic correlation (rp=−0.26) and genetic correlation (rA=−0.41) than mathematics ability and hyperactivity-impulsivity (rp=−0.18; rA=−0.22). The genetic correlation between inattentiveness and mathematics ability was largely independent from hyperactivity-impulsivity, and was only partially accounted for by genetic influences related to reading and general cognitive ability. Conclusions Results revealed the novel finding that mathematics ability shows significantly stronger phenotypic and genetic associations with inattentiveness than with hyperactivity-impulsivity. Genetic associations between inattentiveness and mathematics ability could only partially be accounted for by hyperactivity-impulsivity, reading and general cognitive ability. Results suggest that mathematics ability is associated with ADHD symptoms largely because it shares genetic risk factors with inattentiveness, and provide further evidence for considering inattentiveness and hyperactivity-impulsivity separately. DNA markers for ADHD symptoms (especially inattentiveness) may also

  5. Exploring the cancer risk perception and interest in genetic services among Indigenous people in Queensland, Australia.

    Science.gov (United States)

    Bernardes, Christina M; Valery, Patricia C; Garvey, Gail

    2014-08-01

    The purpose of this study is to explore the levels of interest among Indigenous people with cancer in identifying cancer risk in their family and seeking genetic counselling/testing. A cross-sectional survey of Indigenous cancer patients recruited from four major treating hospitals in Queensland. Participants' family history of cancer and interest in genetic counselling/testing was sought using a structured questionnaire. Overall, 73.0% of 252 participants reported having a family history of cancer; of those, 52.8% had at least one first-degree relative with cancer. A total of 68.3% of participants indicated concern about relatives being affected by cancer and 54.4% of participants indicated they would like to assess the cancer risk in their family with a specialist. Concern was associated with willingness to discuss the risk of cancer with a specialist (pIndigenous cancer patients do have a family history of cancer and appear willing to undergo genetic counselling/investigation. It is of great concern that this population could miss the benefits of the technological advances in health care, creating a much larger disparity in health outcomes. Health service providers should not assume that Indigenous cancer patients will not follow their recommendations when referred to genetic counselling/investigation services. © 2014 Public Health Association of Australia.

  6. Genetic predisposition of IL-10 promoter polymorphisms with risk of multiple sclerosis: A meta-analysis.

    Science.gov (United States)

    Ramakrishnan, V; Akram Husain, R S; Ahmed, Shiek Ssj

    2017-05-15

    Interleukin-10 (IL-10) is a anti-inflammatory cytokine, which controls inflammation by inhibiting the synthesis of several cytokines produced by Th1 cells and macrophages. The association between Interleukin-10 promoter polymorphisms with the risk of multiple sclerosis (MS) remains inconclusive. In this study, a meta-analysis has been performed to assess the relationship between IL-10 gene polymorphisms rs1800896, rs1800871 and rs1800872 with the risk of MS. Nine case-control studies were selected involving 2755 participants. The association between the polymorphisms and MS was examined by the pooled odds ratios (ORs) with 95% confidence intervals (CIs) in allelic, homozygote, heterozygote, dominant and recessive genetic models. Of analyzed genetic models, the pooled ORs and CIs of each SNPs calculated based on random (I 2 >50) or fixed effects (I 2 0.05) of genetic predisposition with MS susceptibility across Asian and Caucasian populations. In addition, assessment based on funnel plot and Egger's linear regression test suggests no publication bias in all analyzed genetic models. Overall, our results demonstrated that rs1800896, rs1800871 and rs1800872 polymorphisms may not be the risk factor for the development of MS in both the populations. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk.

    Science.gov (United States)

    Carmichael, Suzan L; Yang, Wei; Ma, Chen; Roberts, Eric; Kegley, Susan; English, Paul; Lammer, Edward J; Witte, John S; Shaw, Gary M

    2016-08-01

    We examined risks associated with joint exposure of gene variants and pesticides. Analyses included 189 cases and 390 male controls born from 1991 to 2003 in California's San Joaquin Valley. We used logistic regression to examine risks associated with joint exposures of gene variants and pesticides that our previous work identified as associated with hypospadias. Genetic variables were based on variants in DGKK, genes involved in sex steroid synthesis/metabolism, and genes involved in genital tubercle development. Pesticide exposure was based on residential proximity to commercial agricultural pesticide applications. Odds ratios (ORs) were highest among babies with joint exposures, who had two- to fourfold increased risks; for example, the OR was 3.7 (95% confidence interval [CI], 0.8-16.5) among subjects with the risk-associated DGKK haplotype and pesticide exposure; OR, 1.5 (95% CI, 0.7-3.1) among subjects with the haplotype and no pesticide exposure; and OR, 0.9 (95% CI, 0.5-1.6) among subjects without the haplotype but with pesticide exposure, relative to subjects with neither. However, results did not provide statistical evidence that these risks were significantly greater than expected on an additive scale, relative to risks associated with one exposure at a time. We observed elevated risks associated with joint exposures to selected pesticides and genetic variants but no statistical evidence for interaction. Birth Defects Research (Part A) 106:653-658, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles.

    Science.gov (United States)

    McDermott, Kirstie L; McFall, G Peggy; Andrews, Shea J; Anstey, Kaarin J; Dixon, Roger A

    2017-10-01

    Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimer's disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Differential genetic susceptibility to child risk at birth in predicting observed maternal behavior.

    Directory of Open Access Journals (Sweden)

    Keren Fortuna

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

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

    Science.gov (United States)

    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. © The Author 2015. Published by Oxford University Press.

  11. Invited commentary: genetic variants and individual- and societal-level risk factors.

    Science.gov (United States)

    Coughlin, Steven S

    2010-01-01

    Over the past decade, leading epidemiologists have noted the importance of social factors in studying and understanding the distribution and determinants of disease in human populations; but to what extent are epidemiologic studies integrating genetic information and other biologic variables with information about individual-level risk factors and group-level or societal factors related to the broader residential, behavioral, or cultural context? There remains a need to consider ways to integrate genetic information with social and contextual information in epidemiologic studies, partly to combat the overemphasis on the importance of genetic factors as determinants of disease in human populations. Even in genome-wide association studies of coronary heart disease and other common complex diseases, only a small proportion of heritability is explained by the genetic variants identified to date. It is possible that familial clustering due to genetic factors has been overestimated and that important environmental or social influences (acting alone or in combination with genetic variants) have been overlooked. The accompanying article by Bressler et al. (Am J Epidemiol. 2010;171(1):14-23) highlights some of these important issues.

  12. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles

    DEFF Research Database (Denmark)

    Mero, Inger-Lise; Gustavsen, Marte W; Sæther, Hanne S

    2013-01-01

    The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating...... at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB...

  13. Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.

    Science.gov (United States)

    Toth, Reka; Scherer, Dominique; Kelemen, Linda E; Risch, Angela; Hazra, Aditi; Balavarca, Yesilda; Issa, Jean-Pierre J; Moreno, Victor; Eeles, Rosalind A; Ogino, Shuji; Wu, Xifeng; Ye, Yuanqing; Hung, Rayjean J; Goode, Ellen L; Ulrich, Cornelia M

    2017-06-01

    Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-corrected P values (q values epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816-25. ©2017 AACR . ©2017 American Association for Cancer Research.

  14. Women-specific risk factors for heart failure: A genetic approach.

    Science.gov (United States)

    van der Kemp, Jet; van der Schouw, Yvonne T; Asselbergs, Folkert W; Onland-Moret, N Charlotte

    2018-03-01

    Heart failure is a complex disease, which is presented differently by men and women. Several studies have shown that reproductive factors, such as age at natural menopause, parity and polycystic ovarian syndrome (PCOS), may play a role in the development of heart failure. Shared genetics may provide clues to underlying mechanisms; however, this has never been examined. Therefore, the aim of the current study was to explore whether any reproductive factor is potentially related to heart failure in women, based on genetic similarities. Conducting a systematic literature review, single nucleotide polymorphisms (SNPs) associated with reproductive factors, heart failure and its risk factors were extracted from recent genome-wide association studies. We tested whether there was any overlap between the SNPs and their proxies of reproductive risk factors with those known for heart failure or its risk factors. In total, 520 genetic variants were found that are associated with reproductive factors, namely age at menarche, age at natural menopause, menstrual cycle length, PCOS, preeclampsia, preterm delivery and spontaneous dizygotic twinning. For heart failure and associated phenotypes, 25 variants were found. Genetic variants for reproductive factors did not overlap with those for heart failure. However, age at menarche, gestational diabetes and PCOS were found to be genetically linked to risk factors for heart failure, such as atrial fibrillation, diabetes and smoking. Corresponding implicated genes, such as TNNI3K, ErbB3, MKL2, MTNR1B and PRKD1, may explain the associations between reproductive factors and heart failure. Exact effector mechanisms of these genes remain to be investigated further. Copyright © 2017. Published by Elsevier B.V.

  15. IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population

    Directory of Open Access Journals (Sweden)

    Lynnette R. Ferguson

    2010-01-01

    Full Text Available DNA samples from 339 Crohn's disease (CD and 407 randomly selected controls from the Auckland (New Zealand IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677 and two in IL-12B (rs1363670 and rs6887695. While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17–40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.

  16. Neuropsychological Functioning in Adolescents and Young Adults at Genetic Risk for Schizophrenia and Affective Psychoses: Results from the Harvard and Hillside Adolescent High Risk Studies

    OpenAIRE

    Seidman, Larry J.; Giuliano, Anthony J.; Smith, Christopher W.; Stone, William S.; Glatt, Stephen J.; Meyer, Eric; Faraone, Stephen V.; Tsuang, Ming T.; Cornblatt, Barbara

    2006-01-01

    Siblings and offspring of persons with schizophrenia carry elevated genetic risk for the illness and manifest attentional and memory impairments. Because less is known about other neuropsychological functions and their specificity in adolescents, we conducted a genetic high-risk (HR) study of schizophrenia (HR-SCZ) and affective psychosis (HR-AFF). Participants (ages 12–25) were from the Harvard Adolescent High-Risk and Hillside Family studies, including 73 HR-SCZ, 18 HR-AFF, and 84 community...

  17. Linking genetic counseling content to short-term outcomes in individuals at elevated breast cancer risk.

    Science.gov (United States)

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

    2014-10-01

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

  18. Genetic predisposition to dyslipidemia and type 2 diabetes risk in two prospective cohorts.

    Science.gov (United States)

    Qi, Qibin; Liang, Liming; Doria, Alessandro; Hu, Frank B; Qi, Lu

    2012-03-01

    Dyslipidemia has been associated with type 2 diabetes, but it remains unclear whether dyslipidemia plays a causal role in type 2 diabetes. We aimed to examine the association between the genetic predisposition to dyslipdemia and type 2 diabetes risk. The current study included 2,447 patients with type 2 diabetes and 3,052 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-up Study. Genetic predisposition to dyslipidemia was estimated by three genotype scores of lipids (LDL cholesterol, HDL cholesterol, and triglycerides) on the basis of the established loci for blood lipids. Linear relation analysis indicated that the HDL cholesterol and triglyceride genotype scores, but not the LDL cholesterol genotype score, were linearly related to elevated type 2 diabetes risk. Each point of the HDL cholesterol and triglyceride genotype scores was associated with a 3% (odds ratio [OR] 1.03 [95% CI 1.01-1.04]) and a 2% (1.02 [1.00-1.04]) increased risk of developing type 2 diabetes, respectively. The ORs were 1.39 (1.17-1.65) and 1.19 (1.01-1.41) for type 2 diabetes by comparing extreme quartiles of the HDL cholesterol genotype score and triglyceride genotype score, respectively. In conclusion, genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk.

  19. Genetic risk and longitudinal disease activity in systemic lupus erythematosus using targeted maximum likelihood estimation.

    Science.gov (United States)

    Gianfrancesco, M A; Balzer, L; Taylor, K E; Trupin, L; Nititham, J; Seldin, M F; Singer, A W; Criswell, L A; Barcellos, L F

    2016-09-01

    Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal-targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprising 41 established SLE variants and clinically important disease activity as measured by the validated Systemic Lupus Activity Questionnaire (SLAQ) in a multiethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (>4.0) for individuals with a high GRS compared with those with a low GRS across nine time points after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking and education, as well as time-dependent confounding of missing visits. Individual single-nucleotide polymorphism (SNP) analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across time points eight and nine after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors.

  20. Common genetic polymorphisms within NFκB-related genes and the risk of developing invasive aspergillosis

    Directory of Open Access Journals (Sweden)

    Carmen Belén Lupiañez

    2016-08-01

    Full Text Available Invasive Aspergillosis (IA is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mould. 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 6-fold increased risk of developing the infection when compared with those carrying the C allele (OR-Rec=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.

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

    Science.gov (United States)

    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

  2. Psychological stress and risk of incident atrial fibrillation in men and women with known atrial fibrillation genetic risk scores

    Science.gov (United States)

    Svensson, Thomas; Kitlinski, Mariusz; Engström, Gunnar; Melander, Olle

    2017-01-01

    Psychological stress has been reported as a possible trigger of atrial fibrillation (AF). No studies have investigated whether any association between stress and AF could be modified by genetic susceptibility to AF (AF-genetic risk score (AF-GRS)). 8765 men and 13,543 women from the Malmö Diet Cancer Study, a population-based cohort, were included in the analyses. A variable representing stress was constructed from questions measuring job strain, and from one question assessing non-occupational stress. Cox proportional hazards regression models were adjusted for known covariates of AF. Mean follow-up times and number of recorded incident AF were 14.2 years and 1116 events for men, and 15.1 years and 932 events for women. Among women, high stress was associated with AF in the age adjusted model (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01–1.47) but not following multivariable adjustment (HR, 1.15; 95% CI, 0.95–1.39). Stress was not associated with incident AF in men. AF-GRS was significantly associated with incident AF for both genders. Stress did not interact significantly with genetic susceptibility to AF in men or women. Chronic stress is not associated with long-term incident hospital diagnosed AF. This association does not appear to be modified by genetic susceptibility to AF. PMID:28195211

  3. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

    Science.gov (United States)

    Lubitz, Steven A; Lunetta, Kathryn L; Lin, Honghuang; Arking, Dan E; Trompet, Stella; Li, Guo; Krijthe, Bouwe P; Chasman, Daniel I; Barnard, John; Kleber, Marcus E; Dörr, Marcus; Ozaki, Kouichi; Smith, Albert V; Müller-Nurasyid, Martina; Walter, Stefan; Agarwal, Sunil K; Bis, Joshua C; Brody, Jennifer A; Chen, Lin Y; Everett, Brendan M; Ford, Ian; Franco, Oscar H; Harris, Tamara B; Hofman, Albert; Kääb, Stefan; Mahida, Saagar; Kathiresan, Sekar; Kubo, Michiaki; Launer, Lenore J; MacFarlane, Peter W; Magnani, Jared W; McKnight, Barbara; McManus, David D; Peters, Annette; Psaty, Bruce M; Rose, Lynda M; Rotter, Jerome I; Silbernagel, Guenther; Smith, Jonathan D; Sotoodehnia, Nona; Stott, David J; Taylor, Kent D; Tomaschitz, Andreas; Tsunoda, Tatsuhiko; Uitterlinden, Andre G; Van Wagoner, David R; Völker, Uwe; Völzke, Henry; Murabito, Joanne M; Sinner, Moritz F; Gudnason, Vilmundur; Felix, Stephan B; März, Winfried; Chung, Mina; Albert, Christine M; Stricker, Bruno H; Tanaka, Toshihiro; Heckbert, Susan R; Jukema, J Wouter; Alonso, Alvaro; Benjamin, Emelia J; Ellinor, Patrick T

    2014-04-01

    This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2014-10-02

    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. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. Genetic Factors Contribute to Risk for Neonatal Respiratory Distress Syndrome among Moderately Preterm, Late Preterm, and Term Infants

    Science.gov (United States)

    Shen, Carol L.; Zhang, Qunyuan; Meyer, Julia; Cole, F. Sessions; Wambach, Jennifer A.

    2016-01-01

    Objective To determine the genetic contribution to risk for respiratory distress syndrome (RDS) among moderately preterm, late preterm, and term infants (estimated gestational age ≥32 weeks) of African and European-descent. Study Design We reviewed clinical records for 524 consecutive twin pairs ≥32 weeks gestation. We identified pairs in which at least 1 twin had RDS (n=225) and compared the concordance of RDS between monozygotic (MZ) and dizygotic twins (DZ). Using mixed effects logistic regression, we identified covariates that increased disease risk. We performed additive genetic, common environmental, and residual effects modeling to estimate genetic variance and used the ratio of genetic variance to total variance to estimate genetic contribution to RDS disease risk. Results Monozygotic twins were more concordant for RDS than dizygotic twins (p=0.0040). Estimated gestational age, European-descent, male sex, delivery by cesarean, and five minute Apgar score each independently increased risk for RDS. After adjusting for these covariates, genetic effects accounted for 58% (p=0.0002) of the RDS disease risk variance for all twin pairs. Conclusions In addition to environmental factors, genetic factors may contribute to RDS risk among moderately preterm, late preterm, and term infants. Discovery of risk alleles may be important for prediction and management of RDS risk. PMID:26935785

  6. Peer deviance, parental divorce, and genetic risk in the prediction of drug abuse in a nationwide Swedish sample: evidence of environment-environment and gene-environment interaction.

    Science.gov (United States)

    Kendler, Kenneth S; Ohlsson, Henrik; Sundquist, Kristina; Sundquist, Jan

    2014-04-01

    Peer deviance (PD) strongly predicts externalizing psychopathologic conditions but has not been previously assessable in population cohorts. We sought to develop such an index of PD and to clarify its effects on risk of drug abuse (DA). To examine how strongly PD increases the risk of DA and whether this community-level liability indicator interacts with key DA risk factors at the individual and family levels. Studies of future DA registration in 1,401,698 Swedish probands born from January 1, 1970, through December 31, 1985, and their adolescent peers in approximately 9200 small community areas. Peer deviance was defined as the proportion of individuals born within 5 years of the proband living in the same small community when the proband was 15 years old who eventually were registered for DA. Drug abuse recorded in medical, legal, or pharmacy registry records. Peer deviance was associated with future DA in the proband, with rates of DA in older and male peers more strongly predictive than in younger or female peers. The predictive power of PD was only slightly attenuated by adding measures of community deprivation, collective efficacy, or family socioeconomic status. Probands whose parents were divorced were more sensitive to the pathogenic effects of high PD environments. A robust positive interaction was also seen between genetic risk of DA (indexed by rates of DA in first-, second-, and third-degree relatives) and PD exposure. With sufficient data, PD can be measured in populations and strongly predicts DA. In a nationwide sample, risk factors at the level of the individual (genetic vulnerability), family (parental loss), and community (PD) contribute substantially to risk of DA. Individuals at elevated DA risk because of parental divorce or high genetic liability are more sensitive to the pathogenic effects of PD. Although the effect of our PD measure on DA liability cannot be explained by standard measures of community or family risk, we cannot, with

  7. Communicating about the risks and benefits of genetically modified foods: The mediating role of trust

    DEFF Research Database (Denmark)

    Frewer, Lynn J.; Scholderer, Joachim; Bredahl, Lone

    2003-01-01

    role, direct as well as mediating effects of trust were tested in an attitude change experiment involving 1203 consumers from Denmark, Germany, Italy and the UK. After prior attitudes to genetic modification in food production had been assessed, participants received different information materials...... (either product-specific information or balanced/general information about genetic modification in food production) and were asked to evaluate different types of genetically modified foods (either beer or yoghurt). The information materials were attributed to different information sources (either...... an industry association, a consumer organization, or a government source). After completion, perceived risk and perceived benefit were assessed, and participants indicated their trust in the information sources to which the materials had been attributed. Direct and trust-mediated attitude change effects were...

  8. The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA

    Science.gov (United States)

    Yarwood, Annie; Huizinga, Tom W. J.

    2016-01-01

    There is now a general consensus that RA has a spectrum of disease stages that can begin many years before the onset of clinical symptoms. It is widely thought that understanding the complex interplay between genetics and environment, and their role in pathogenesis, is essential in gaining further insight into the mechanisms that drive disease development and progression. More than 100 genetic susceptibility loci have now been identified for RA through studies that have focused on patients with established RA compared with healthy controls. Studying the early preclinical phases of disease will provide valuable insights into the biological events that precede disease and could potentially identify biomarkers to predict disease onset and future therapeutic targets. In this review we will cover recent advances in the knowledge of genetic and environmental risk factors and speculate on how these factors may influence the transition from one stage of disease to another. PMID:25239882

  9. A Decade of Genetic and Metabolomic Contributions to Type 2 Diabetes Risk Prediction

    Science.gov (United States)

    Merino, Jordi; Leong, Aaron; Meigs, James B.

    2018-01-01

    Purpose of Review The purpose of this review was to summarize and reflect on advances over the past decade in human genetic and metabolomic discovery with particular focus on their contributions to type 2 diabetes (T2D) risk prediction. Recent Findings In the past 10 years, a combination of advances in genotyping efficiency, metabolomic profiling, bio-informatics approaches, and international collaboration have moved T2D genetics and metabolomics from a state of frustration to an abundance of new knowledge. Summary Efforts to control and prevent T2D have failed to stop this global epidemic. New approaches are needed, and although neither genetic nor metabolomic profiling yet have a clear clinical role, the rapid pace of accumulating knowledge offers the possibility for “multi-omic” prediction to improve health. PMID:29103096

  10. Ischemic stroke risk, smoking, and the genetics of inflammation in a biracial population: the stroke prevention in young women study

    OpenAIRE

    Cole, John W; Brown, David W; Giles, Wayne H; Stine, Oscar C; O'Connell, Jeffrey R; Mitchell, Braxton D; Sorkin, John D; Wozniak, Marcella A; Stern, Barney J; Sparks, Mary J; Dobbins, Mark T; Shoffner, Latasha T; Zappala, Nancy K; Reinhart, Laurie J; Kittner, Steven J

    2008-01-01

    Abstract Background Although cigarette smoking is a well-established risk factor for vascular disease, the genetic mechanisms that link cigarette smoking to an increased incidence of stroke are not well understood. Genetic variations within the genes of the inflammatory pathways are thought to partially mediate this risk. Here we evaluate the association of several inflammatory gene single nucleotide polymorphisms (SNPs) with ischemic stroke risk among young women, further stratified by curre...

  11. Being at risk for cardiovascular disease: perceptions and preventive behavior in people with and without a known genetic predisposition.

    Science.gov (United States)

    Claassen, L; Henneman, L; van der Weijden, T; Marteau, T M; Timmermans, D R M

    2012-01-01

    This study compares and explains differences in perceptions of cardiovascular disease (CVD) risk and preventive behaviors in people with and without a known genetic predisposition to CVD. A cross-sectional study using two samples was performed. The first sample (genetic predisposition; n = 51) consisted of individuals recently diagnosed with familial hypercholesterolemia (FH) through DNA testing. The second sample (no genetic predisposition; n = 49) was recruited among patients with CVD-risk profiles based on family history of CVD, cholesterol levels, and blood pressure, registered at general practices. Participants filled out a postal questionnaire asking about their perceived risk, causal attributions (i.e. genetic and lifestyle), and about perceived efficacy and adoption of preventive behavior (i.e. medication adherence and adoption of a healthy diet and being sufficiently active). Perceived comparative risk, genetic attributions of CVD, and perceived efficacy of medication were higher in the "genetic predisposition" sample than in the "no genetic predisposition" sample. The samples did not differ on lifestyle attributions, efficacy of a healthy lifestyle, or preventive behavior. Individual differences in perceived risk, genetic attributions, perceived efficacy of medication, and adoption of a healthy lifestyle were best explained by family history of CVD. Our findings suggest that in people diagnosed with a single gene disorder characterized by a family disease history such as FH, family disease history may be more important than DNA information in explaining perceptions of and responses to risk.

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

    Science.gov (United States)

    Bawa, A S; Anilakumar, K R

    2013-12-01

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

  13. Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS).

    Science.gov (United States)

    Quaid, K A; Eberly, S W; Kayson-Rubin, E; Oakes, D; Shoulson, I

    2017-06-01

    Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Science.gov (United States)

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

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

    Science.gov (United States)

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

    2016-01-05

    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.

  16. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients

    DEFF Research Database (Denmark)

    Brorsson, Caroline A; Nielsen, Lotte B; Andersen, Marie-Louise

    2016-01-01

    Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type...... 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease...... of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment....

  17. Modes of risk explanation in telephone consultations between nurses and parents for a genetic condition

    DEFF Research Database (Denmark)

    Zayts, Olga; Sarangi, Srikant

    2013-01-01

    consultations in Hong Kong between genetic nurses and parents whose infants have been diagnosed with a mild hereditary disorder, G6PD deficiency, commonly known as favism. Using discourse analytic methods, we focus on 50 audio-recorded telephone consultations. First, we show the distribution of different types...... of risk explanation in terms of their volume and sequential positioning in the study corpus. The two predominant explanation types – physiological explanations and hereditary explanations – are then discussed in relation to their respective functions in these telephone consultations, namely serving...... as warrants for advice-giving and providing reassurance. We then examine how the genetic nurses interactionally orient themselves to the parents’ existing knowledge regarding G6PD deficiency while delivering these risk explanations. The differences in explanation trajectories are linked to the presence...

  18. Epidemiological, neurobiological, and genetic clues to the mechanisms linking cannabis use to risk for nonaffective psychosis.

    Science.gov (United States)

    van Winkel, Ruud; Kuepper, Rebecca

    2014-01-01

    Epidemiological studies have shown that the association between cannabis and psychosis is robust and consistent across different samples, with compelling evidence for a dose-response relationship. Because longitudinal work indicates that cannabis use precedes psychotic symptoms, it seems reasonable to assume a causal relationship. However, more work is needed to address the possibility of gene-environment correlation (for example, genetic risk for psychosis causing onset of cannabis use). Moreover, knowledge about underlying biological mechanisms linking cannabis use and psychosis is still relatively limited. In order to understand how cannabis use may lead to an increased risk for psychosis, in the present article we (a) review the epidemiological, neurobiological, and genetic evidence linking cannabinoids and psychosis, (b) assess the quality of the evidence, and finally (c) try to integrate the most robust findings into a neurodevelopmental model of cannabis-induced psychosis and identify the gaps in knowledge that are in need of further investigation.

  19. Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children

    DEFF Research Database (Denmark)

    Lundbo, Lene F; Harboe, Zitta Barrella; Clausen, Louise N

    2016-01-01

    NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). METHODS: Cases with IPD and IMD and controls were identified......BACKGROUND: Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes.......86-1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. CONCLUSIONS: A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis....

  20. Genetics

    Science.gov (United States)

    ... Likelihood of getting certain diseases Mental abilities Natural talents An abnormal trait (anomaly) that is passed down ... one of them has a genetic disorder. Information Human beings have cells with 46 chromosomes . These consist ...

  1. Genetic variants associated with celiac disease and the risk for coronary artery disease.

    Science.gov (United States)

    Jansen, Henning; Willenborg, Christina; Schlesinger, Sabrina; Ferrario, Paola G; König, Inke R; Erdmann, Jeanette; Samani, Nilesh J; Lieb, Wolfgang; Schunkert, Heribert

    2015-10-01

    Epidemiological evidence suggests that patients with celiac disease are at increased risk for coronary artery disease (CAD). Genetic-epidemiological analyses identified many single nucleotide polymorphisms (SNPs) associated with celiac disease. If there is a causal relation between celiac disease and CAD, one might expect that risk alleles primarily associated with celiac disease also increase the risk of CAD. In this study we identified from literature 41 SNPs that have been previously described to be genome-wide associated with celiac disease (p DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) dataset, a meta-analysis comprising genome-wide SNP association data from 22,233 CAD cases and 64,762 controls. 24 out of 41 (58.5 %) risk alleles for celiac disease displayed a positive association with CAD (CAD-OR range 1.001-1.081). The remaining risk alleles for celiac disease (n = 16) revealed CAD-ORs of ≤1.0 (range 0.951-1.0). The proportion of CAD associated alleles was greater but did not differ significantly from the proportion of 50 % expected by chance (p = 0.069). One SNP (rs653178 at the SH2B3/ATXN2 locus) displayed study-wise statistically significant association with CAD with directionality consistent effects on celiac disease and CAD. However, the effect of this locus is most likely driven by pleiotropic effects on multiple other diseases. In conclusion, this genetically based approach provided no convincing evidence that SNPs associated with celiac disease contribute to the risk of CAD. Hence, common non-genetic factors may play a more important role explaining the coincidence of these two complex disease conditions.

  2. Methylation diet and methyl group genetics in risk for adenomatous polyp occurrence

    Directory of Open Access Journals (Sweden)

    Mark Lucock

    2015-06-01

    Conclusion: A methylation diet influences methyl group synthesis in the regulation of blood homocysteine level, and is modulated by genetic interactions. Methylation-related nutrients also interact with key genes to modify risk of AP, a precursor of colorectal cancer. Independent of diet, two methylation-related genes (A2756G-MS and A66G-MSR were directly associated with AP occurrence.

  3. Genetic variants within the serotonin transporter associated with familial risk for major depression

    Science.gov (United States)

    Talati, Ardesheer; Guffanti, Guia; Odgerel, Zagaa; Ionita-Laza, Iuliana; Malm, Heli; Sourander, Andre; Brown, Alan S.; Wickramaratne, Priya J.; Gingrich, Jay A.; Weissman, Myrna M.

    2015-01-01

    The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N=192) as compared to low (N=101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences. PMID:25920807

  4. Distribution, ecology, life history, genetic variation, and risk of extinction of nonhuman primates from Costa Rica

    OpenAIRE

    Zaldívar, María E.; Rocha, Oscar; Glander, Kenneth E.; Aguilar, Gabriel; Huertas, Ana S; Sánchez, Ronald; Wong, Grace

    2014-01-01

    We examined the association between geographic distribution, ecological traits, life history, genetic diversity, and risk of extinction in nonhuman primate species from Costa Rica. All of the current nonhuman primate species from Costa Rica are included in the study; spider monkeys (Ateles geoffroyi), howling monkeys (Alouatta palliata), capuchins (Cebus capucinus), and squirrel monkeys (Saimiri oerstedii). Geographic distribution was characterized accessing existing databases. Data on ecolog...

  5. Distribution, ecology, life history, genetic variation, and risk of extinction of nonhuman primates from Costa Rica

    OpenAIRE

    María E Zaldívar; Oscar Rocha; Kenneth E Glander; Gabriel Aguilar; Ana S Huertas; Ronald Sánchez; Grace Wong

    2004-01-01

    We examined the association between geographic distribution, ecological traits, life history, genetic diversity, and risk of extinction in nonhuman primate species from Costa Rica. All of the current nonhuman primate species from Costa Rica are included in the study; spider monkeys (Ateles geoffroyi), howling monkeys (Alouatta palliata), capuchins (Cebus capucinus), and squirrel monkeys (Saimiri oerstedii). Geographic distribution was characterized accessing existing databases. Data on ecolog...

  6. Strengthening the reporting of genetic risk prediction studies: The GRIPS statement

    OpenAIRE

    Janssens, Cécile; Ioannidis, John; Duijn, Cornelia; Little, Julian; Khoury, Muin Joseph

    2011-01-01

    Abstract The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting ...

  7. Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population.

    Science.gov (United States)

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

    2014-10-15

    Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population. Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623). Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003). These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  8. Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.

    Directory of Open Access Journals (Sweden)

    Rahul S Desikan

    2017-03-01

    Full Text Available Identifying individuals at risk for developing Alzheimer disease (AD is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1, we identified AD-associated SNPs (at p < 10-5. We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC, providing a polygenic hazard score (PHS for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680. Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22. In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26 and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10, and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6 and in vivo markers of AD neurodegeneration (ADNI

  9. Genetic Variation in ABCG1 and Risk of Myocardial Infarction and Ischemic Heart Disease

    DEFF Research Database (Denmark)

    Schou, Jesper; Frikke-Schmidt, Ruth; Kardassis, Dimitris

    2012-01-01

    OBJECTIVE: ATP binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux from macrophages to mature high-density lipoprotein particles. Whether genetic variation in ABCG1 affects risk of atherosclerosis in humans remains to be determined. METHODS AND RESULTS: We resequenced the core...... promoter and coding regions of ABCG1 in 380 individuals from the general population. Next, we genotyped 10 237 individuals from the Copenhagen City Heart Study for the identified variants and determined the effect on lipid and lipoprotein levels and on risk of myocardial infarction (MI) and ischemic heart...

  10. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women

    DEFF Research Database (Denmark)

    Tabor, A; Philip, J; Madsen, Mette

    1986-01-01

    Outcome of pregnancy after amniocentesis was studied in a randomised controlled trial of 4606 women, age-range 25-34 years, without known risk of genetic disease. Spontaneous abortion rate was 1.7% in the study group after amniocentesis and 0.7% in the control group after ultrasound (relative risk...... amniocentesis/ultrasound scan, amniotic fluid leakage occurred more often in the study group but there was no difference in the rate of vaginal bleeding. Frequency of postural malformations in the infants in the two groups was the same. In the study group, respiratory distress syndrome was diagnosed more often...

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

    DEFF Research Database (Denmark)

    Pearce, C L; Near, A M; Van Den Berg, D J

    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... and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted....

  12. The Debate on the Risk of Genetically Modified Food: The Politics of Science

    OpenAIRE

    Gaivoronskaia, Galina; Solem, Knut Erik

    2000-01-01

    Scientific research on the use of genetic engineering in the production of new food is facing a difficult situation. Further development in this field is being impacted more and more by the debate on the risk of GM food, where consumers’ tools and the ability to influence decision-making are being enhanced. In Norway regulatory mechanisms have been introduced to address a wide range of GM-food risks, but at the same time have created certain obstacles for scientists and industry. Not yet usin...

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

    DEFF Research Database (Denmark)

    Vaag, Allan; Brøns, Charlotte; Gillberg, Linn

    2014-01-01

    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...... 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...

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

    Science.gov (United States)

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

    2015-09-01

    Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Characterization of clinical and genetic risk factors associated with dyslipidemia after kidney transplantation.

    Science.gov (United States)

    Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Inoue, Takamitsu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

    2015-01-01

    We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8-12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia.

  16. Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

    Science.gov (United States)

    Gottesman, Omri; Drill, Esther; Lotay, Vaneet; Bottinger, Erwin; Peter, Inga

    2012-01-01

    The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS) catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.

  17. Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

    Directory of Open Access Journals (Sweden)

    Omri Gottesman

    Full Text Available The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.

  18. Elevated partial antiphospholipid score is a strong risk factor for thrombosis in patients with systemic lupus erythematosus: a validation study.

    Science.gov (United States)

    Chen, Jie; Sun, Shuhui; Yan, Qingran; Bao, Chunde; Fu, Qiong

    2016-02-01

    This study aims to identify risk factors for thrombosis in patients with systemic lupus erythematosus (SLE) and to validate the efficacy of the partial antiphospholipid (aPL) score for thrombosis prediction and diagnosis of antiphospholipid syndrome (APS). This study included 325 SLE patients, 188 of whom completed a follow-up of 31.01 months (range 23-48 months). Partial aPL score was calculated by adding up the individual scores for activated partial thromboplastin time (APTT), lupus anticoagulant, IgG/IgM anticardiolipin antibodies (aCL), and IgG/IgM anti-β2-glycoprotein I (anti-β2GPI). A simplified aPL score was developed using only APTT, IgG/IgM aCL, and IgG/IgM anti-β2GPI. Partial aPL scores were significantly higher in SLE patients with thrombosis (p thrombosis (p 10 (p thrombosis. For patients with a history of thrombosis, partial aPL score was the strongest risk factor for recurrent thrombosis (p thrombosis (p thrombosis in SLE patients and is a useful tool to predict recurrent thrombosis. Partial aPL score and simplified aPL score, although comprising fewer items than the original aPL score, also represent valuable quantitative indices for APS diagnosis.

  19. Strong genetic structure revealed by multilocus patterns of variation in Giardia duodenalis isolates of patients from Galicia (NW-Iberian Peninsula).

    Science.gov (United States)

    Gabín-García, Luis B; Bartolomé, Carolina; Abal-Fabeiro, José L; Méndez, Santiago; Llovo, José; Maside, Xulio

    2017-03-01

    We report a survey of genetic variation at three coding loci in Giardia duodenalis of assemblages A and B obtained from stool samples of patients from Santiago de Compostela (Galicia, NW-Iberian Peninsula). The mean pooled synonymous diversity for assemblage A was nearly five times lower than for assemblage B (0.77%±0.30% and 4.14%±1.65%, respectively). Synonymous variation in both assemblages was in mutation-drift equilibrium and an excess of low-frequency nonsynonymous variants suggested the action of purifying selection at the three loci. Differences between isolates contributed to 40% and 60% of total genetic variance in assemblages A and B, respectively, which revealed a significant genetic structure. These results, together with the lack of evidence for recombination, support that (i) Giardia assemblages A and B are in demographic equilibrium and behave as two genetically isolated populations, (ii) infections are initiated by a reduced number of individuals, which may be genetically diverse and even belong to different assemblages, and (iii) parasites reproduce clonally within the host. However, the observation of invariant loci in some isolates means that mechanisms for the homogenization of the genetic content of the two diploid nuclei in each individual must exist. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Genetic predisposition, parity, age at first childbirth and risk for breast cancer

    Directory of Open Access Journals (Sweden)

    Butt Salma

    2012-08-01

    Full Text Available Abstract Background Recent studies have identified several single-nucleotide polymorphisms (SNPs associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk. Methods The Malmö Diet and Cancer Study (MDCS included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR with 95% confidence intervals (CI. Results Six of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2, rs3803662 (TNRC9, rs12443621 (TNRC9, rs889312 (MAP3K1, rs3817198 (LSP1 and rs2107425 (H19. We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons. Conclusions The results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

  1. Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study

    Directory of Open Access Journals (Sweden)

    Joshua W. Knowles

    2017-08-01

    Full Text Available PurposeWe tested whether providing a genetic risk score (GRS for coronary artery disease (CAD would serve as a motivator to improve adherence to risk-reducing strategies.MethodsWe randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49 or without (N = 45 their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C between the 3- and 6-month follow-up visits (ΔLDL-C. Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS.ResultsSixty-five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (ΔLDL-C: −13 vs. −9 mg/dl. Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry.ConclusionAdding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials.

  2. Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease - risk discounting in preventive genetics.

    Science.gov (United States)

    Schulman, J D; Stern, H J

    2015-09-01

    Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J. D. S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Antimicrobial drug use in food-producing animals and associated human health risks: what, and how strong, is the evidence?

    Science.gov (United States)

    Hoelzer, Karin; Wong, Nora; Thomas, Joe; Talkington, Kathy; Jungman, Elizabeth; Coukell, Allan

    2017-07-04

    Antimicrobial resistance is a public health threat. Because antimicrobial consumption in food-producing animals contributes to the problem, policies restricting the inappropriate or unnecessary agricultural use of antimicrobial drugs are important. However, this link between agricultural antibiotic use and antibiotic resistance has remained contested by some, with potentially disruptive effects on efforts to move towards the judicious or prudent use of these drugs. The goal of this review is to systematically evaluate the types of evidence available for each step in the causal pathway from antimicrobial use on farms to human public health risk, and to evaluate the strength of evidence within a 'Grades of Recommendations Assessment, Development and Evaluation'(GRADE) framework. The review clearly demonstrates that there is compelling scientific evidence available to support each step in the causal pathway, from antimicrobial use on farms to a public health burden caused by infections with resistant pathogens. Importantly, the pathogen, antimicrobial drug and treatment regimen, and general setting (e.g., feed type) can have significant impacts on how quickly resistance emerges or spreads, for how long resistance may persist after antimicrobial exposures cease, and what public health impacts may be associated with antimicrobial use on farms. Therefore an exact quantification of the public health burden attributable to antimicrobial drug use in animal agriculture compared to other sources remains challenging. Even though more research is needed to close existing data gaps, obtain a better understanding of how antimicrobial drugs are actually used on farms or feedlots, and quantify the risk associated with antimicrobial use in animal agriculture, these findings reinforce the need to act now and restrict antibiotic use in animal agriculture to those instances necessary to ensure the health and well-being of the animals.

  4. Pulse pressure strongly predicts cardiovascular disease risk in patients with type 2 diabetes from the Swedish National Diabetes Register (NDR).

    Science.gov (United States)

    Nilsson, P M; Cederholm, J; Eeg-Olofsson, K; Eliasson, B; Zethelius, B; Gudbjörnsdóttir, S

    2009-12-01

    To analyze pulse pressure (PP) as a risk predictor for coronary heart disease (CHD), stroke and cardiovascular disease (CVD; CHD and/or stroke) in type 2 diabetic patients. A total of 11,128 female and male type 2 diabetic patients with known baseline PP values and no CVD, aged 50-74 years, were followed for a mean duration of 5.6 years (1998-2003). A subgroup of 5521 patients with known mean PP values (mean values at baseline and at the end of the study) was also included. Hazard ratios (HRs) with 95% CI for fatal/nonfatal CHD with baseline or mean PP>or=75mmHg, compared to diabetes duration, HbA(1c), body mass index (BMI), lipid-reducing drugs, microalbuminuria > 20microg/min, antihypertensive drugs and hypoglycaemic treatment, using Cox regression analyses. Fully-adjusted respective HRs for stroke were 1.17 (0.98-1.39) and 1.21 (0.90-1.61) and, for CVD, 1.23 (1.10-1.37; Por=75mmHg were to be avoided, then 15% and 17% of CHD and or CVD, cases, respectively, in such a cohort might be prevented after multivariable adjustments, with a further 10% of cases avoided if also adjusted for MBP and age. Increasing baseline MBP, age and microalbuminuria were independently and significantly associated (Prisk predictor of CVD in type 2 diabetic patients, and lowering PP can lead to a marked reduction in risk.

  5. Genetic variation in DNA repair pathways and risk of non-Hodgkin's lymphoma.

    Directory of Open Access Journals (Sweden)

    Justin Rendleman

    Full Text Available 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.

  6. Effect of Genetic Predisposition on Blood Lipid Traits Using Cumulative Risk Assessment in the Korean Population

    Directory of Open Access Journals (Sweden)

    Min Jin Go

    2012-06-01

    Full Text Available Dyslipidemia, mainly characterized by high triglyceride (TG and low high-density lipoprotein cholesterol (HDL-C levels, is an important etiological factor in the development of cardiovascular disease (CVD. Considering the relationship between childhood obesity and CVD risk, it would be worthwhile to evaluate whether previously identified lipid-related variants in adult subjects are associated with lipid variations in a childhood obesity study (n = 482. In an association analysis for 16 genome-wide association study (GWAS-based candidate loci, we confirmed significant associations of a genetic predisposition to lipoprotein concentrations in a childhood obesity study. Having two loci (rs10503669 at LPL and rs16940212 at LIPC that showed the strongest association with blood levels of TG and HDL-C, we calculated a genetic risk score (GRS, representing the sum of the risk alleles. It has been observed that increasing GRS is significantly associated with decreased HDL-C (effect size, -1.13 ± 0.07 compared to single nucleotide polymorphism combinations without two risk variants. In addition, a positive correlation was observed between allelic dosage score and risk allele (rs10503669 at LPL on high TG levels (effect size, 10.89 ± 0.84. These two loci yielded consistent associations in our previous meta-analysis. Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C overlap to a large extent in childhood as well as in adulthood. Post-GWAS functional characterization of these variants is further required to elucidate their pathophysiological roles and biological mechanisms.

  7. Population-related genetic aspects of the low doses radiological risk and melanin influence on genetic radiosensitivity

    International Nuclear Information System (INIS)

    Mosse, I.B.; Plotnikova, S.I.; Kostrova, L.N.; Subbot, S.T.; Maksymenia, I.P.; Dubovic, B.V.

    1997-01-01

    From the genetic point of view, radiation sensitivity is a quantitative character, and the distribution of individuals in the population with different radiation sensitivities is characterized by a binomial curve. Thus rise in irradiation dose first results in a very slow increase in the number of sensitive genotypes, and then in a sharp rise. Since quantitative characters are dependent on several polymeric genes, and their manifestation is strongly affected by external conditions, radiation sensitivity of the organism depends on many hereditary and environmental factors. One of them is the presence of melanin pigment in cells. In particular, we have shown that the introduction of exogenous melanin into the organisms of mice reduces (2-4 times) the frequency of mutations, induced not only by acute, but also by chronic irradiation. It was also established, that mutational load, accumulated in drosophila populations, irradiated within 125 generations, has been decreased under melanin influence almost to the control level. Antimutagenic action of melanin is also manifested on cultured human cells. So, it was shown by the example of melanin, that it is possible to increase the radiation resistance of individuals, and in the first place of the population highly sensitive fraction. (author)

  8. An ecologically-based method for selecting ecological indicators for assessing risks to biological diversity from genetically-engineered plants

    DEFF Research Database (Denmark)

    Andow, D. A.; Lövei, Gabor L; Arpaia, Salvatore

    2013-01-01

    The environmental risks associated with genetically-engineered (GE) organisms have been controversial, and so have the models for the assessment of these risks. We propose an ecologically-based environmental risk assessment (ERA) model that follows the 1998 USEPA guidelines, focusing on potential...

  9. Association between LDL-cholesterol lowering genetic variants and risk of type 2 diabetes

    Science.gov (United States)

    Lotta, Luca A.; Sharp, Stephen. J; Burgess, Stephen; Perry, John R. B.; Stewart, Isobel. D; Willems, Sara M.; Luan, Jian’an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G; Franks, Paul W; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose-Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca, Elena C; Slimani, Nadia; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; McCarthy, Mark I.; Barroso, Inês; O’Rahilly, Stephen; Savage, David. B; Sattar, Naveed; Langenberg, Claudia

    2017-01-01

    Importance Low-density lipoprotein (LDL) cholesterol-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, mimicking the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are also associated with the risk of type 2 diabetes. Objective To investigate whether LDL-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (i.e. HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting and Participants The associations with type 2 diabetes and coronary artery disease of LDL-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50,775 individuals with type 2 diabetes and 270,269 controls including three studies and 60,801 individuals with coronary artery disease and 123,504 controls from a published meta-analysis. Data collection took place in Europe and the United States between 1991 and 2016. Exposure LDL-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDLR. Main Outcomes and Measures Odds ratio of type 2 diabetes and coronary artery disease. Results LDL-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (odds ratio for a genetically-predicted reduction of 1 mmol/L in LDL cholesterol, 0.61; 95% confidence interval, 0.42-0.88; p=0.008) and directly associated with type 2 diabetes (2.42, 1.70-3.43; p<0.001). The odds ratio of type 2 diabetes for PCSK9 genetic variants was 1.19 (95% confidence interval, 1.02-1.38, p=0.03). For a given reduction in LDL cholesterol, genetic variants were associated with a similar reduction in coronary artery

  10. Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.

    Science.gov (United States)

    Laugsand, Lars E; Ix, Joachim H; Bartz, Traci M; Djousse, Luc; Kizer, Jorge R; Tracy, Russell P; Dehghan, Abbas; Rexrode, Kathryn; Lopez, Oscar L; Rimm, Eric B; Siscovick, David S; O'Donnell, Christopher J; Newman, Anne; Mukamal, Kenneth J; Jensen, Majken K

    2015-11-01

    Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993. Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048). Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. A genetic risk tool for obesity predisposition assessment and personalized nutrition implementation based on macronutrient intake.

    Science.gov (United States)

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

    2015-01-01

    There is little evidence about genetic risk score (GRS)-diet interactions in order to provide personalized nutrition based on the genotype. The aim of the study was to assess the value of a GRS on obesity prediction and to further evaluate the interactions between the GRS and dietary intake on obesity. A total of 711 seekers of a Nutrigenetic Service were examined for anthropometric and body composition measurements and also for dietary habits and physical activity. Oral epithelial cells were collected for the identification of 16 SNPs (related with obesity or lipid metabolism) using DNA zip-coded beads. Genotypes were coded as 0, 1 or 2 according to the number of risk alleles, and the GRS was calculated by adding risk alleles with such a criterion. After being adjusted for gender, age, physical activity and energy intake, the GRS demonstrated that individuals carrying >7 risk alleles had in average 0.93 kg/m(2) of BMI, 1.69 % of body fat mass, 1.94 cm of waist circumference and 0.01 waist-to-height ratio more than the individuals with ≤7 risk alleles. Significant interactions for GRS and the consumption of energy, total protein, animal protein, vegetable protein, total fat, saturated fatty acids, polyunsaturated fatty acids, total carbohydrates, complex carbohydrates and fiber intake on adiposity traits were found after adjusted for confounders variables. The GRS confirmed that the high genetic risk group showed greater values of adiposity than the low risk group and demonstrated that macronutrient intake modifies the GRS association with adiposity traits.

  12. Genetic determinants of facial clefting

    DEFF Research Database (Denmark)

    Jugessur, Astanand; Shi, Min; Gjessing, Håkon Kristian

    2009-01-01

    BACKGROUND: Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark...

  13. Common genetic variants, acting additively, are a major source of risk for autism

    Directory of Open Access Journals (Sweden)

    Klei Lambertus

    2012-10-01

    Full Text Available Abstract Background Autism spectrum disorders (ASD are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context

  14. Common genetic variants, acting additively, are a major source of risk for autism.

    Science.gov (United States)

    Klei, Lambertus; Sanders, Stephan J; Murtha, Michael T; Hus, Vanessa; Lowe, Jennifer K; Willsey, A Jeremy; Moreno-De-Luca, Daniel; Yu, Timothy W; Fombonne, Eric; Geschwind, Daniel; Grice, Dorothy E; Ledbetter, David H; Lord, Catherine; Mane, Shrikant M; Martin, Christa Lese; Martin, Donna M; Morrow, Eric M; Walsh, Christopher A; Melhem, Nadine M; Chaste, Pauline; Sutcliffe, James S; State, Matthew W; Cook, Edwin H; Roeder, Kathryn; Devlin, Bernie

    2012-10-15

    Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a

  15. Effects of provision of type 2 diabetes genetic risk feedback on patient perceptions of diabetes control and diet and physical activity self-efficacy.

    Science.gov (United States)

    McVay, Megan A; Beadles, Christopher; Wu, Ryanne; Grubber, Janet; Coffman, Cynthia J; Yancy, William S; Reiner, Isaac Lipkus; Voils, Corrine I

    2015-06-30

    We examined effects of providing type 2 diabetes genetic risk feedback on controllability perceptions. This is a secondary analysis of a randomized controlled trial in which overweight/obese Veterans Affairs patients without diabetes received conventional type 2 diabetes risk counseling that included either (1) personalized diabetes genetic risk feedback (genetic risk arm) or (2) eye disease counseling (comparison arm). Perceived diabetes control, and dietary and physical activity self-efficacy were compared between study arms, and between the comparison arm and each of 3 DNA-based genetic risk levels. Participants (N=531) were predominately male, middle-age, and African American. Immediately post-counseling, perceived diabetes control was higher for the genetic risk arm (risk levels combined) than the comparison arm (p=0.005). In analyses by genetic risk levels, low genetic risk participants reported higher perceived diabetes control than comparison participants (p=0.007). Immediately post-counseling, low genetic risk participants reported higher dietary self-efficacy in situations when mood is negative compared with controls(p=0.01). At 3 months, no differences in constructs were observed. Genetic risk feedback for diabetes has temporary effects on perceived controllability among patients with low genetic risk. Clinicians and other stakeholders should consider the limited effects on behavior change of diabetes genetic risk feedback. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Genetics

    International Nuclear Information System (INIS)

    Hubitschek, H.E.

    1975-01-01

    Progress is reported on the following research projects: genetic effects of high LET radiations; genetic regulation, alteration, and repair; chromosome replication and the division cycle of Escherichia coli; effects of radioisotope decay in the DNA of microorganisms; initiation and termination of DNA replication in Bacillus subtilis; mutagenesis in mouse myeloma cells; lethal and mutagenic effects of near-uv radiation; effect of 8-methoxypsoralen on photodynamic lethality and mutagenicity in Escherichia coli; DNA repair of the lethal effects of far-uv; and near uv irradiation of bacterial cells

  17. The structure of genetic and environmental risk factors for DSM-IV personality disorders: a multivariate twin study.

    Science.gov (United States)

    Kendler, Kenneth S; Aggen, Steven H; Czajkowski, Nikolai; Røysamb, Espen; Tambs, Kristian; Torgersen, Svenn; Neale, Michael C; Reichborn-Kjennerud, Ted

    2008-12-01

    Although both genetic and environmental factors affect risk of individual personality disorders (PDs), we know little of how they contribute to the pattern of comorbidity between the PDs in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV). To clarify the structure of the genetic and environmental risk factors for the 10 DSM-IV PDs. Assessment of PDs at personal interview and multivariate twin modeling with the Mx program. General community. A total of 2794 young adult members of the Norwegian Institute of Public Health Twin Panel. Main Outcome Measure Number of endorsed criteria for the 10 DSM-IV PDs. The best-fit multivariate twin model required 3 genetic and 3 individual-specific environmental factors and genetic and individual-specific factors unique to each PD. The first genetic factor had high loadings on PDs from all 3 clusters including paranoid, histrionic, borderline, narcissistic, dependent, and obsessive-compulsive. The second genetic factor had substantial loadings only on borderline and antisocial PD. The third genetic factor had high loadings only on schizoid and avoidant PD. Several PDs had substantial disorder-specific genetic risk factors. The first, second, and third individual-specific environmental factors had high loadings on the cluster B, A, and C PDs, respectively, with 1 exception: obsessive-compulsive PD loaded with cluster B and not cluster C PDs. Genetic risk factors for DSM-IV PDs do not reflect the cluster A, B, and C typology. Rather, 1 genetic factor reflects a broad vulnerability to PD pathology and/or negative emotionality. The 2 other genetic factors are more specific and reflect high impulsivity/low agreeableness and introversion. Unexpectedly, the cluster A, B, and C typology is well reflected in the structure of environmental risk factors, suggesting that environmental experiences may be responsible for the tendency of cluster A, B, and C PDs to co-occur.

  18. Clinical and Genetic Association of Serum Paraoxonase and Arylesterase Activities with Cardiovascular Risk

    Science.gov (United States)

    Tang, W. H. Wilson; Hartiala, Jaana; Fan, Yiying; Wu, Yuping; Stewart, Alexandre F.R.; Erdmann, Jeanette; Kathiresan, Sekar; Roberts, Robert; McPherson, Ruth; Allayee, Hooman; Hazen, Stanley L.

    2012-01-01

    Objective Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic utility of measuring distinct PON1 activities has not been established, and the genetic determinants of PON-1 activities are not known. Methods and Results We established analytically robust high throughput assays for serum paraoxonase and arylesterase activities and measured these in 3,668 stable subjects undergoing elective coronary angiography without acute coronary syndrome, and were prospectively followed for major adverse cardiac events (MACE = death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (Q4 versus Q1, Hazard Ratio [HR] 2.63, 95%CI 1.97–3.50, pparaoxonase (1.18×10−303) or arylesterase (4.99×10−116) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2,136) or history of either coronary artery disease or myocardial infarction in the CARDIoGRAM consortium (n~80,000 subjects). Conclusions Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE. PMID:22982463

  19. Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer.

    Science.gov (United States)

    Kiyohara, C

    2000-09-01

    Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Msp1 polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotyp