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Sample records for increased genetic risk

  1. Environmental Adversity Increases Genetic Risk for Externalizing Disorders

    PubMed Central

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

    2008-01-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2015-10-01

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

  4. MTHFR genetic polymorphism increases the risk of preterm delivery

    PubMed Central

    Nan, Yanrong; Li, Hongmei

    2015-01-01

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

  5. Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity

    PubMed Central

    Ahmed, Mahbubl; Dorling, Leila; Kerns, Sarah; Fachal, Laura; Elliott, Rebecca; Partliament, Matt; Rosenstein, Barry S; Vega, Ana; Gómez-Caamaño, Antonio; Barnett, Gill; Dearnaley, David P; Hall, Emma; Sydes, Matt; Burnet, Neil; Pharoah, Paul D P; Eeles, Ros; West, Catharine M L

    2016-01-01

    Background: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. Methods: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. Results: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. Conclusion: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens. PMID:27070714

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-04-15

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2016-04-01

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

  12. Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children

    PubMed Central

    Lundbo, Lene F.; Harboe, Zitta Barrella; Clausen, Louise N.; Hollegaard, Mads V.; Sørensen, Henrik T.; Hougaard, David M.; Konradsen, Helle B.; Nørgaard, Mette; Benfield, Thomas

    2015-01-01

    Background Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). Methods Cases with IPD and IMD and controls were identified by linking Danish national registries. DNA was obtained from the Danish Neonatal Screening Biobank. The association between SNPs and susceptibility to IPD and IMD, mortality and pneumococcal serotypes was investigated. Results 372 children with pneumococcal meningitis, 907 with pneumococcal bacteremia and 1273 controls were included. We included 406 cases with meningococcal meningitis, 272 with meningococcal bacteremia, and 672 controls. The NFKBIE SNP was associated with increased risk of pneumococcal meningitis (aOR 1.68; 95% CI: 1.20–2.36), but not bacteremia (aOR 1.08; 95% CI: 0.86–1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. Conclusions A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis. PMID:26870821

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

    PubMed Central

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

    2015-01-01

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

  14. Using a family history questionnaire to identify adult patients with increased genetic risk for sarcoma

    PubMed Central

    Schiavi, A.; Lavigne, J.; Turcotte, R.; Kasprzak, L.; Dumas, N.; Chong, G.; Freeman, C.; Alameldin, M.; Galiatsatos, P.; Palma, L.; Foulkes, W.D.

    2015-01-01

    Background Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset predisposition to numerous types of cancer. Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, ascertainment of patients for whom a genetics evaluation is most indicated poses challenges. We assessed the utility of a Sarcoma Clinic Genetic Screening (scgs) questionnaire in facilitating that task. Methods Between 2008 and 2012, 169 patients (median age: 53 years; range: 17–88 years) completed a self-administered scgs questionnaire. A retrospective chart review was completed for all respondents, and descriptive statistics were reported. Probands were divided into two groups depending on whether they did or did not report a family history of Li–Fraumeni syndrome–type cancers. Results A family history of cancer (as far as 3rd-degree relatives) was reported in 113 of 163 sarcoma patients (69%). Eeles Li–Fraumeni–like (lfl) criteria were fulfilled in 46 probands (28%), Chompret lfl in 21 (13%), Birch lfl in 8 (5%), and classic Li–Fraumeni in none. In the 10 probands tested for TP53 mutations, 1 pathogenic mutation was found. Further investigation of selected families led to the discovery of germline mutations in MLH1, MSH2, and APC genes in 3 individuals. Conclusions The scgs questionnaire was useful for ascertaining probands with sarcoma who could benefit from a genetic assessment. The tool allowed us to identify high-risk families fitting the criteria for lfl and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers. PMID:26628864

  15. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

    PubMed Central

    Chapuis, J; Hansmannel, F; Gistelinck, M; Mounier, A; Van Cauwenberghe, C; Kolen, K V; Geller, F; Sottejeau, Y; Harold, D; Dourlen, P; Grenier-Boley, B; Kamatani, Y; Delepine, B; Demiautte, F; Zelenika, D; Zommer, N; Hamdane, M; Bellenguez, C; Dartigues, J-F; Hauw, J-J; Letronne, F; Ayral, A-M; Sleegers, K; Schellens, A; Broeck, L V; Engelborghs, S; De Deyn, P P; Vandenberghe, R; O'Donovan, M; Owen, M; Epelbaum, J; Mercken, M; Karran, E; Bantscheff, M; Drewes, G; Joberty, G; Campion, D; Octave, J-N; Berr, C; Lathrop, M; Callaerts, P; Mann, D; Williams, J; Buée, L; Dewachter, I; Van Broeckhoven, C; Amouyel, P; Moechars, D; Dermaut, B; Lambert, J-C

    2013-01-01

    Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology. PMID:23399914

  16. Assessing genetically modified crops to minimize the risk of increased food allergy: a review.

    PubMed

    Goodman, Richard E; Hefle, Susan L; Taylor, Steven L; van Ree, Ronald

    2005-06-01

    The first genetically modified (GM) crops approved for food use (tomato and soybean) were evaluated for safety by the United States Food and Drug Administration prior to commercial production. Among other factors, those products and all additional GM crops that have been grown commercially have been evaluated for potential increases in allergenic properties using methods that are consistent with the current understanding of food allergens and knowledge regarding the prediction of allergenic activity. Although there have been refinements, the key aspects of the evaluation have not changed. The allergenic properties of the gene donor and the host (recipient) organisms are considered in determining the appropriate testing strategy. The amino acid sequence of the encoded protein is compared to all known allergens to determine whether the protein is a known allergen or is sufficiently similar to any known allergen to indicate an increased probability of allergic cross-reactivity. Stability of the protein in the presence of acid with the stomach protease pepsin is tested as a risk factor for food allergenicity. In vitro or in vivo human IgE binding are tested when appropriate, if the gene donor is an allergen or the sequence of the protein is similar to an allergen. Serum donors and skin test subjects are selected based on their proven allergic responses to the gene donor or to material containing the allergen that was matched in sequence. While some scientists and regulators have suggested using animal models, performing broadly targeted serum IgE testing or extensive pre- or post-market clinical tests, current evidence does not support these tests as being predictive or practical. Based on the evidence to date, the current assessment process has worked well to prevent the unintended introduction of allergens in commercial GM crops.

  17. An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency.

    PubMed Central

    Hasstedt, S J; Bovill, E G; Callas, P W; Long, G L

    1998-01-01

    We used two-locus segregation analysis to test whether an unknown genetic defect interacts with protein C deficiency to increase susceptibility to venous thromboembolic disease in a single large pedigree. Sixty-seven pedigree members carry a His107Pro mutation in the protein C gene, which reduces protein C levels to a mean of 46% of normal. Twenty-one carriers of the mutation and five other pedigree members had verified thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficiency, by rejecting the hypothesis that the cases of thromboembolic disease resulted from protein C deficiency alone and by not rejecting Mendelian transmission of the interacting gene. When coinherited with protein C deficiency, the interacting gene conferred a probability of a thrombotic episode of approximately 79% for men and approximately 99% for women, before age 60 years. PMID:9683579

  18. Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children.

    PubMed

    Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C; Reyes-López, Miguel A; Quiñones, Luis A

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11-5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62-78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42-191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94-31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05-6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19-31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children. PMID:27547186

  19. Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

    PubMed Central

    Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C.; Reyes-López, Miguel A.; Quiñones, Luis A.

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children. PMID:27547186

  20. Mitochondrial genetic background plays a role in increasing risk to asthma.

    PubMed

    Zifa, Emily; Daniil, Zoe; Skoumi, Eleutheria; Stavrou, Maria; Papadimitriou, Kostantinos; Terzenidou, Marini; Kostikas, Konstantinos; Bagiatis, Vasileios; Gourgoulianis, Konstantinos I; Mamuris, Zissis

    2012-04-01

    A number of studies suggest that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To shed light for the first time on the role of the mitochondrial genome in the etiology of asthma we analyzed the mitochondrial tRNA genes and part of their flanking regions in patients with asthma compared with a set of healthy controls. We found a total of 10 mutations in 56 out of 76 asthmatic patients. Four of these mutations were not found in the control group, five were observed at a significantly lower frequency in controls, but none of the combinations of mutations detected in asthma patients was observed in the controls. Furthermore, we observed that 27.6% of the asthma patients (vs. 4% of the controls) belonged to the haplogroup U (Fisher test P = 0.00) and a positive significant correlation was found between the occurrence of the haplogroup U and the severity of the disease (Fisher test P = 0.02). Whereas further studies in larger cohorts are needed to confirm these observations we suggest that the mitochondrial genetic background plays a key role in asthma development.

  1. Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk

    PubMed Central

    Menke, Ricarda A L; Proudfoot, Malcolm; Wuu, Joanne; Andersen, Peter M; Talbot, Kevin; Benatar, Michael; Turner, Martin R

    2016-01-01

    Objective To discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS). Methods T1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3 T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed. Results Grey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls. Conclusions Rather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies. PMID:26733601

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

    PubMed Central

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

    2015-01-01

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

  3. Genetic factors associated with population size may increase extinction risks and decrease colonization potential in a keystone tropical pine

    PubMed Central

    del Castillo, Rafael F; Trujillo-Argueta, Sonia; Sánchez-Vargas, Nahúm; Newton, Adrian C

    2011-01-01

    Pioneer species are essential for forest regeneration and ecosystem resilience. Pinus chiapensis is an endangered pioneer key species for tropical montane cloud forest regeneration in Mesoamerica. Human activities have severely reduced some P. chiapensis populations, which exhibited a small or null colonization potential suggesting the involvement of genetic factors associated with small populations. We explored the relationships between (i) population genetic diversity (allozymes) and population size, including sampling size effects, (ii) fitness estimates associated with colonization potential (seed viability and seedling performance) in a common environment and population size, and (iii) fitness estimates and observed heterozygosity in populations with sizes spanning five orders of magnitude. All the estimates of genetic diversity and fitness increased significantly with population size. Low fitness was detected in progenies of small populations of disturbed and undisturbed habitats. Progenies with the lowest observed heterozygosity displayed the lowest fitness estimates, which, in turn, increased with heterozygosity, but seed viability peaked at intermediate heterozygosity values suggesting inbreeding and outbreeding depression. Inbreeding depression appears to be the most immediate genetic factor in population decline. Conservation efforts should try to maintain large and genetically diverse populations, enhance gene flow by restoring connectivity between adjacent populations, and avoid genetically distant individuals. PMID:25568006

  4. Familial skin cancer syndromes: Increased melanoma risk.

    PubMed

    Ransohoff, Katherine J; Jaju, Prajakta D; Jaju, Prajaka D; Tang, Jean Y; Carbone, Michele; Leachman, Sancy; Sarin, Kavita Y

    2016-03-01

    Phenotypic traits, such as red hair and freckling, increase melanoma risk by 2- to 3-fold. In addition, approximately 10% of melanomas are caused by inherited germline mutations that increase melanoma risk from 4- to >1000-fold. This review highlights the key genes responsible for inherited melanoma, with an emphasis on when a patient should undergo genetic testing. Many genetic syndromes associated with increased melanoma risk are also associated with an increased risk of other cancers. Identification of these high-risk patients is essential for preventive behavior reinforcement, genetic counseling, and ensuring other required cancer screenings.

  5. Genetic Testing for Lung Cancer Risk

    PubMed Central

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

    2002-01-01

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

  6. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels.

    PubMed

    Uitte de Willige, Shirley; de Visser, Marieke C H; Houwing-Duistermaat, Jeanine J; Rosendaal, Frits R; Vos, Hans L; Bertina, Rogier M

    2005-12-15

    We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen gamma' (gammaA/gamma' plus gamma'/gamma') levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen gamma' levels and reduced ratios of fibrinogen gamma' to total fibrinogen. Multivariate analysis showed that reduced fibrinogen gamma' levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen gamma' to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5). We propose that FGG-H2 influences thrombosis risk through htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring the formation of gammaA chain above that of gamma' chain. Fibrinogen gamma' contains a unique high-affinity, nonsubstrate binding site for thrombin, which seems critical for the expression of the antithrombin activity that develops during fibrin formation (antithrombin 1).

  7. VEGF, eNOS, and ABCB1 genetic polymorphisms may increase the risk of osteonecrosis of the femoral head.

    PubMed

    Zhou, Z C; Gu, S Z; Wu, J; Liang, Q W

    2015-01-01

    We investigated the associations between vascular endothelial growth factors (VEGF), endothelial nitric oxide synthase (eNOS), and ATP-binding cassette subfamily B member 1 transporter (ABCB1) polymorphisms and the risk of osteonecrosis of the femoral head (ONFH). Published studies were reviewed and analyzed based on predefined selection criteria. The strength of the association between VEGF, eNOS, and ABCB1 polymorphisms and ONFH risk was evaluated based on the odds ratio with corresponding 95%CIs. Meta-analysis was performed using the Comprehensive Meta-analysis 2.0 software. A total of 135 relevant articles were retrieved, of which 10 studies met the selection criteria, and included a total of 1025 patients with ONFH and 1730 healthy controls. The meta-analysis study results revealed that the VEGF rs2010963 G>C polymorphism increased the risk of ONFH, while the VEGF rs2010963 G>C and ABCB1 rs1045642 C>T polymorphisms increased the risk of ONFH under the allele model. In conclusion, the VEGF, eNOS, and ABCB1 polymorphisms may contribute to ONFH, but further studies including larger sample sizes are needed to confirm the results. PMID:26535684

  8. From observation to intervention: development of a psychoeducational intervention to increase uptake of BRCA genetic counseling among high-risk breast cancer survivors.

    PubMed

    Vadaparampil, Susan T; Malo, Teri L; Nam, Kelli M; Nelson, Alison; de la Cruz, Cara Z; Quinn, Gwendolyn P

    2014-12-01

    We describe the development of a psychoeducational intervention (PEI) to increase uptake of genetic counseling targeted to high-risk breast cancer survivors. Based on previous research, scientific literature, and a review of cancer education websites, we identified potential PEI content. We then assessed the initial acceptability and preference of two booklets of identical content but different layouts, by presenting the booklets to individuals with a personal or family history of breast cancer (n = 57). The preferred booklet was evaluated by two focus groups of ten breast cancer patients who had not attended genetic counseling. The booklet was refined based on participants' feedback at each stage. Focus group participants generally found the booklet visually appealing, informative, and helpful, but some thought that it was too long. Final changes were made based on learner verification principles of attraction, comprehension, cultural acceptability, and persuasion. This project produced an interventional tool to present key constructs that may facilitate decision making about risk-appropriate genetic counseling uptake among high-risk breast cancer survivors. The process described for creating, testing, and adapting materials from a patient perspective can be used for developing other PEIs. This newly developed, unique PEI can be used in many clinical settings. PMID:24706196

  9. From Observation to Intervention: Development of a Psychoeducational Intervention to Increase Uptake of BRCA Genetic Counseling Among High-Risk Breast Cancer Survivors

    PubMed Central

    Malo, Teri L.; Nam, Kelli M.; Nelson, Alison; de la Cruz, Cara Z.; Quinn, Gwendolyn P.

    2015-01-01

    We describe the development of a psychoeducational intervention (PEI) to increase uptake of genetic counseling targeted to high-risk breast cancer survivors. Based on previous research, scientific literature, and a review of cancer education websites, we identified potential PEI content. We then assessed the initial acceptability and preference of two booklets of identical content but different layouts, by presenting the booklets to individuals with a personal or family history of breast cancer (n=57). The preferred booklet was evaluated by two focus groups of ten breast cancer patients who had not attended genetic counseling. The booklet was refined based on participants' feedback at each stage. Focus group participants generally found the booklet visually appealing, informative, and helpful, but some thought that it was too long. Final changes were made based on learner verification principles of attraction, comprehension, cultural acceptability, and persuasion. This project produced an interventional tool to present key constructs that may facilitate decision making about risk-appropriate genetic counseling uptake among high-risk breast cancer survivors. The process described for creating, testing, and adapting materials from a patient perspective can be used for developing other PEIs. This newly developed, unique PEI can be used in many clinical settings. PMID:24706196

  10. Functional Genetic Polymorphisms in PP2A Subunit Genes Confer Increased Risks of Lung Cancer in Southern and Eastern Chinese

    PubMed Central

    Yang, Rongrong; Yang, Lei; Qiu, Fuman; Zhang, Lisha; Wang, Hui; Yang, Xiaorong; Deng, Jieqiong; Fang, Wenxiang; Zhou, Yifeng; Lu, Jiachun

    2013-01-01

    Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and functions as a tumor suppressor that negatively regulates the activity of some oncogenic kinases. Recent studies have reported that PP2A expression was suppressed during lung carcinogenesis, we there hypothesized that the single nucleotide polymorphisms (SNPs) in PP2A subunit genes may affect PP2A function and thus contribute to lung cancer susceptibility. In a two-stage case-control study with a total of 1559 lung cancer patients and 1679 controls, we genotyped eight putative functional SNPs and one identified functional SNP (i.e., rs11453459) in seven major PP2A subunits (i.e., PPP2R1A, PPP2R1B, PPP2CA, PPP2R2A, PPP2R2B, PPP2R5C, PPP2R5E) in southern and eastern Chinese. We found that rs11453459G (-G/GG) variant genotypes of PPP2R1A and the rs1255722AA variant genotype of PPP2R5E conferred increased risks of lung cancer (rs11453459, -G/GG vs. –: OR = 1.31, 95% CI = 1.13–1.51; rs1255722, AA vs. AG/GG: OR = 1.27, 95% CI = 1.07–1.51). After combined the two variants, the number of the adverse genotypes was positively associated with lung cancer risk in a dose-response manner (Ptrend  = 5.63×10−6). Further functional assay showed that lung cancer tissues carrying rs1255722AA variant genotype had a significantly lower mRNA level of PPP2R5E compared with tissues carrying GG/GA genotypes. However, such effect was not observed for the other SNPs and other combinations. Our findings suggested that the two functional variants in PPP2R1A and PPP2R5E and their combination are associated with lung cancer risk in Chinese, which may be valuable biomarkers to predict risk of lung cancer. PMID:24204789

  11. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control

    PubMed Central

    Brorsson, Caroline A.; Nielsen, Lotte B.; Andersen, Marie Louise; Kaur, Simranjeet; Bergholdt, Regine; Hansen, Lars; Mortensen, Henrik B.; Pociot, Flemming; Størling, Joachim; Hvidoere Study Group on Childhood Diabetes

    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 progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several 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. PMID:26904692

  12. Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy.

    PubMed Central

    Brézin, A P; Béchetoille, A; Hamard, P; Valtot, F; Berkani, M; Belmouden, A; Adam, M F; Dupont de Dinechin, S; Bach, J F; Garchon, H J

    1997-01-01

    The GLC1A locus for autosomal dominant juvenile and middle age onset primary open angle glaucoma (OAG) has been mapped to chromosome 1q21-q31. OAG, however, is a heterogeneous disease. We tested linkage of OAG and ocular hypertension (OHT), a major risk factor for OAG, to GLC1A in eight French families with multiple cases of juvenile and middle age onset OAG. There was strong evidence of genetic heterogeneity, four families being linked to GLC1A and two or three others being unlinked, depending on whether the complete OAG phenotype was analysed alone or jointly with OHT. Peak intraocular pressure (IOP) did not differ significantly between the two groups of families, while linkage to GLC1A conferred a highly increased risk of developing OAG and of having severe glaucomatous optic neuropathy. Testing linkage of familial OAG to GLC1A may therefore have prognostic value too. PMID:9222961

  13. Genetic Variants and Their Interactions in the Prediction of Increased Pre-Clinical Carotid Atherosclerosis: The Cardiovascular Risk in Young Finns Study

    PubMed Central

    Elo, Laura L.; Mononen, Nina; Peltonen, Nina; Kähönen, Mika; Juonala, Markus; Fan, Yue-Mei; Hernesniemi, Jussi A.; Laitinen, Tomi; Lyytikäinen, Leo-Pekka; Rontu, Riikka; Eklund, Carita; Hutri-Kähönen, Nina; Taittonen, Leena; Hurme, Mikko; Viikari, Jorma S. A.; Raitakari, Olli T.; Aittokallio, Tero

    2010-01-01

    The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach—in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population—can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the

  14. Acceptance of, inclination for, and barriers in genetic testing for gene mutations that increase the risk of breast and ovarian cancers among female residents of Warsaw

    PubMed Central

    Dera, Paulina; Religioni, Urszula; Duda-Zalewska, Aneta; Deptała, Andrzej

    2016-01-01

    Aim of the study To check the degree of acceptance of, inclination for, and barriers in genetic testing for gene mutations that increase the risk of breast and ovarian cancers among female residents of Warsaw Material and methods This study involved 562 women between 20 and 77 years of age, all of whom were patients visiting gynaecologists practising in clinics in the City of Warsaw. The studied population was divided into six age categories. The study method was a diagnostic poll conducted with the use of an original questionnaire containing 10 multiple-choice questions. Results Nearly 70% of the women showed an interest in taking a test to detect predispositions to develop breast and ovarian cancer. More than 10% did not want to take such a test, while every fifth women was undecided. No statistically significant differences between the respondents’ willingness to pay and education were found (p = 0.05). The most frequent answer given by women in all groups was that the amount to pay was too high. Such an answer was given by 52.17% of women with primary education, 65.22% of women with vocational education, 58.61% of women with secondary education, and 41.62% of women with higher education. Conclusions Women with a confirmed increased risk of developing breast and/or ovarian cancer due to inter alia the presence of BRCA1 and BRCA2 gene mutations should pay particular attention to 1st and 2nd level prophylaxis. PMID:27095945

  15. Impact of NGS in the medical sciences: Genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies.

    PubMed

    Lapunzina, Pablo; López, Rocío Ortiz; Rodríguez-Laguna, Lara; García-Miguel, Purificación; Martínez, Augusto Rojas; Martínez-Glez, Víctor

    2014-03-01

    The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Currently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform complete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole genome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes.

  16. Genetic research on biospecimens poses minimal risk.

    PubMed

    Wendler, David S; Rid, Annette

    2015-01-01

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

  17. Increased rodenticide exposure rate and risk of toxicosis in barn owls (Tyto alba) from southwestern Canada and linkage with demographic but not genetic factors.

    PubMed

    Huang, Andrew C; Elliott, John E; Hindmarch, Sofi; Lee, Sandi L; Maisonneuve, France; Bowes, Victoria; Cheng, Kimberly M; Martin, Kathy

    2016-08-01

    Among many anthropogenic drivers of population decline, continual rapid urbanization and industrialization pose major challenges for the survival of wildlife species. Barn owls (Tyto alba) in southwestern British Columbia (BC) face a multitude of threats ranging from habitat fragmentation to vehicle strikes. They are also at risk from secondary poisoning of second-generation anticoagulant rodenticides (SGARs), a suite of toxic compounds which at high doses results in a depletion of blood clotting factors leading to internal bleeding and death. Here, using long-term data (N = 119) for the hepatic residue levels of SGAR, we assessed the risk of toxicosis from SGAR for the BC barn owl population over the past two decades. We also investigated whether sensitivity to SGAR is associated with genetic factors, namely Single Nucleotide Polymorphisms (SNPs) found in the CYP2C45 gene of barn owls. We found that residue concentration for total SGAR was significantly higher in 2006-2013 (141 ng/g) relative to 1992-2003 (57 ng/g). The proportion of owls exposed to multiple SGAR types was also significantly higher in 2006-2013. Those measures accordingly translate directly into an increase in toxicosis risk level. We also detected demographic differences, where adult females showed on average lower concentration of total SGAR (64 ng/g) when compared to adult males (106 ng/g). Juveniles were overall more likely to show signs of toxicosis than adults (33.3 and 6.9 %, respectively), and those symptoms were positively predicted by SGAR concentrations. We found no evidence that SNPs in the CYP2C45 gene of barn owls were associated with intraspecific variation in SGAR sensitivity. We recommend several preventative measures be taken to minimize wildlife exposure to SGAR. PMID:27151403

  18. Improving genetic risk prediction by leveraging pleiotropy

    PubMed Central

    Li, Cong; Yang, Can; Gelernter, Joel

    2014-01-01

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

  19. Responding to the increased genetic risk associated with customary consanguineous marriage among minority ethnic populations: lessons from local innovations in England.

    PubMed

    Salway, Sarah; Ali, Parveen; Ratcliffe, Giles; Such, Elizabeth; Khan, Nasaim; Kingston, Helen; Quarrell, Oliver

    2016-07-01

    Populations practising customary consanguineous marriage have a higher incidence of autosomal recessive genetic disorders than those in which reproductive partners are usually unrelated. In the absence of any national-level response, English service developments to address the additional needs of families living with or at risk of such disorders have been locally led. These interventions remain in their infancy here, as elsewhere in Europe, and important questions remain regarding how appropriate, effective and sustainable responses can be operationalised in practice. This formative service review employed four local case studies together with wider consultation exercises over a 4-year period (2011-2015) to document recent responses to this area of need, issues arising and lessons to inform future work. Service components included the following: enhancements to genetic services to provide family-centred, culturally competent approaches to counselling and testing; community genetic literacy approaches; and capacity development among health professionals. Local approaches were, however, very varied in their detail, scope, level of investment and longevity. The provisions of culturally competent genetic counselling services and community-level genetic literacy interventions were generally well received by those who accessed them. Coordinated action across all service components appeared important for an effective service, but healthcare professionals, particularly general practitioners, were often difficult to engage in this agenda. An evaluative culture and engagement in a wider community of practice had supported service development across sites. However, sustaining investment was challenging, particularly where new services were not well integrated into core provision and where commissioning was driven by expectations of short-term reductions in infant mortality and disability.

  20. Responding to the increased genetic risk associated with customary consanguineous marriage among minority ethnic populations: lessons from local innovations in England.

    PubMed

    Salway, Sarah; Ali, Parveen; Ratcliffe, Giles; Such, Elizabeth; Khan, Nasaim; Kingston, Helen; Quarrell, Oliver

    2016-07-01

    Populations practising customary consanguineous marriage have a higher incidence of autosomal recessive genetic disorders than those in which reproductive partners are usually unrelated. In the absence of any national-level response, English service developments to address the additional needs of families living with or at risk of such disorders have been locally led. These interventions remain in their infancy here, as elsewhere in Europe, and important questions remain regarding how appropriate, effective and sustainable responses can be operationalised in practice. This formative service review employed four local case studies together with wider consultation exercises over a 4-year period (2011-2015) to document recent responses to this area of need, issues arising and lessons to inform future work. Service components included the following: enhancements to genetic services to provide family-centred, culturally competent approaches to counselling and testing; community genetic literacy approaches; and capacity development among health professionals. Local approaches were, however, very varied in their detail, scope, level of investment and longevity. The provisions of culturally competent genetic counselling services and community-level genetic literacy interventions were generally well received by those who accessed them. Coordinated action across all service components appeared important for an effective service, but healthcare professionals, particularly general practitioners, were often difficult to engage in this agenda. An evaluative culture and engagement in a wider community of practice had supported service development across sites. However, sustaining investment was challenging, particularly where new services were not well integrated into core provision and where commissioning was driven by expectations of short-term reductions in infant mortality and disability. PMID:27311843

  1. Experiencing discrimination increases risk taking.

    PubMed

    Jamieson, Jeremy P; Koslov, Katrina; Nock, Matthew K; Mendes, Wendy Berry

    2013-02-01

    Prior research has revealed racial disparities in health outcomes and health-compromising behaviors, such as smoking and drug abuse. It has been suggested that discrimination contributes to such disparities, but the mechanisms through which this might occur are not well understood. In the research reported here, we examined whether the experience of discrimination affects acute physiological stress responses and increases risk-taking behavior. Black and White participants each received rejecting feedback from partners who were either of their own race (in-group rejection) or of a different race (out-group rejection, which could be interpreted as discrimination). Physiological (cardiovascular and neuroendocrine) changes, cognition (memory and attentional bias), affect, and risk-taking behavior were assessed. Significant participant race × partner race interactions were observed. Cross-race rejection, compared with same-race rejection, was associated with lower levels of cortisol, increased cardiac output, decreased vascular resistance, greater anger, increased attentional bias, and more risk-taking behavior. These data suggest that perceived discrimination is associated with distinct profiles of physiological reactivity, affect, cognitive processing, and risk taking, implicating direct and indirect pathways to health disparities.

  2. GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: association hypothesis for an uncommon genetic variant.

    PubMed

    Piacentini, Sara; Polimanti, Renato; Squitti, Rosanna; Mariani, Stefania; Migliore, Simone; Vernieri, Fabrizio; Rossini, Paolo Maria; Manfellotto, Dario; Fuciarelli, Maria

    2012-01-11

    Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimer's Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P=0.003; adjusted OR=3.70 (1.57-8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1-1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin-1β activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk. PMID:22100662

  3. Use of a patient-entered family health history tool with decision support in primary care: impact of identification of increased risk patients on genetic counseling attendance.

    PubMed

    Buchanan, Adam H; Christianson, Carol A; Himmel, Tiffany; Powell, Karen P; Agbaje, Astrid; Ginsburg, Geoffrey S; Henrich, Vincent C; Orlando, Lori A

    2015-02-01

    Several barriers inhibit collection and use of detailed family health history (FHH) in primary care. MeTree, a computer-based FHH intake and risk assessment tool with clinical decision support, was developed to overcome these barriers. Here, we describe the impact of MeTree on genetic counseling (GC) referrals and attendance. Non-adopted, English speaking adults scheduled for a well-visit in two community-based primary-care clinics were invited to participate in an Implementation-Effectiveness study of MeTree. Participants' demographic characteristics and beliefs were assessed at baseline. Immediately after an appointment with a patient for whom GC was recommended, clinicians indicated whether they referred the patient and, if not, why. The study genetic counselor kept a database of patients with a GC recommendation and contacted those with a referral. Of 542 patients completing MeTree, 156 (29 %) received a GC recommendation. Of these, 46 % (n = 72) were referred and 21 % (n = 33) underwent counseling. Patient preferences, additional clinical information unavailable to MeTree, and an incomplete clinician evaluation of the FHH accounted for the 85 patients clinicians chose not to refer. Although MeTree identified a significant proportion of patients for whom GC was recommended, persistent barriers indicate the need for improved referral processes and patient and physician education about the benefits of GC.

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

    PubMed

    Che, Ronglin; Motsinger-Reif, Alison A

    2012-09-25

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

  5. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.

    PubMed

    Machiela, Mitchell J; Hsiung, Chao Agnes; Shu, Xiao-Ou; Seow, Wei Jie; Wang, Zhaoming; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wu, Chen; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Wen, Wanqing; Cawthon, Richard; Chatterjee, Nilanjan; Hu, Wei; Caporaso, Neil E; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert J; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel C H; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wong, Maria Pik; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Zheng, Wei; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2015-07-15

    Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

  6. The genetics of cancer risk.

    PubMed

    Pomerantz, Mark M; Freedman, Matthew L

    2011-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    MedlinePlus

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

  11. Reflections on the Field of Human Genetics: A Call for Increased Disease Genetics Theory

    PubMed Central

    Schrodi, Steven J.

    2016-01-01

    Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant. PMID:27375680

  12. A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 is Associated with Increased Risk for Selective Mutism and Social Anxiety-Related Traits

    PubMed Central

    Stein, Murray B.; Yang, Bao-Zhu; Chavira, Denise A.; Hitchcock, Carla A.; Sung, Sharon C.; Shipon-Blum, Elisa; Gelernter, Joel

    2010-01-01

    Background Selective mutism (SM), considered an early-onset variant of social anxiety disorder (SAD), shares features of impaired social interaction and communication with autism spectrum disorders (ASDs) that suggest a possible shared pathophysiology. We examined the association of a susceptibility gene, contactin-associated protein-like 2 (CNTNAP2), for ASDs and specific language impairment (SLI) with SM and social anxiety-related traits. Methods Sample 1 subjects were 99 nuclear families including 106 children with SM. Sample 2 subjects were young adults who completed measures of social interactional anxiety (SIAS; N = 1028) and childhood behavioral inhibition (RSRI; N = 920). Five SNPs in CNTNAP2 (including rs7794745 and rs2710102, previously associated with ASDs) were genotyped. Results FBAT analyses revealed nominal significance (p = 0.018) for association of SM with rs2710102 which, with rs6944808, was part of a common haplotype associated with SM (permutation p = 0.022). Adjusting for sex and ancestral proportion, each copy of the rs2710102*a risk allele in the young adults was associated with increased odds of being >1SD above the mean on the SIAS (OR = 1.33, p = 0.015) and RSRI (OR = 1.40, p = 0.010). Discussion Although association was found with rs2710102, the risk allele (“a”) for the traits studied here is the non-risk allele for ASD and SLI (“g”). These findings suggest a partially shared etiology between ASDs and SM, but raise additional questions about specific aspects of these syndromes (i.e., language impairment and/or social anxiety) potentially influenced by CNTNAP2 and mechanism(s) by which these influences may be conveyed. PMID:21193173

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  14. Genetic risk, risk perception, and decision making

    SciTech Connect

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

    1987-01-01

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

  15. Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent.

    PubMed

    Aminkeng, F; Ross, C J D; Rassekh, S R; Brunham, L R; Sistonen, J; Dube, M-P; Ibrahim, M; Nyambo, T B; Omar, S A; Froment, A; Bodo, J-M; Tishkoff, S; Carleton, B C; Hayden, M R

    2014-04-01

    There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

  16. Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent

    PubMed Central

    Aminkeng, F; Ross, CJD; Rassekh, SR; Brunham, LR; Sistonen, J; Dube, M-P; Ibrahim, M; Nyambo, TB; Omar, SA; Froment, A; Bodo, J-M; Tishkoff, S; Carleton, BC; Hayden, MR

    2015-01-01

    There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n = 372) and European (n = 958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care. PMID:23588107

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

    PubMed

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

    2000-01-01

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

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

    PubMed

    Belsky, Daniel W; Israel, Salomon

    2014-01-01

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

  19. Non-disclosure of genetic risks

    PubMed Central

    2016-01-01

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

  20. Non-disclosure of genetic risks

    PubMed Central

    2016-01-01

    In ABC v. St Georges Healthcare NHS Trust, the High Court of England and Wales rejected the argument that doctors have a legal duty to disclose actionable genetic risks to a patient’s relatives. This article reconsiders the concept of a duty to disclose actionable genetic risks in the context of widening perceptions of legal harm and developing professional and public perceptions of corresponding wrongs. PMID:27630453

  1. Homogeneous case subgroups increase power in genetic association studies.

    PubMed

    Traylor, Matthew; Markus, Hugh; Lewis, Cathryn M

    2015-06-01

    Genome-wide association studies of clinically defined cases against controls have transformed our understanding of the genetic causes of many diseases. However, there are limitations to the simple clinical definitions used in these studies, and GWAS analyses are beginning to explore more refined phenotypes in subgroups of the existing data sets. These analyses are often performed ad hoc without considering the power requirements to justify such analyses. Here we derive expressions for the relative power of such subgroup analyses and determine the genotypic relative risks (GRRs) required to achieve equivalent power to a full analysis for relevant scenarios. We show that only modest increases in GRRs may be required to offset the reduction in power from analysing fewer cases, implying that analyses of more genetically homogenous case subgroups may have the potential to identify further associations. We find that, for lower genotypic relative risks in the full sample, subgroup analyses of more homogeneous cases have relatively more power than for higher index genotypic relative risks and that this effect is stronger for rare as opposed to common variants. As GWA studies are likely to have now identified the majority of SNPs with stronger effects, these results strongly advocate a renewed effort to identify phenotypically homogeneous disease groups, in which power to detect genetic variants with small effects will be greater. These results suggest that analysis of case subsets could be a powerful strategy to uncover some of the hidden heritability for common complex disorders, particularly in identifying rarer variants of modest effect.

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

    SciTech Connect

    Sankaranarayanan, K.

    1996-12-31

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

  3. Genetic predisposition to schizophrenia associated with increased use of cannabis.

    PubMed

    Power, R A; Verweij, K J H; Zuhair, M; Montgomery, G W; Henders, A K; Heath, A C; Madden, P A F; Medland, S E; Wray, N R; Martin, N G

    2014-11-01

    Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric disorder affecting ~1% of the population over their lifetime. Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use. In a sample of 2082 healthy individuals, we show an association between an individual's burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever versus never used cannabis (P=2.6 × 10(-4)), and for quantity of use within users (P=3.0 × 10(-3)). Although directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use. PMID:24957864

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

    PubMed

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

    2015-01-01

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

  5. Genetic Variation in the REL Gene Increases Risk of Behcet’s Disease in a Chinese Han Population but That of PRKCQ Does Not

    PubMed Central

    Chen, Feilan; Xu, Lei; Zhao, Tingting; Xiao, Xiang; Pan, Yongquan; Hou, Shengping

    2016-01-01

    Genome-wide association studies (GWAS) and candidate gene studies have identified the REL and PRKCQ genes as risk loci for various autoimmune diseases. The purpose of the present study was to investigate the association of the REL and PRKCQ genes with Behcet’s disease (BD) in a Chinese Han population. A case-control study was conducted on three single nucleotide polymorphisms (SNPs), rs13031237, rs702873, and rs842647 of the REL gene and three SNPs (rs4750316, rs11258747, and rs947474) of the PRKCQ gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a total of 623 BD patients and 1,074 healthy controls. Multiple variables were assessed, including age, sex distribution, and extra-ocular findings. In the present study, the frequencies of rs842647 GG genotypes and rs842647 G alleles were significantly higher in patients than in controls and those of the rs842647 AG genotypes were lower in patients than in controls [GG genotype: Bonferroni corrected P-value for gender adjustment (Pca) = 0.0074, odds ratio (OR) = 1.63; G allele: Pca = 0.0072, OR = 1.57; AG genotype: Pca = 0.024, OR = 0.63, respectively]. No statistically significant differences in the frequencies of rs702873, rs13031237, rs4750316, rs11258747, and rs947474 between BD patients and controls were observed. Stratification analysis indicated that the REL rs842647 polymorphism was associated with BD patients with skin lesions. No significant association of the other five SNPs between BD patients with other extra-ocular findings, including genital ulcer, arthritis, and positive pathergy test results was found. The REL rs842647 polymorphism may be a susceptibility factor for BD pathogenesis and skin lesions, which indicate that c-Rel may be involved in the pathogenesis and skin lesions of BD through the NF-κB pathway. PMID:26784953

  6. Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease.

    PubMed

    Proitsi, Petroula; Lupton, Michelle K; Velayudhan, Latha; Hunter, Gillian; Newhouse, Stephen; Lin, Kuang; Fogh, Isabella; Tsolaki, Magda; Daniilidou, Makrina; Pritchard, Megan; Craig, David; Todd, Stephen; Johnston, Janet A; McGuinness, Bernadette; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Vellas, Bruno; Passmore, Peter A; Sims, Rebecca; Williams, Julie; Brayne, Carol; Stewart, Robert; Sham, Pak; Lovestone, Simon; Powell, John F

    2014-12-01

    Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.

  7. [Risk assessment of genetically modified organisms].

    PubMed

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

    2011-01-01

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

  8. Multilocus Genetic Risk Scores for Venous Thromboembolism Risk Assessment

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-03-01

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

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

    PubMed

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

    2004-07-15

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

  11. Ego depletion increases risk-taking.

    PubMed

    Fischer, Peter; Kastenmüller, Andreas; Asal, Kathrin

    2012-01-01

    We investigated how the availability of self-control resources affects risk-taking inclinations and behaviors. We proposed that risk-taking often occurs from suboptimal decision processes and heuristic information processing (e.g., when a smoker suppresses or neglects information about the health risks of smoking). Research revealed that depleted self-regulation resources are associated with reduced intellectual performance and reduced abilities to regulate spontaneous and automatic responses (e.g., control aggressive responses in the face of frustration). The present studies transferred these ideas to the area of risk-taking. We propose that risk-taking is increased when individuals find themselves in a state of reduced cognitive self-control resources (ego-depletion). Four studies supported these ideas. In Study 1, ego-depleted participants reported higher levels of sensation seeking than non-depleted participants. In Study 2, ego-depleted participants showed higher levels of risk-tolerance in critical road traffic situations than non-depleted participants. In Study 3, we ruled out two alternative explanations for these results: neither cognitive load nor feelings of anger mediated the effect of ego-depletion on risk-taking. Finally, Study 4 clarified the underlying psychological process: ego-depleted participants feel more cognitively exhausted than non-depleted participants and thus are more willing to take risks. Discussion focuses on the theoretical and practical implications of these findings. PMID:22931000

  12. The increased risk of predation enhances cooperation

    PubMed Central

    Krams, Indrikis; Bērziņš, Arnis; Krama, Tatjana; Wheatcroft, David; Igaune, Kristīne; Rantala, Markus J.

    2010-01-01

    Theory predicts that animals in adverse conditions can decrease individual risks and increase long-term benefits by cooperating with neighbours. However, some empirical studies suggest that animals often focus on short-term benefits, which can reduce the likelihood that they will cooperate with others. In this experimental study, we tested between these two alternatives by evaluating whether increased predation risk (as a correlate of environmental adversity) enhances or diminishes the occurrence of cooperation in mobbing, a common anti-predator behaviour, among breeding pied flycatchers Ficedula hypoleuca. We tested whether birds would join their mobbing neighbours more often and harass a stuffed predator placed near their neighbours' nests more intensely in areas with a higher perceived risk of predation. Our results show that birds attended mobs initiated by their neighbours more often, approached the stuffed predator significantly more closely, and mobbed it at a higher intensity in areas where the perceived risk of predation was experimentally increased. In such high-risk areas, birds also were more often involved in between-pair cooperation. This study demonstrates the positive impact of predation risk on cooperation in breeding songbirds, which might help in explaining the emergence and evolution of cooperation. PMID:19846454

  13. Increased risk of Graves' disease after pregnancy.

    PubMed

    Benhaim Rochester, Dana; Davies, Terry F

    2005-11-01

    The improvement in autoimmune thyroid disease during pregnancy and the subsequent exacerbation postpartum is secondary to immune system changes necessary to a normal pregnancy. Prior studies have shown that a clinically significant number of women develop Graves' disease (GD) in the postpartum period. The aim of this study was to examine the risk of post pregnancy GD and define patient characteristics that may impact the diagnosis and treatment strategies for this group. We performed a retrospective review of 152 consecutive women, aged 18-39 years when diagnosed with GD, to examine the relation between disease diagnosis and prior pregnancy. Differences in patient characteristics and treatment outcomes of women were analyzed. New York City population data were used to estimate a relative risk for the development of postpartum GD. We found that in parous women, 45% were diagnosed with GD in the postpartum period and 55% had an onset in subsequent years. No significant differences were noted in patient characteristics or treatment outcomes. We found that the risk of women developing post pregnancy GD was greatest in the older patients (35-39 years), with 56% developing GD compared to 42% of nulliparous women. These data, therefore, suggest an increased risk for older women. We were able to calculate the increase in estimated relative risk for postpartum disease by using control population data. The risk maximized at 5.6 for the age group 35-39 years when compared to the control population. These data support earlier studies that showed that a clinically significant number of women develop GD after childbirth compared to nulliparous women and extends this risk for many years. The mechanism of this long-standing increased susceptibility requires further delineation.

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

    PubMed

    Carulli, Lucia

    2015-01-14

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

  15. The ecological risks of genetically engineered organisms

    NASA Astrophysics Data System (ADS)

    Wolfenbarger, Lareesa

    2001-03-01

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

  16. Genetic factors affecting dental caries risk.

    PubMed

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

    2015-03-01

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

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

    PubMed

    d'Agincourt-Canning, L

    2001-06-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Phillips, Tamara J; Shabani, Shkelzen

    2015-01-01

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

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

    PubMed Central

    Phillips, Tamara J.; Shabani, Shkelzen

    2015-01-01

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

  1. Genetic Diversity Increases Insect Herbivory on Oak Saplings

    PubMed Central

    Castagneyrol, Bastien; Lagache, Lélia; Giffard, Brice; Kremer, Antoine; Jactel, Hervé

    2012-01-01

    A growing body of evidence from community genetics studies suggests that ecosystem functions supported by plant species richness can also be provided by genetic diversity within plant species. This is not yet true for the diversity-resistance relationship as it is still unclear whether damage by insect herbivores responds to genetic diversity in host plant populations. We developed a manipulative field experiment based on a synthetic community approach, with 15 mixtures of one to four oak (Quercus robur) half-sib families. We quantified genetic diversity at the plot level by genotyping all oak saplings and assessed overall damage caused by ectophagous and endophagous herbivores along a gradient of increasing genetic diversity. Damage due to ectophagous herbivores increased with the genetic diversity in oak sapling populations as a result of higher levels of damage in mixtures than in monocultures for all families (complementarity effect) rather than because of the presence of more susceptible oak genotypes in mixtures (selection effect). Assemblages of different oak genotypes would benefit polyphagous herbivores via improved host patch location, spill over among neighbouring saplings and diet mixing. By contrast, genetic diversity was a poor predictor of the abundance of endophagous herbivores, which increased with individual sapling apparency. Plant genetic diversity may not provide sufficient functional contrast to prevent tree sapling colonization by specialist herbivores while enhancing the foraging of generalist herbivores. Long term studies are nevertheless required to test whether the effect of genetic diversity on herbivory change with the ontogeny of trees and local adaptation of specialist herbivores. PMID:22937168

  2. Genetic diversity increases insect herbivory on oak saplings.

    PubMed

    Castagneyrol, Bastien; Lagache, Lélia; Giffard, Brice; Kremer, Antoine; Jactel, Hervé

    2012-01-01

    A growing body of evidence from community genetics studies suggests that ecosystem functions supported by plant species richness can also be provided by genetic diversity within plant species. This is not yet true for the diversity-resistance relationship as it is still unclear whether damage by insect herbivores responds to genetic diversity in host plant populations. We developed a manipulative field experiment based on a synthetic community approach, with 15 mixtures of one to four oak (Quercus robur) half-sib families. We quantified genetic diversity at the plot level by genotyping all oak saplings and assessed overall damage caused by ectophagous and endophagous herbivores along a gradient of increasing genetic diversity. Damage due to ectophagous herbivores increased with the genetic diversity in oak sapling populations as a result of higher levels of damage in mixtures than in monocultures for all families (complementarity effect) rather than because of the presence of more susceptible oak genotypes in mixtures (selection effect). Assemblages of different oak genotypes would benefit polyphagous herbivores via improved host patch location, spill over among neighbouring saplings and diet mixing. By contrast, genetic diversity was a poor predictor of the abundance of endophagous herbivores, which increased with individual sapling apparency. Plant genetic diversity may not provide sufficient functional contrast to prevent tree sapling colonization by specialist herbivores while enhancing the foraging of generalist herbivores. Long term studies are nevertheless required to test whether the effect of genetic diversity on herbivory change with the ontogeny of trees and local adaptation of specialist herbivores.

  3. Burden of risk alleles for Hypertension Increases Risk of Intracerebral Hemorrhage

    PubMed Central

    Falcone, Guido J.; Biffi, Alessandro; Devan, William; Jagiella, Jeremiasz M.; Schmidt, Helena; Kissela, Brett; Hansen, Björn M.; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; Ayres, Alison M.; Schwab, Kristin; Pera, Joanna; Urbanik, Andrzej; Rost, Natalia S.; Goldstein, Joshua N.; Viswanathan, Anand; Pichler, Alexander; Enzinger, Christian; Norrving, Bo; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Chelsea S.; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Broderick, Joseph P.; Greenberg, Steven M.; Roquer, Jaume; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Flaherty, Matthew L.; Kleindorfer, Dawn O.; Langefeld, Carl D.; Woo, Daniel; Rosand, Jonathan

    2012-01-01

    SUMMARY Background and Purpose Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (SNPs) associated with blood pressure (BP) levels have been identified. We sought to determine whether the cumulative burden of BP-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods Prospective multicenter case-control study in 2272 subjects of European descent (1025 cases and 1247 controls). Thirty-nine SNPs reported to be associated with BP levels were identified from the National Human Genome Research Institute GWAS catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results No single SNP was associated with either ICH or pre-ICH HTN. The BP-based unweighted genetic risk score was associated with risk of ICH (odds ratio [OR] = 1.11, 95% confidence interval [CI] 1.02–1.21, p=0.01) and the subset of ICH in deep regions (OR=1.18, 95%CI 1.07–1.30, p=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among controls (OR=1.17, 95%CI 1.04–1.31, p=0.009) and ICH cases (OR=1.15, 95%CI 1.01–1.31, p=0.04). Similar results were obtained when using a weighted score. Conclusion Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. PMID:22933587

  4. Increased thyroid cancer risk in acromegaly.

    PubMed

    Dagdelen, Selcuk; Cinar, Nese; Erbas, Tomris

    2014-08-01

    Acromegaly increases cancer risk. We aimed to determine the prevalence and the predictors of tumors in acromegalic patients treated at our department. We retrospectively evaluated 160 acromegalic patients [79 female (mean age 52.0 ± 10.4 years) and 81 male (mean age 49.1 ± 12.4 years)] between 1990 and 2012, with a mean follow up period of 7.1 ± 5.7 years. The patients were screened with colonoscopy, mammography, thyroid and prostate ultrasonography. Malignancy was found in 34 (21.3%) patients. No significant difference was observed in the distribution of malignancy among sexes (20.3% in F vs. 22.2% in M). Thyroid cancer was the most frequent (n = 17, 10.6%) followed by the breast cancer (n = 4, 2.5%) and colorectal cancer (n = 3, 1.8%). Renal cell cancer in two patients, bladder cancer in two patients, periampullary tumor, rectal carcinoid tumor, malignant melanoma, prostate cancer, lung cancer, parotid mucoepidermoid carcinoma and malignant mesenchymal tumor in brain in one patient were detected. One patient had both thyroid and renal cell cancer. Age of patients at diagnosis of acromegaly was significantly higher in patients with cancer (45.8 ± 9.9 vs. 40.9 ± 11.3 years, p < 0.05). No significant difference was found in duration of the disease, initial GH levels and IGF-1% upper limit of normal values, the prevalence of diabetes, hypertension, coronary heart disease, hyperlipidemia and treatment modalities between the patients with/without cancer. In logistic regression analysis, older age at diagnosis was associated with malignancy risk. The risk of cancer in acromegaly especially the thyroid cancer risk seems to be more increased than known in the literature. Therefore, acromegaly patients should be screened routinely for cancer, especially for thyroid cancer due to it being up to four times higher prevalence than breast and colorectal cancer.

  5. Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families.

    PubMed

    Muranen, Taru A; Mavaddat, Nasim; Khan, Sofia; Fagerholm, Rainer; Pelttari, Liisa; Lee, Andrew; Aittomäki, Kristiina; Blomqvist, Carl; Easton, Douglas F; Nevanlinna, Heli

    2016-08-01

    The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on ~4000 additional individuals by comparing the affected to healthy family members, as well as in a case-control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26-1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case-control dataset (1.49 [1.38-1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment. PMID:27438779

  6. Adiposity significantly modifies genetic risk for dyslipidemia.

    PubMed

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

    2014-11-01

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

  7. Genetic risk factors for type 1 diabetes.

    PubMed

    Pociot, Flemming; Lernmark, Åke

    2016-06-01

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

  8. Genetic determinants of risk and progression in multiple sclerosis

    PubMed Central

    Didonna, Alessandro; Oksenberg, Jorge R.

    2015-01-01

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

  9. Identifying Common Genetic Risk Factors of Diabetic Neuropathies

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Musunuru, Kiran; Kathiresan, Sekar

    2016-02-19

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

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

    PubMed Central

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

    2016-01-01

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

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

    MedlinePlus

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

  13. SATIETY MECHANISMS IN GENETIC RISK OF OBESITY

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2013-06-01

    Dyslipidemia is an important etiological factor for development of cardiovascular disease, which is the leading cause of deaths in adults. Given the growing global epidemic of dyslipidemia, lipoprotein metabolism disorders have become an important health problem not only in adulthood, but have also emerged as an increasingly risk factor in childhood. Although several genome-wide association studies in multiple large population-based cohorts of adults and meta-analyses have identified susceptibility genes or loci, especially in lipid-related traits, it is of great importance to evaluate genetic predisposition at an early age. Recent findings suggest that the identification of polymorphisms in the metabolism of lipids in childhood may help fight subclinical atherosclerosis and its progression to cardiovascular complications in adulthood. Therefore, the aim of this study was to review genetic polymorphisms as risk factors associated with dyslipidemia in children and adolescents. PMID:27625842

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

    PubMed Central

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

    2013-01-01

    Dyslipidemia is an important etiological factor for development of cardiovascular disease, which is the leading cause of deaths in adults. Given the growing global epidemic of dyslipidemia, lipoprotein metabolism disorders have become an important health problem not only in adulthood, but have also emerged as an increasingly risk factor in childhood. Although several genome-wide association studies in multiple large population-based cohorts of adults and meta-analyses have identified susceptibility genes or loci, especially in lipid-related traits, it is of great importance to evaluate genetic predisposition at an early age. Recent findings suggest that the identification of polymorphisms in the metabolism of lipids in childhood may help fight subclinical atherosclerosis and its progression to cardiovascular complications in adulthood. Therefore, the aim of this study was to review genetic polymorphisms as risk factors associated with dyslipidemia in children and adolescents. PMID:27625842

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

    PubMed

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

    2016-02-01

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

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

    PubMed Central

    Mousavi, Maryam; Armstrong, Richard A.

    2013-01-01

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

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

    PubMed

    Álvarez, Teresa; Soto, Immaculada; Astermark, Jan

    2015-02-01

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

  19. Management increases genetic diversity of honey bees via admixture.

    PubMed

    Harpur, Brock A; Minaei, Shermineh; Kent, Clement F; Zayed, Amro

    2012-09-01

    The process of domestication often brings about profound changes in levels of genetic variation in animals and plants. The honey bee, Apis mellifera, has been managed by humans for centuries for both honey and wax production and crop pollination. Human management and selective breeding are believed to have caused reductions in genetic diversity in honey bee populations, thereby contributing to the global declines threatening this ecologically and economically important insect. However, previous studies supporting this claim mostly relied on population genetic comparisons of European and African (or Africanized) honey bee races; such conclusions require reassessment given recent evidence demonstrating that the honey bee originated in Africa and colonized Europe via two independent expansions. We sampled honey bee workers from two managed populations in North America and Europe as well as several old-world progenitor populations in Africa, East and West Europe. Managed bees had highly introgressed genomes representing admixture between East and West European progenitor populations. We found that managed honey bees actually have higher levels of genetic diversity compared with their progenitors in East and West Europe, providing an unusual example whereby human management increases genetic diversity by promoting admixture. The relationship between genetic diversity and honey bee declines is tenuous given that managed bees have more genetic diversity than their progenitors and many viable domesticated animals.

  20. Genetic risks and familial associations of small bowel carcinoma

    PubMed Central

    Shenoy, Santosh

    2016-01-01

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

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

    PubMed

    Shenoy, Santosh

    2016-06-15

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2007-09-01

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

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

    PubMed

    Dudley, Katherine A; Patel, Sanjay R

    2016-02-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Kramkowska, Marta; Grzelak, Teresa; Czyżewska, Krystyna

    2013-01-01

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

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

    EPA Science Inventory

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

  8. Knowledge of risk management strategies, and information and risk management preferences of women at increased risk for ovarian cancer.

    PubMed

    Tiller, K; Meiser, B; Gould, L; Tucker, K; Dudding, T; Franklin, J; Friedlander, M; Andrews, L

    2005-04-01

    Little research is available on the level of knowledge about ovarian cancer risk management options in women at increased risk for this disease. The study objectives were to evaluate this together with the information and ovarian cancer risk management preferences of high-risk women. One hundred and twenty-nine women were assessed after their attendance at one of six familial cancer clinics in relation to knowledge of surveillance and/or preventative strategies for reduction of ovarian cancer risk, preferences for particular strategies, and information preferences. Screening was selected by 57 (44%) women as the preferred risk management option. One hundred and five women (82%) indicated a wish for as much information as possible about ovarian cancer, including both good and bad outcomes and 114 (89%) reported a preference for sharing treatment decisions with their health professional. Participants' knowledge about ovarian cancer risk management options was significantly associated with educational levels (Z = -3.2, p=0.001) and whether or not ovarian cancer was included in the family history (Z = -2.3, p = 0.018). Findings from this present study indicate that women at increased risk of ovarian cancer who attend familial cancer clinics want as much information as possible about this disease and they want to be involved in the decision-making process. Women who reported a lower level of education (no post-school qualifications) may be most likely to benefit from additional educational strategies designed to supplement genetic counseling to improve their knowledge levels.

  9. GENETICS AND POPULATION-LEVEL RISK ASSESSMENT

    EPA Science Inventory

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

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

    PubMed

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

    2015-01-01

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

  11. Increased leukemia risk in Chernobyl cleanup workers

    Cancer.gov

    A new study found a significantly elevated risk for chronic lymphocytic leukemia among workers who were engaged in recovery and clean-up activities following the Chernobyl power plant accident in 1986.

  12. Ethnic Differences in Knowledge and Attitudes about BRCA1 Testing in Women at Increased Risk.

    ERIC Educational Resources Information Center

    Hughes, Chanita; Gomez-Caminero, Andres; Benkendorf, Judith; Kerner, Jon; Isaacs, Claudine; Barter, James; Lerman, Caryn

    1997-01-01

    Knowledge about the inheritance of breast cancer and attitudes about genetic testing for breast-ovarian cancer susceptibility in women at increased risk were studied in Caucasian and African-American women (N=407). Participants had at least one first-degree relative with cancer. Differences in knowledge and attitudes toward risk may be attributed…

  13. Convergent synaptic and circuit substrates underlying autism genetic risks

    PubMed Central

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

    2014-01-01

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

  14. Association between OPN genetic variations and nephrolithiasis risk

    PubMed Central

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

    2016-01-01

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

  15. Association between OPN genetic variations and nephrolithiasis risk

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    1999-08-01

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

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

    PubMed

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

    2014-09-01

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

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

    ERIC Educational Resources Information Center

    Bamberg, Richard; And Others

    1990-01-01

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

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

    PubMed

    Rajan, S Ravi; Letourneau, Deborah K

    2012-01-01

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

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

    PubMed Central

    Rajan, S. Ravi; Letourneau, Deborah K.

    2012-01-01

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

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

    PubMed

    Rajan, S Ravi; Letourneau, Deborah K

    2012-01-01

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

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

    PubMed

    Weitzel, J N

    1999-12-01

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

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

    PubMed

    Rose, R J

    1998-01-01

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

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

    PubMed

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

    2016-06-14

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

  5. Does Migraine Increase the Risk of Glaucoma?

    PubMed Central

    Chen, Hsin-Yi; Lin, Cheng-Li; Kao, Chia-Hung

    2016-01-01

    Abstract This study investigated whether migraine influences the risk of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) in Taiwan. We retrieved the data analyzed in this study from the National Health Insurance Research Database in Taiwan. We included 17,606 newly diagnosed migraine patients without preexisting glaucoma and randomly selected and matched 70,423 subjects without migraine as the comparison cohort. The same exclusion criteria were also applied to comparison subjects. Multivariate Cox proportion-hazards regression model was used to assess the effects of migraines on the risk of glaucoma after adjusting for demographic characteristics and comorbidities. The cumulative incidence of POAG was higher in the migraine cohort than that in the comparison cohort (log-rank P = 0.04). The overall incidence of POAG (per 10,000 person-years) was 9.62 and 7.69, respectively, for migraine cohort and nonmigraine cohort (crude hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.01–1.54). After adjusting the covariates, the risk of POAG was not significantly higher in the migraine cohort than in the comparison cohort (adjusted HR [aHR] = 1.15, 95% CI = 0.93–1.42). The cumulative incidence of PACG did not differ between the migraine cohort and the comparison cohort (log-rank test P = 0.53). The overall incidence of PACG was not significantly higher in the migraine cohort than that in the comparison cohort (7.42 vs 6.84 per 10,000 person-years), with an aHR of 1.04 (95% CI = 0.82–1.32). This study shows that migraines are not associated with a higher risk either in POAG or in PACG. PMID:27175700

  6. Increasing global participation in genetics research through DNA barcoding.

    PubMed

    Adamowicz, Sarah J; Steinke, Dirk

    2015-12-01

    DNA barcoding--the sequencing of short, standardized DNA regions for specimen identification and species discovery--has promised to facilitate rapid access to biodiversity knowledge by diverse users. Here, we advance our opinion that increased global participation in genetics research is beneficial, both to scientists and for science, and explore the premise that DNA barcoding can help to democratize participation in genetics research. We examine publication patterns (2003-2014) in the DNA barcoding literature and compare trends with those in the broader, related domain of genomics. While genomics is the older and much larger field, the number of nations contributing to the published literature is similar between disciplines. Meanwhile, DNA barcoding exhibits a higher pace of growth in the number of publications as well as greater evenness among nations in their proportional contribution to total authorships. This exploration revealed DNA barcoding to be a highly international discipline, with growing participation by researchers in especially biodiverse nations. We briefly consider several of the challenges that may hinder further participation in genetics research, including access to training and molecular facilities as well as policy relating to the movement of genetic resources. PMID:26642251

  7. Health risks of genetically modified foods.

    PubMed

    Dona, Artemis; Arvanitoyannis, Ioannis S

    2009-02-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2015-01-01

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

  10. Adaptive genetic variation and heart disease risk

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  11. Chronically Alternating Light Cycles Increase Breast Cancer Risk in Mice.

    PubMed

    Van Dycke, Kirsten C G; Rodenburg, Wendy; van Oostrom, Conny T M; van Kerkhof, Linda W M; Pennings, Jeroen L A; Roenneberg, Till; van Steeg, Harry; van der Horst, Gijsbertus T J

    2015-07-20

    Although epidemiological studies in shift workers and flight attendants have associated chronic circadian rhythm disturbance (CRD) with increased breast cancer risk, causal evidence for this association is lacking. Several scenarios have been proposed to contribute to the shift work-cancer connection: (1) internal desynchronization, (2) light at night (resulting in melatonin suppression), (3) sleep disruption, (4) lifestyle disturbances, and (5) decreased vitamin D levels due to lack of sunlight. The confounders inherent in human field studies are less problematic in animal studies, which are therefore a good approach to assess the causal relation between circadian disturbance and cancer. However, the experimental conditions of many of these animal studies were far from the reality of human shift workers. For example, some involved xenografts (addressing tumor growth rather than cancer initiation and/or progression), chemically induced tumor models, or continuous bright light exposure, which can lead to suppression of circadian rhythmicity. Here, we have exposed breast cancer-prone p53(R270H/+)WAPCre conditional mutant mice (in a FVB genetic background) to chronic CRD by subjecting them to a weekly alternating light-dark (LD) cycle throughout their life. Animals exposed to the weekly LD inversions showed a decrease in tumor suppression. In addition, these animals showed an increase in body weight. Importantly, this study provides the first experimental proof that CRD increases breast cancer development. Finally, our data suggest internal desynchronization and sleep disturbance as mechanisms linking shift work with cancer development and obesity. PMID:26196479

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

    PubMed Central

    Reitz, Frauke; Barth, Jürgen; Bengel, Jürgen

    2004-01-01

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

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

    PubMed

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

    2002-11-15

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

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

    SciTech Connect

    Duster, T.

    1998-11-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  18. Genetic risk factors associated with respiratory distress syndrome.

    PubMed

    Jo, Heui Seung

    2014-04-01

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

  19. Loss of genetic diversity and increased subdivision in an endemic Alpine Stonefly threatened by climate change

    USGS Publications Warehouse

    Jordan, Steve; Giersch, Jonathan J.; Muhlfeld, Clint C.; Hotalling, Scott; Fanning, Liz; Luikart, Gordon

    2016-01-01

    Much remains unknown about the genetic status and population connectivity of high-elevation and high-latitude freshwater invertebrates, which often persist near snow and ice masses that are disappearing due to climate change. Here we report on the conservation genetics of the meltwater stonefly Lednia tumana (Ricker) of Montana, USA, a cold-water obligate species. We sequenced 1530 bp of mtDNA from 116 L. tumana individuals representing “historic” (>10 yr old) and 2010 populations. The dominant haplotype was common in both time periods, while the second-most-common haplotype was found only in historic samples, having been lost in the interim. The 2010 populations also showed reduced gene and nucleotide diversity and increased genetic isolation. We found lower genetic diversity in L. tumana compared to two other North American stonefly species, Amphinemura linda (Ricker) and Pteronarcys californica Newport. Our results imply small effective sizes, increased fragmentation, limited gene flow, and loss of genetic variation among contemporary L. tumana populations, which can lead to reduced adaptive capacity and increased extinction risk. This study reinforces concerns that ongoing glacier loss threatens the persistence of L. tumana, and provides baseline data and analysis of how future environmental change could impact populations of similar organisms.

  20. Loss of Genetic Diversity and Increased Subdivision in an Endemic Alpine Stonefly Threatened by Climate Change

    PubMed Central

    Jordan, Steve; Giersch, J. Joseph; Muhlfeld, Clint C.; Hotaling, Scott; Fanning, Liz; Tappenbeck, Tyler H.; Luikart, Gordon

    2016-01-01

    Much remains unknown about the genetic status and population connectivity of high-elevation and high-latitude freshwater invertebrates, which often persist near snow and ice masses that are disappearing due to climate change. Here we report on the conservation genetics of the meltwater stonefly Lednia tumana (Ricker) of Montana, USA, a cold-water obligate species. We sequenced 1530 bp of mtDNA from 116 L. tumana individuals representing “historic” (>10 yr old) and 2010 populations. The dominant haplotype was common in both time periods, while the second-most-common haplotype was found only in historic samples, having been lost in the interim. The 2010 populations also showed reduced gene and nucleotide diversity and increased genetic isolation. We found lower genetic diversity in L. tumana compared to two other North American stonefly species, Amphinemura linda (Ricker) and Pteronarcys californica Newport. Our results imply small effective sizes, increased fragmentation, limited gene flow, and loss of genetic variation among contemporary L. tumana populations, which can lead to reduced adaptive capacity and increased extinction risk. This study reinforces concerns that ongoing glacier loss threatens the persistence of L. tumana, and provides baseline data and analysis of how future environmental change could impact populations of similar organisms. PMID:27348125

  1. Loss of Genetic Diversity and Increased Subdivision in an Endemic Alpine Stonefly Threatened by Climate Change.

    PubMed

    Jordan, Steve; Giersch, J Joseph; Muhlfeld, Clint C; Hotaling, Scott; Fanning, Liz; Tappenbeck, Tyler H; Luikart, Gordon

    2016-01-01

    Much remains unknown about the genetic status and population connectivity of high-elevation and high-latitude freshwater invertebrates, which often persist near snow and ice masses that are disappearing due to climate change. Here we report on the conservation genetics of the meltwater stonefly Lednia tumana (Ricker) of Montana, USA, a cold-water obligate species. We sequenced 1530 bp of mtDNA from 116 L. tumana individuals representing "historic" (>10 yr old) and 2010 populations. The dominant haplotype was common in both time periods, while the second-most-common haplotype was found only in historic samples, having been lost in the interim. The 2010 populations also showed reduced gene and nucleotide diversity and increased genetic isolation. We found lower genetic diversity in L. tumana compared to two other North American stonefly species, Amphinemura linda (Ricker) and Pteronarcys californica Newport. Our results imply small effective sizes, increased fragmentation, limited gene flow, and loss of genetic variation among contemporary L. tumana populations, which can lead to reduced adaptive capacity and increased extinction risk. This study reinforces concerns that ongoing glacier loss threatens the persistence of L. tumana, and provides baseline data and analysis of how future environmental change could impact populations of similar organisms. PMID:27348125

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

    PubMed

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

    2003-07-30

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

  3. Health risks from increases in methylmercury exposure.

    PubMed Central

    Mottet, N K; Shaw, C M; Burbacher, T M

    1985-01-01

    Our present knowledge of the human health effects of methylmercury exposure is derived from study of major outbreaks of human poisonings in Japan and Iraq and experimental studies on primates. Methylmercury readily passes through such physiological barriers as the blood-brain barrier, blood-testes barrier, and the placenta. Its major pathological effects are on the nervous and reproductive systems and the developing embryo/fetus. The neurotoxicity of methylmercury is well established in both humans and non-human primates. Lesions in the cerebral and cerebellar gray matter consist of necrosis and lysis of neurons, phagocytosis and gliosis. The changes are most prominent in the deep sulci and may have a vascular component. A late effect is cerebral atrophy. At high dose levels the liver, kidneys, and other organs may also have degenerative changes. Although not yet described in humans, a major effect of exposure of female primates is an adverse effect on pregnancy. Maternal female M. fascicularis blood mercury levels above 1 ppm are associated with a decreased pregnancy rate and increased abortion rate. To date our experimental data lack sufficient numbers to detect infrequent pregnancy effects below 1 ppm. Preliminary studies also reveal that methylmercury may also decrease the number and function (swim speed) of sperm. Both human and primate studies demonstrate deleterious effects of methylmercury on the developing embryo/fetus. Autopsies on human and primate infants reveal retarded brain development and the occurrence of a cerebral palsy-like behavior in the newborns, whereas the mother may be free of signs and symptoms of methylmercury toxicity. The fetal blood level of mercury is higher than the maternal level.(ABSTRACT TRUNCATED AT 250 WORDS) Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 5. PMID:3908085

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

    PubMed Central

    Hill, Shirley Y.

    2013-01-01

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

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

    PubMed

    Simonstein, Frida; Mashiach-Eizenberg, Michal

    2016-02-01

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

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  8. [Genetic risk factors for rheumatoid arthritis].

    PubMed

    Ikari, Katsunori

    2016-06-01

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

  9. Quantification of the genetic risk of environmental mutagens

    SciTech Connect

    Ehling, U.H.

    1988-03-01

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

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

    PubMed Central

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

    2015-01-01

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

  11. Increasing genetic variability in black oats using gamma irradiation.

    PubMed

    Silveira, G; Moliterno, E; Ribeiro, G; Costa, P M A; Woyann, L G; Tessmann, E W; Oliveira, A C; Cruz, C D

    2014-12-04

    The black oat (Avena strigosa Schreb) is commonly used for forage, soil cover, and green manure. Despite its importance, little improvement has been made to this species, leading to high levels of genotypic disuniformity within commercial cultivars. The objective of this study was to evaluate the efficiency of different doses of gamma rays [(60)Co] applied to black oat seeds on the increase of genetic variability of agronomic traits. We applied doses of 0, 10, 50, 100, and 200 Gy to the genotype ALPHA 94087 through exposure to [(60)Co]. Two experiments were conducted in the winter of 2008. The first aimed to test forage trait measurements such as plant height, dry matter yield, number of surviving tillers, and seedling stand. The second test assessed seed traits, such as yield and dormancy levels. Gamma irradiation seems not to increase seed yield in black oats, but it was effective in generating variability for the other traits. Tiller number and plant height are important selection traits to increase dry matter yield. Selection in advanced generations of mutant populations can increase the probability of identifying superior genotypes.

  12. Multiple mating but not recombination causes quantitative increase in offspring genetic diversity for varying genetic architectures.

    PubMed

    Rueppell, Olav; Meier, Stephen; Deutsch, Roland

    2012-01-01

    Explaining the evolution of sex and recombination is particularly intriguing for some species of eusocial insects because they display exceptionally high mating frequencies and genomic recombination rates. Explanations for both phenomena are based on the notion that both increase colony genetic diversity, with demonstrated benefits for colony disease resistance and division of labor. However, the relative contributions of mating number and recombination rate to colony genetic diversity have never been simultaneously assessed. Our study simulates colonies, assuming different mating numbers, recombination rates, and genetic architectures, to assess their worker genotypic diversity. The number of loci has a strong negative effect on genotypic diversity when the allelic effects are inversely scaled to locus number. In contrast, dominance, epistasis, lethal effects, or limiting the allelic diversity at each locus does not significantly affect the model outcomes. Mating number increases colony genotypic variance and lowers variation among colonies with quickly diminishing returns. Genomic recombination rate does not affect intra- and inter-colonial genotypic variance, regardless of mating frequency and genetic architecture. Recombination slightly increases the genotypic range of colonies and more strongly the number of workers with unique allele combinations across all loci. Overall, our study contradicts the argument that the exceptionally high recombination rates cause a quantitative increase in offspring genotypic diversity across one generation. Alternative explanations for the evolution of high recombination rates in social insects are therefore needed. Short-term benefits are central to most explanations of the evolution of multiple mating and high recombination rates in social insects but our results also apply to other species.

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

    Dossus, Laure; Benusiglio, Patrick R

    2015-01-01

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

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

    PubMed

    Dossus, Laure; Benusiglio, Patrick R

    2015-01-01

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

  16. Disparities in Cancer Genetic Risk Assessment and Testing.

    PubMed

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

    2016-07-01

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

  17. Are centenarians genetically predisposed to lower disease risk?

    PubMed

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

    2012-10-01

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

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

    PubMed

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

    2014-11-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-06-01

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

  1. Modular genetic regulatory networks increase organization during pattern formation.

    PubMed

    Mohamadlou, Hamid; Podgorski, Gregory J; Flann, Nicholas S

    2016-08-01

    Studies have shown that genetic regulatory networks (GRNs) consist of modules that are densely connected subnetworks that function quasi-autonomously. Modules may be recognized motifs that comprise of two or three genes with particular regulatory functions and connectivity or be purely structural and identified through connection density. It is unclear what evolutionary and developmental advantages modular structure and in particular motifs provide that have led to this enrichment. This study seeks to understand how modules within developmental GRNs influence the complexity of multicellular patterns that emerge from the dynamics of the regulatory networks. We apply an algorithmic complexity to measure the organization of the patterns. A computational study was performed by creating Boolean intracellular networks within a simulated epithelial field of embryonic cells, where each cell contains the same network and communicates with adjacent cells using contact-mediated signaling. Intracellular networks with random connectivity were compared to those with modular connectivity and with motifs. Results show that modularity effects network dynamics and pattern organization significantly. In particular: (1) modular connectivity alone increases complexity in network dynamics and patterns; (2) bistable switch motifs simplify both the pattern and network dynamics; (3) all other motifs with feedback loops increase multicellular pattern complexity while simplifying the network dynamics; (4) negative feedback loops affect the dynamics complexity more significantly than positive feedback loops.

  2. Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function.

    PubMed

    Hughes, Kim; Flynn, Tanya; de Zoysa, Janak; Dalbeth, Nicola; Merriman, Tony R

    2014-02-01

    Increased serum urate predicts chronic kidney disease independent of other risk factors. The use of xanthine oxidase inhibitors coincides with improved renal function. Whether this is due to reduced serum urate or reduced production of oxidants by xanthine oxidase or another physiological mechanism remains unresolved. Here we applied Mendelian randomization, a statistical genetics approach allowing disentangling of cause and effect in the presence of potential confounding, to determine whether lowering of serum urate by genetic modulation of renal excretion benefits renal function using data from 7979 patients of the Atherosclerosis Risk in Communities and Framingham Heart studies. Mendelian randomization by the two-stage least squares method was done with serum urate as the exposure, a uric acid transporter genetic risk score as instrumental variable, and estimated glomerular filtration rate and serum creatinine as the outcomes. Increased genetic risk score was associated with significantly improved renal function in men but not in women. Analysis of individual genetic variants showed the effect size associated with serum urate did not correlate with that associated with renal function in the Mendelian randomization model. This is consistent with the possibility that the physiological action of these genetic variants in raising serum urate correlates directly with improved renal function. Further studies are required to understand the mechanism of the potential renal function protection mediated by xanthine oxidase inhibitors.

  3. Does using marijuana increase the risk for developing schizophrenia?

    PubMed

    Evins, A Eden; Green, Alan I; Kane, John M; Murray, Robin M

    2013-04-01

    As more US states and other countries consider legalizing marijuana, clinicians need to know the possible effects of this drug. Research has shown a connection between marijuana use and an increased risk for schizophrenia in young people who are vulnerable to developing psychosis. An international panel of experts addresses topics such as risk factors for schizophrenia, the potency and effects of cannabis use on adolescents, the effects of concurrent drug use with cannabis on schizophrenia risk, and current attitudes toward marijuana.

  4. Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

    PubMed Central

    Kim, Christi; Baer, Lea; Zhu, Xiaolei

    2010-01-01

    Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum- and non–platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P = 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome. PMID:20538785

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

    PubMed

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

    2014-12-01

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

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

    PubMed Central

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

    2015-01-01

    Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals’ willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25–$2000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤200 vs. ≥$500). All statistical tests are two-sided (α=0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p<0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p<0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care. PMID:24794065

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

    PubMed

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

    2012-12-01

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

  8. Diffusion of information about genetic risk within families.

    PubMed

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

    1993-01-01

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

  9. Increased risk of venous thromboembolism in patients with acute leukaemia

    PubMed Central

    Mohren, M; Markmann, I; Jentsch-Ullrich, K; Koenigsmann, M; Lutze, G; Franke, A

    2006-01-01

    Patients with malignancies have an increased risk for venous thromboembolisms (VTE), but data on patients with acute leukaemia are very limited so far. We found VTE in 12% of 455 patients with acute leukaemia, half of which occurred in association with central venous catheters, with equal risk of ALL and AML. PMID:16421591

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

    PubMed

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

    2014-02-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  13. People with Increased Risk of Eye Damage from UV Light

    MedlinePlus

    ... With Increased Risk of Eye Damage from UV Light Written by: Shirley Dang Apr. 30, 2014 Everyone ... photosensitivity, though the reaction is rare. People with light-colored eyes Have blue or green eyes? Cover ...

  14. Who Is at Increased Risk of Health Problems during Pregnancy?

    MedlinePlus

    ... obese mothers also have an increased risk of neural tube defects (NTDs), stillbirth, and being large for ... Reviewed: 07/15/2013 Related A-Z Topics Neural Tube Defects (NTDs) Preeclampsia and Eclampsia Pregnancy All ...

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

    PubMed Central

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

    2014-01-01

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

  16. Can shrub cover increase predation risk for a desert rodent?

    USGS Publications Warehouse

    Schooley, R.L.; Sharpe, Peter B.

    1996-01-01

    Previous research indicates that predation risk may influence activity patterns, habitat partitioning, and community structure of nocturnal desert rodents. Shrub microhabitat is typically considered safer than open microhabitat for these small mammals. We investigated predation risk for Townsend's ground squirrels (Spermophilus townsendii), which are diurnal desert rodents that detect predators visually and use burrows for refuge. Our results suggested that shrub cover may increase risk for these squirrels by decreasing their ability to escape from predators. Our field experiment indicated that running speeds of juvenile squirrels were lower in shrub (Ceratoides lanata) habitat than in open areas. Shrub cover was also associated with shorter predator-detection distances (mammalian and avian) and fewer refuges (burrow entrances per hectare) than in open areas in one year but not in another. Our study demonstrated that the visual and locomotive obstruction of vegetative cover may increase predation risk for diurnal desert rodents and that elements of habitat-dependent risk may be temporally dynamic.

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

    PubMed

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

    2015-02-01

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

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

    SciTech Connect

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

    1995-12-31

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

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

    2010-01-01

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

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

    PubMed

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

    2010-01-01

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

  2. Can prenatal maternal stress increase the risk of asthma?

    PubMed

    Heinrich, Joachim

    2015-08-01

    Maternal stress adversely affects a mother's well-being and health and also negatively impacts her offspring. That this relationship also holds true for maternal stress during the pregnancy period is intuitive. However, whether maternal stress increases the risk of asthma development in her offspring is less clear and will be evaluated in this review. There is evidence from murine models to suggest that maternal stress during pregnancy increases the risk of asthma in the offspring. While recent experimental research adds to the increasing body of evidence supporting a causal relationship between prenatal maternal stress and asthma risk in the offspring, the epidemiological evidence supporting this notion is insufficient. Almost all existing observational studies suffer from severe methodological limitations. Nevertheless, the results from experimental work on maternal stress during pregnancy and asthma risk in the offspring, in concert with other obvious adverse health effects in the offspring are sufficient to justify a recommendation to reduce maternal stressors, particularly during pregnancy.

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

    PubMed Central

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

    2015-01-01

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

  4. Increased Risk of Stroke in Patients With Fibromyalgia

    PubMed Central

    Tseng, Chun-Hung; Chen, Jiunn-Horng; Wang, Yu-Chiao; Lin, Ming-Chia; Kao, Chia-Hung

    2016-01-01

    Abstract Neuropsychiatric diseases might enhance stroke development, possibly through inflammation and atherosclerosis. Approximately 25% to 40% of patients with stroke, largely younger patients, are not associated with any conventional stroke risk factors. In this research, we explored whether fibromyalgia (FM), a neuropsychosomatic disorder, increases stroke risk. From a claims dataset with one million enrollees sourced of the Taiwan National Health Insurance database, we selected 47,279 patients with FM and randomly selected 189,112 age- and sex-matched controls within a 3-year period from January 1, 2000 to December 31, 2002. Stroke risk was assessed using Cox proportional hazards regression. Comorbidities associated with increased stroke risk, such as hypertension, diabetes, hyperlipidemia, coronary heart disease, irritable bowel syndrome, and interstitial cystitis, were more prevalent in patients with FM and high stroke risk than in the controls. The overall stroke risk was 1.25-fold (95% confidence interval [CI]: 1.21–1.30) higher in the FM group than in the non-FM group. Even without comorbidities, stroke risk was higher in patients with FM than in the controls (adjusted hazard ratio [aHR] = 1.44, 95% CI: 1.35–1.53, P < 0.001). The relative risk of stroke was 2.26-fold between FM and non-FM groups in younger patients (age <35 years, 95% CI: 1.86–2.75). This is the first investigation associating FM with an increased risk of stroke development. The outcomes imply that FM is a significant risk factor for stroke and that patients with FM, particularly younger patients, require close attention and rigorous measures for preventing stroke. PMID:26937918

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-08-01

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

  8. KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2010-02-01

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

  10. Risk Factors for Increased Severity of Paediatric Medication Administration Errors

    PubMed Central

    Sears, Kim; Goodman, William M.

    2012-01-01

    Patients' risks from medication errors are widely acknowledged. Yet not all errors, if they occur, have the same risks for severe consequences. Facing resource constraints, policy makers could prioritize factors having the greatest severe–outcome risks. This study assists such prioritization by identifying work-related risk factors most clearly associated with more severe consequences. Data from three Canadian paediatric centres were collected, without identifiers, on actual or potential errors that occurred. Three hundred seventy-two errors were reported, with outcome severities ranging from time delays up to fatalities. Four factors correlated significantly with increased risk for more severe outcomes: insufficient training; overtime; precepting a student; and off-service patient. Factors' impacts on severity also vary with error class: for wrong-time errors, the factors precepting a student or working overtime significantly increase severe-outcomes risk. For other types, caring for an off-service patient has greatest severity risk. To expand such research, better standardization is needed for categorizing outcome severities. PMID:23968607

  11. The increasing risk of Lyme disease in Canada.

    PubMed

    Bouchard, Catherine; Leonard, Erin; Koffi, Jules Konan; Pelcat, Yann; Peregrine, Andrew; Chilton, Neil; Rochon, Kateryn; Lysyk, Tim; Lindsay, L Robbin; Ogden, Nicholas Hume

    2015-07-01

    There is an increasing risk of Lyme disease in Canada due to range expansion of the tick vector, Ixodes scapularis. The objectives of this article are to i) raise public awareness with the help of veterinarians on the emerging and expanding risk of Lyme disease across Canada, ii) review the key clinical features of Lyme disease in dogs, and iii) provide recommendations for veterinarians on the management of Lyme disease in dogs.

  12. The increasing risk of Lyme disease in Canada

    PubMed Central

    Bouchard, Catherine; Leonard, Erin; Koffi, Jules Konan; Pelcat, Yann; Peregrine, Andrew; Chilton, Neil; Rochon, Kateryn; Lysyk, Tim; Lindsay, L. Robbin; Ogden, Nicholas Hume

    2015-01-01

    There is an increasing risk of Lyme disease in Canada due to range expansion of the tick vector, Ixodes scapularis. The objectives of this article are to i) raise public awareness with the help of veterinarians on the emerging and expanding risk of Lyme disease across Canada, ii) review the key clinical features of Lyme disease in dogs, and iii) provide recommendations for veterinarians on the management of Lyme disease in dogs. PMID:26130829

  13. Increasing stress on disaster risk finance due to large floods

    NASA Astrophysics Data System (ADS)

    Jongman, Brenden; Hochrainer-Stigler, Stefan; Feyen, Luc; Aerts, Jeroen; Mechler, Reinhard; Botzen, Wouter; Bouwer, Laurens; Pflug, Georg; Rojas, Rodrigo; Ward, Philip

    2014-05-01

    Recent major flood disasters have shown that single extreme events can affect multiple countries simultaneously, which puts high pressure on trans-national risk reduction and risk transfer mechanisms. To date, little is known about such flood hazard interdependencies across regions, and the corresponding joint risks at regional to continental scales. Reliable information on correlated loss probabilities is crucial for developing robust insurance schemes and public adaptation funds, and for enhancing our understanding of climate change impacts. Here we show that extreme discharges are strongly correlated across European river basins and that these correlations can, or should, be used in national to continental scale risk assessment. We present probabilistic trends in continental flood risk, and demonstrate that currently observed extreme flood losses could more than double in frequency by 2050 under future climate change and socioeconomic development. The results demonstrate that accounting for tail dependencies leads to higher estimates of extreme losses than estimates based on the traditional assumption of independence between basins. We suggest that risk management for these increasing losses is largely feasible, and we demonstrate that risk can be shared by expanding risk transfer financing, reduced by investing in flood protection, or absorbed by enhanced solidarity between countries. We conclude that these measures have vastly different efficiency, equity and acceptability implications, which need to be taken into account in broader consultation, for which our analysis provides a basis.

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  16. Does ovulation induction increase the risk of gynecological cancer?

    PubMed Central

    Sallam, H.N.; Abdel-Bak, M.; Sallam, N.H.

    2013-01-01

    The risk of developing gynaecological cancer following ovulation induction therapy in infertile patients is not easy to determine due to many confounding factors. These include the fact that infertility in itself is a known risk factor for some of these cancers, that these patients are subjected to increased surveillance compared to the general population and that the drugs used for ovulation induction are sometimes used in combination. Notwithstanding these limitations, most of the studies have not confirmed a link between these drugs and invasive ovarian cancers, although some studies have suggested that the risk of borderline ovarian tumors may be increased. Investigations regarding breast cancer risk have produced inconsistent results and more information on the subject is warranted. On the contrary, many studies suggest that drugs used for ovulation induction may increase the risk of uterine cancers. More large well-designed studies are still needed to further clarify the effects on cancer risk of these drugs and will allow more in-depth subgroup analysis based on both patient and disease characteristics. PMID:24753954

  17. Rapid range expansion increases genetic differentiation while causing limited reduction in genetic diversity in a damselfly.

    PubMed

    Swaegers, J; Mergeay, J; Therry, L; Larmuseau, M H D; Bonte, D; Stoks, R

    2013-11-01

    Many ectothermic species are currently expanding their geographic range due to global warming. This can modify the population genetic diversity and structure of these species because of genetic drift during the colonization of new areas. Although the genetic signatures of historical range expansions have been investigated in an array of species, the genetic consequences of natural, contemporary range expansions have received little attention, with the only studies available focusing on range expansions along a narrow front. We investigate the genetic consequences of a natural range expansion in the Mediterranean damselfly Coenagrion scitulum, which is currently rapidly expanding along a broad front in different directions. We assessed genetic diversity and genetic structure using 12 microsatellite markers in five centrally located populations and five recently established populations at the edge of the geographic distribution. Our results suggest that, although a marginal significant decrease in the allelic richness was found in the edge populations, genetic diversity has been preserved during the range expansion of this species. Nevertheless, edge populations were genetically more differentiated compared with core populations, suggesting genetic drift during the range expansion. The smaller effective population sizes of the edge populations compared with central populations also suggest a contribution of genetic drift after colonization. We argue and document that range expansion along multiple axes of a broad expansion front generates little reduction in genetic diversity, yet stronger differentiation of the edge populations.

  18. Rapid range expansion increases genetic differentiation while causing limited reduction in genetic diversity in a damselfly

    PubMed Central

    Swaegers, J; Mergeay, J; Therry, L; Larmuseau, M H D; Bonte, D; Stoks, R

    2013-01-01

    Many ectothermic species are currently expanding their geographic range due to global warming. This can modify the population genetic diversity and structure of these species because of genetic drift during the colonization of new areas. Although the genetic signatures of historical range expansions have been investigated in an array of species, the genetic consequences of natural, contemporary range expansions have received little attention, with the only studies available focusing on range expansions along a narrow front. We investigate the genetic consequences of a natural range expansion in the Mediterranean damselfly Coenagrion scitulum, which is currently rapidly expanding along a broad front in different directions. We assessed genetic diversity and genetic structure using 12 microsatellite markers in five centrally located populations and five recently established populations at the edge of the geographic distribution. Our results suggest that, although a marginal significant decrease in the allelic richness was found in the edge populations, genetic diversity has been preserved during the range expansion of this species. Nevertheless, edge populations were genetically more differentiated compared with core populations, suggesting genetic drift during the range expansion. The smaller effective population sizes of the edge populations compared with central populations also suggest a contribution of genetic drift after colonization. We argue and document that range expansion along multiple axes of a broad expansion front generates little reduction in genetic diversity, yet stronger differentiation of the edge populations. PMID:23820582

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

    PubMed

    Ito, Nobuyuki

    2002-07-01

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

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

    PubMed

    Dandona, Sonny; Roberts, Robert

    2009-05-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2009-01-01

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

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

    PubMed

    Daly, Mary B

    2015-01-01

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

  4. Circadian misalignment increases cardiovascular disease risk factors in humans

    PubMed Central

    Morris, Christopher J.; Purvis, Taylor E.; Hu, Kun; Scheer, Frank A. J. L.

    2016-01-01

    Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk. PMID:26858430

  5. Circadian misalignment increases cardiovascular disease risk factors in humans.

    PubMed

    Morris, Christopher J; Purvis, Taylor E; Hu, Kun; Scheer, Frank A J L

    2016-03-01

    Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show-by using two 8-d laboratory protocols-that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8-15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3-29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.

  6. Increasing resilience through participative flood risk map design

    NASA Astrophysics Data System (ADS)

    Fuchs, Sven; Spira, Yvonne; Stickler, Therese

    2013-04-01

    In recent years, an increasing number of flood hazards has shown to the European Commission and the Member States of the European Union the importance of flood risk management strategies in order to reduce losses and to protect the environment and the citizens. Exposure to floods as well as flood vulnerability might increase across Europe due to the ongoing economic development in many EU countries. Thus even without taking climate change into account an increase of flood disasters in Europe might be foreseeable. These circumstances have produced a reaction in the European Commission, and a Directive on the Assessment and Management of Flood Risks was issued as one of the three components of the European Action Programme on Flood Risk Management. Floods have the potential to jeopardise economic development, above all due to an increase of human activities in floodplains and the reduction of natural water retention by land use activities. As a result, an increase in the likelihood and adverse impacts of flood events is expected. Therefore, concentrated action is needed at the European level to avoid severe impacts on human life and property. In order to have an effective tool available for gathering information, as well as a valuable basis for priority setting and further technical, financial and political decisions regarding flood risk mitigation and management, it is necessary to provide for the establishment of flood risk maps which show the potential adverse consequences associated with different flood scenarios. So far, hazard and risk maps are compiled in terms of a top-down linear approach: planning authorities take the responsibility to create and implement these maps on different national and local scales, and the general public will only be informed about the outcomes (EU Floods Directive, Article 10). For the flood risk management plans, however, an "active involvement of interested parties" is required, which means at least some kind of multilateral

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

    PubMed

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

    2012-01-01

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

  8. Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.

    PubMed

    Arloth, Janine; Bogdan, Ryan; Weber, Peter; Frishman, Goar; Menke, Andreas; Wagner, Klaus V; Balsevich, Georgia; Schmidt, Mathias V; Karbalai, Nazanin; Czamara, Darina; Altmann, Andre; Trümbach, Dietrich; Wurst, Wolfgang; Mehta, Divya; Uhr, Manfred; Klengel, Torsten; Erhardt, Angelika; Carey, Caitlin E; Conley, Emily Drabant; Ruepp, Andreas; Müller-Myhsok, Bertram; Hariri, Ahmad R; Binder, Elisabeth B

    2015-06-01

    Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. PMID:26050039

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

    PubMed Central

    2014-01-01

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

  10. Increased risk of cancer among relatives of patients with lung cancer in China

    PubMed Central

    Jin, Yongtang; Xu, Yingchun; Xu, Ming; Xue, Saoli

    2005-01-01

    Background Genetic factors were considered as one of the risk factors for lung cancer or other cancers. The aim of this work was to determine whether a genetic predisposition accounts for such familial aggregation of cancer among relatives of lung cancer probands. Methods A case-control study was conducted in 800 case families identified by lung cancer patients (probands), and in 800 control families identified by the probands'spouses. The data were analysed with logistic regression analysis model. Results The data revealed a significantly greater overall risk of cancer (OR = 1.82, P < 0.01) in the proband group. The relatives of lung cancer probands maintained an increased risk of non-lung cancer (P < 0.05) after adjusting for confounder factors. The crude odds ratio of a proband family having one family member with cancer was 1.67 compared with control families. Proband families were 2.56 times more likely to have two other family members with cancer. For three cancers and four or more cancers, the risk increased to 3.50 and 5.91, respectively. The most striking differences in cancer prevalence between proband and control families were noted for cancer risk among female relatives. The strongest effects were for not only lung cancer in any female relatives (OR 2.17, 95%CI 1.60–3.64) and mothers (OR 2.78, 95%CI 1.23–5.12) and sisters (OR 2.03, 95%CI 1.26–3.97), but also non-lung cancer in females and mothers (OR 2.00, 95%CI 1.26–3.01, and OR 2.34, 95%CI 1.28–4.40, respectively). Conclusion These data support the hypothesis of a genetic susceptibility to cancer in families with lung cancer, and the female genetic susceptibility to cancer might be greater than male. PMID:16281985

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

    PubMed

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

    2014-10-01

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

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

    PubMed

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

    2015-09-15

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-09-15

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

  15. Consumers indirectly increase infection risk in grassland food webs.

    PubMed

    Borer, Elizabeth T; Mitchell, Charles E; Power, Alison G; Seabloom, Eric W

    2009-01-13

    Most pathogens exist within complicated food webs of interacting hosts, vectors, competitors, and predators. Although theory has demonstrated a variety of mechanisms by which predation and competition in food webs can indirectly control infection risk in hosts, there have until now been no experimental tests of this theory. We sampled the effect of long-term exclusion of large vertebrate herbivores on the prevalence of infection by a group of aphid-vectored viruses that infect grasses (barley and cereal yellow dwarf viruses) in an oak savannah in central California. We found that pathogen prevalence was approximately 4-fold higher in the presence of consumers than in areas where they were excluded. Vertebrate consumers did not directly alter infection rates by this aphid-vectored pathogen group, but rather increased infection risk by increasing the relative abundance of highly-competent hosts in the grassland community. This large-scale experiment, measuring changes in host abundance and infection risk in response to altered consumption rates, confirms theoretical predictions that consumers can indirectly increase infection risk by altering the composition of whole communities. Most importantly, these results demonstrate that, even in complex natural communities, alterations to food web composition such as consumer invasion or extinction can lead to significant impacts that cascade throughout entire communities, including changes in infection risk.

  16. Hispanic Americans living in the United States and their risk for obesity, diabetes and kidney disease: Genetic and environmental considerations.

    PubMed

    Yracheta, Joseph M; Alfonso, Javier; Lanaspa, Miguel A; Roncal-Jimenez, Carlos; Johnson, Sarah B; Sánchez-Lozada, Laura G; Johnson, Richard J

    2015-06-01

    The Hispanic American, the largest minority population in the United States, is at increased risk for obesity, diabetes and end-stage renal disease. Here we review genetic and environmental factors that might account for their increased risk for these conditions. Whereas many environmental and genetic factors have important roles in driving the increased risk for obesity and kidney disease in this population, a case is made that excessive intake of sugary beverages is a contributory cause. Studies focusing on decreasing intake of sugary beverages among the Hispanic American could potentially reduce renal and cardiovascular complications in this population.

  17. Increasing risk of great floods in a changing climate

    USGS Publications Warehouse

    Milly, P.C.D.; Wetherald, R.T.; Dunne, K.A.; Delworth, T.L.

    2002-01-01

    Radiative effects of anthropogenic changes in atmospheric composition are expected to cause climate changes, in particular an intensification of the global water cycle with a consequent increase in flood risk. But the detection of anthropogenically forced changes in flooding is difficult because of the substantial natural variability; the dependence of streamflow trends on flow regime further complicates the issue. Here we investigate the changes in risk of great floods - that is, floods with discharges exceeding 100-year levels from basins larger than 200,000 km2 - using both streamflow measurements and numerical simulations of the anthropogenic climate change associated with greenhouse gases and direct radiative effects of sulphate aerosols. We find that the frequency of great floods increased substantially during the twentieth century. The recent emergence of a statistically significant positive trend in risk of great floods is consistent with results from the climate model, and the model suggests that the trend will continue.

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

    PubMed Central

    Helfand, Brian T

    2016-01-01

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

  19. Charter Schools and the Risk of Increased Segregation

    ERIC Educational Resources Information Center

    Rotberg, Iris C.

    2014-01-01

    This article examines a wide array of research on the link between school choice programs and student segregation and draws implications for the Obama Administration's policy promoting the national expansion of charter schools. The research demonstrates how the proliferation of charter schools risks increasing current levels of segregation…

  20. Rare disaster information can increase risk-taking

    NASA Astrophysics Data System (ADS)

    Newell, Ben R.; Rakow, Tim; Yechiam, Eldad; Sambur, Michael

    2016-02-01

    The recent increase in the frequency and impact of natural disasters highlights the need to provide the public with accurate information concerning disaster prevalence. Most approaches to this problem assume that providing summaries of the nature and scale of disasters will lead people to reduce their exposure to risk. Here we present experimental evidence that such ex post `news reports’ of disaster occurrences can increase the tolerance for risk-taking (which implies that rare events are underweighted). This result is robust across several hundred rounds of choices in a simulated microworld, persists even when the long-run expected value of risky choices is substantially lower than safe choices, and is contingent on providing risk information about disasters that have been (personally) experienced and those that have been avoided (`forgone’ outcomes). The results suggest that augmenting personal experience with information summaries of the number of adverse events (for example, storms, floods) in different regions may, paradoxically, increase the appeal of a disaster-prone region. This finding implies a need to communicate long-term trends in severe climatic events, thereby reinforcing the accumulation of events, and the increase in their associated risks, across time.

  1. Does Childhood Disability Increase Risk for Child Abuse and Neglect?

    ERIC Educational Resources Information Center

    Leeb, Rebecca T.; Bitsko, Rebecca H.; Merrick, Melissa T.; Armour, Brian S.

    2012-01-01

    In this article we review the empirical evidence for the presumptions that children with disabilities are at increased risk for child maltreatment, and parents with disabilities are more likely to perpetrate child abuse and neglect. Challenges to the epidemiological examination of the prevalence of child maltreatment and disabilities are…

  2. Increasing Risk Awareness: The Coastal Community Resilience Index

    ERIC Educational Resources Information Center

    Thompson, Jody A.; Sempier, Tracie; Swann, LaDon

    2012-01-01

    As the number of people moving to the Gulf Coast increases, so does the risk of exposure to floods, hurricanes, and other storm-related events. In an effort to assist communities in preparing for future storm events, the Coastal Community Resilience Index was created. The end result is for communities to take actions to address the weaknesses they…

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-08-18

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

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

    PubMed

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

    2016-09-15

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  9. Increased Risk of Restless Legs Syndrome in Patients With Migraine

    PubMed Central

    Yang, Fu-Chi; Lin, Te-Yu; Chen, Hsuan-Ju; Lee, Jiunn-Tay; Lin, Chun-Chieh; Huang, Wen-Yen; Chen, Hsin-Hung; Kao, Chia-Hung

    2016-01-01

    Abstract Previous studies suggest that an association between restless legs syndrome (RLS) and migraine exists. However, population-based data are unavailable in Asian cohorts. Our study thus aims to evaluate the association between migraine and RLS in a nationwide, population-based cohort in Taiwan and to examine the effects of age, sex, migraine subtype, and comorbidities on RLS development. Data from the Taiwan National Health Insurance Research Database were used. Patients aged 20 years or older with newly diagnosed migraine from 2000 to 2008 were included; 23,641 patients with newly diagnosed migraine and 94,564 subjects without migraine were randomly selected and followed until RLS development, withdrawal from the National Health Insurance, or until the end of 2011. A multivariate Cox proportional hazards regression model was used to explore the risk of RLS in patients with migraine after adjustment for demographic characteristics and comorbidities. Both cohorts were followed for a mean of 7.38 years. After adjustment for covariates, the risk of RLS was 1.42-fold higher (95% confidence interval = 1.13–1.79) in the migraine cohort than in the nonmigraine cohort (7.19 versus 3.42 years per 10,000 person-years). The increased risk was more prominent in males in the migraine cohort (1.87-fold increased risk, 95% confidence interval 1.22–2.85). Neither comorbidity status nor migraine subtype influenced the RLS risk. This population-based study demonstrated that migraine is associated with an increased risk of RLS compared with those without migraine, particularly in male patients with migraine and regardless of the comorbidity status. PMID:26844484

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

    PubMed Central

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

    2011-01-01

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

  11. DYT1 dystonia increases risk taking in humans

    PubMed Central

    Arkadir, David; Radulescu, Angela; Raymond, Deborah; Lubarr, Naomi; Bressman, Susan B; Mazzoni, Pietro; Niv, Yael

    2016-01-01

    It has been difficult to link synaptic modification to overt behavioral changes. Rodent models of DYT1 dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term potentiation and decreased long-term depression in corticostriatal synapses. Computationally, such asymmetric learning predicts risk taking in probabilistic tasks. Here we demonstrate abnormal risk taking in DYT1 dystonia patients, which is correlated with disease severity, thereby supporting striatal plasticity in shaping choice behavior in humans. DOI: http://dx.doi.org/10.7554/eLife.14155.001 PMID:27249418

  12. Increasing resilience through participative flood risk map design

    NASA Astrophysics Data System (ADS)

    Fuchs, Sven; Spira, Yvonne; Stickler, Therese

    2013-04-01

    In recent years, an increasing number of flood hazards has shown to the European Commission and the Member States of the European Union the importance of flood risk management strategies in order to reduce losses and to protect the environment and the citizens. Exposure to floods as well as flood vulnerability might increase across Europe due to the ongoing economic development in many EU countries. Thus even without taking climate change into account an increase of flood disasters in Europe might be foreseeable. These circumstances have produced a reaction in the European Commission, and a Directive on the Assessment and Management of Flood Risks was issued as one of the three components of the European Action Programme on Flood Risk Management. Floods have the potential to jeopardise economic development, above all due to an increase of human activities in floodplains and the reduction of natural water retention by land use activities. As a result, an increase in the likelihood and adverse impacts of flood events is expected. Therefore, concentrated action is needed at the European level to avoid severe impacts on human life and property. In order to have an effective tool available for gathering information, as well as a valuable basis for priority setting and further technical, financial and political decisions regarding flood risk mitigation and management, it is necessary to provide for the establishment of flood risk maps which show the potential adverse consequences associated with different flood scenarios. So far, hazard and risk maps are compiled in terms of a top-down linear approach: planning authorities take the responsibility to create and implement these maps on different national and local scales, and the general public will only be informed about the outcomes (EU Floods Directive, Article 10). For the flood risk management plans, however, an "active involvement of interested parties" is required, which means at least some kind of multilateral

  13. Financing increasing flood risk: evidence from millions of buildings

    NASA Astrophysics Data System (ADS)

    Jongman, B.; Koks, E. E.; Husby, T. G.; Ward, P. J.

    2014-01-01

    The effectiveness of disaster risk management and financing mechanisms depends on the accurate assessment of current and future hazard exposure. The increasing availability of detailed data offers policy makers and the insurance sector new opportunities to understand trends in risk, and to make informed decisions on the ways to deal with these trends. In this paper we show how comprehensive property level information can be used for the assessment of exposure to flooding on a national scale, and how this information can contribute to discussions on possible risk financing practices. The case-study used is the Netherlands, which is one of the countries most exposed to flooding globally, and which is currently undergoing a debate on strategies for the compensation of potential losses. Our results show that flood exposure has increased rapidly between 1960 and 2012, and that the growth of the building stock and its economic value in flood prone areas has been higher than in not flood prone areas. We also find that property values in flood prone areas are lower than those in not flood prone areas. We argue that the increase in the share of economic value located in potential flood prone areas can have a negative effect on the feasibility of private insurance schemes in the Netherlands. The methodologies and results presented in this study are relevant for many regions around the world where the effects of rising flood exposure create a challenge for risk financing.

  14. Increasing flood exposure in the Netherlands: implications for risk financing

    NASA Astrophysics Data System (ADS)

    Jongman, B.; Koks, E. E.; Husby, T. G.; Ward, P. J.

    2014-05-01

    The effectiveness of disaster risk management and financing mechanisms depends on an accurate assessment of current and future hazard exposure. The increasing availability of detailed data offers policy makers and the insurance sector new opportunities to understand trends in risk, and to make informed decisions on ways to deal with these trends. In this paper we show how comprehensive property level information can be used for the assessment of exposure to flooding on a national scale, and how this information provides valuable input to discussions on possible risk financing practices. The case study used is the Netherlands, which is one of the countries most exposed to flooding globally, and which is currently undergoing a debate on strategies for the compensation of potential losses. Our results show that flood exposure has increased rapidly between 1960 and 2012, and that the growth of the building stock and its economic value in flood-prone areas has been higher than in non-flood-prone areas. We also find that property values in flood-prone areas are lower than those in non-flood-prone areas. We argue that the increase in the share of economic value located in potential flood-prone areas can have a negative effect on the feasibility of private insurance schemes in the Netherlands. The methodologies and results presented in this study are relevant for many regions around the world where the effects of rising flood exposure create a challenge for risk financing.

  15. Cured meat consumption increases risk of readmission in COPD patients.

    PubMed

    de Batlle, Jordi; Mendez, Michelle; Romieu, Isabelle; Balcells, Eva; Benet, Marta; Donaire-Gonzalez, David; Ferrer, Jaume J; Orozco-Levi, Mauricio; Antó, Josep M; Garcia-Aymerich, Judith

    2012-09-01

    Recent studies have shown that a high dietary intake of cured meat increases the risk of chronic obstructive pulmonary disease (COPD) development. However, its potential effects on COPD evolution have not been tested. We aimed to assess the association between dietary intake of cured meat and risk of COPD readmission in COPD patients. 274 COPD patients were recruited during their first COPD admission between 2004 and 2006, provided information on dietary intake of cured meat during the previous 2 yrs, and were followed until December 31, 2007 (median follow-up 2.6 yrs). Associations between cured meat intake and COPD admissions were assessed using parametric regression survival-time models. Mean ± SD age was 68 ± 8 yrs, 93% of patients were male, 42% were current smokers, mean post-bronchodilator forced expiratory volume in 1 s (FEV(1)) was 53 ± 16% predicted, and median cured meat intake was 23 g · day(-1). After adjusting for age, FEV(1), and total caloric intake, high cured meat intake (more than median value) increased the risk of COPD readmission (adjusted HR 2.02, 95% CI 1.31-3.12; p=0.001). High cured meat consumption increases the risk of COPD readmission in COPD patients. The assessment of the effectiveness of healthy diet advice should be considered in the future.

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

    SciTech Connect

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

    1994-12-31

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2011-01-01

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

  19. Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by Bacteroides species.

    PubMed

    Sánchez, Ester; De Palma, Giada; Capilla, Amalia; Nova, Esther; Pozo, Tamara; Castillejo, Gemma; Varea, Vicente; Marcos, Ascensión; Garrote, José Antonio; Polanco, Isabel; López, Ana; Ribes-Koninckx, Carmen; García-Novo, Maria Dolores; Calvo, Carmen; Ortigosa, Luis; Palau, Francesc; Sanz, Yolanda

    2011-08-01

    Celiac disease (CD) is an immune-mediated enteropathy involving genetic and environmental factors whose interaction might influence disease risk. The aim of this study was to determine the effects of milk-feeding practices and the HLA-DQ genotype on intestinal colonization of Bacteroides species in infants at risk of CD development. This study included 75 full-term newborns with at least one first-degree relative suffering from CD. Infants were classified according to milk-feeding practice (breast-feeding or formula feeding) and HLA-DQ genotype (high or low genetic risk). Stools were analyzed at 7 days, 1 month, and 4 months by PCR and denaturing gradient gel electrophoresis (DGGE). The Bacteroides species diversity index was higher in formula-fed infants than in breast-fed infants. Breast-fed infants showed a higher prevalence of Bacteroides uniformis at 1 and 4 months of age, while formula-fed infants had a higher prevalence of B. intestinalis at all sampling times, of B. caccae at 7 days and 4 months, and of B. plebeius at 4 months. Infants with high genetic risk showed a higher prevalence of B. vulgatus, while those with low genetic risk showed a higher prevalence of B. ovatus, B. plebeius, and B. uniformis. Among breast-fed infants, the prevalence of B. uniformis was higher in those with low genetic risk than in those with high genetic risk. Among formula-fed infants, the prevalence of B. ovatus and B. plebeius was increased in those with low genetic risk, while the prevalence of B. vulgatus was higher in those with high genetic risk. The results indicate that both the type of milk feeding and the HLA-DQ genotype influence the colonization process of Bacteroides species, and possibly the disease risk.

  20. Influence of Environmental and Genetic Factors Linked to Celiac Disease Risk on Infant Gut Colonization by Bacteroides Species▿

    PubMed Central

    Sánchez, Ester; De Palma, Giada; Capilla, Amalia; Nova, Esther; Pozo, Tamara; Castillejo, Gemma; Varea, Vicente; Marcos, Ascensión; Garrote, José Antonio; Polanco, Isabel; López, Ana; Ribes-Koninckx, Carmen; García-Novo, Maria Dolores; Calvo, Carmen; Ortigosa, Luis; Palau, Francesc; Sanz, Yolanda

    2011-01-01

    Celiac disease (CD) is an immune-mediated enteropathy involving genetic and environmental factors whose interaction might influence disease risk. The aim of this study was to determine the effects of milk-feeding practices and the HLA-DQ genotype on intestinal colonization of Bacteroides species in infants at risk of CD development. This study included 75 full-term newborns with at least one first-degree relative suffering from CD. Infants were classified according to milk-feeding practice (breast-feeding or formula feeding) and HLA-DQ genotype (high or low genetic risk). Stools were analyzed at 7 days, 1 month, and 4 months by PCR and denaturing gradient gel electrophoresis (DGGE). The Bacteroides species diversity index was higher in formula-fed infants than in breast-fed infants. Breast-fed infants showed a higher prevalence of Bacteroides uniformis at 1 and 4 months of age, while formula-fed infants had a higher prevalence of B. intestinalis at all sampling times, of B. caccae at 7 days and 4 months, and of B. plebeius at 4 months. Infants with high genetic risk showed a higher prevalence of B. vulgatus, while those with low genetic risk showed a higher prevalence of B. ovatus, B. plebeius, and B. uniformis. Among breast-fed infants, the prevalence of B. uniformis was higher in those with low genetic risk than in those with high genetic risk. Among formula-fed infants, the prevalence of B. ovatus and B. plebeius was increased in those with low genetic risk, while the prevalence of B. vulgatus was higher in those with high genetic risk. The results indicate that both the type of milk feeding and the HLA-DQ genotype influence the colonization process of Bacteroides species, and possibly the disease risk. PMID:21642397

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Takagi, Masatoshi; Urayama, Kevin

    2016-07-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed

    Dayan, Niu; Weili, Yan

    2015-12-01

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

  6. Herpes zoster infection increases the risk of peripheral arterial disease

    PubMed Central

    Lin, Te-Yu; Yang, Fu-Chi; Lin, Cheng-Li; Kao, Chia-Hung; Lo, Hsin-Yi; Yang, Tse-Yen

    2016-01-01

    Abstract Varicella-zoster virus infection can cause meningoencephalitis, myelitis, ocular disorders, and vasculopathy. However, no study has investigated the association between herpes zoster (HZ) and peripheral arterial disease (PAD). We identified newly diagnosed HZ from the Taiwan's National Health Insurance Research Database recorded during 2000 to 2010, with a follow-up period extending until December 31, 2011. In addition, we included a comparison cohort that was randomly frequency-matched with the HZ cohort according to age, sex, and index year. We analyzed the risk of PAD with respect to sex, age, and comorbidities by using Cox proportional-hazards regression models. In total, 35,391 HZ patients and 141,556 controls were enrolled in this study. The risk of PAD was 13% increased in the HZ cohort than in the comparison cohort after adjustment for age, sex, and comorbidities. The Kaplan–Meier survival curve showed that the risk of PAD was significantly higher in the HZ cohort than in the non-HZ cohort (P < 0.001). This nationwide population-based cohort study revealed a higher risk of PAD in patients with HZ infection than in those without the infection. Careful follow-up and aggressive treatment is recommended for patients with HZ to reduce the risk of PAD. PMID:27583856

  7. Increased risk of ischemic heart disease among subjects with cataracts

    PubMed Central

    Hu, Wei-Syun; Lin, Cheng-Li; Chang, Shih-Sheng; Chen, Ming-Fong; Chang, Kuan-Cheng

    2016-01-01

    Abstract Background: Association between cataract and the risk of ischemic heart disease (IHD) development is not completely clear. Purpose: The primary aim of the study was to evaluate the association between cataract and the risk of incident IHD. The secondary aim was to investigate the subsequent IHD risk of patients with cataracts undergoing cataract surgery. Methods: Retrospective data from the Longitudinal Health Insurance Database 2000 (LHID2000) was analyzed. Study participants were composed of patients with cataracts (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 366) (n = 32,456), and a comparison cohort without the cataracts (n = 32,456) from 2000 to 2010. Cox proportional hazards regression was used to address the hazard ratio (HR) of IHD associated with cataract. Results: Within 12 years of follow up, the overall incidence rates of IHD were 24.2 per 1000 person-years in the cataract cohort and 18.2 per 1000 person-years in the noncataract cohort with an adjusted hazard ratio (aHR) of 1.35 (95% CI = 1.29–1.41; P < 0.001). Furthermore, the cataract patients undergoing cataract surgery were associated with a higher risk of IHD compared with those cataract patients without surgery (aHR = 1.07, 95% CI: 1.01–1.14; P < 0.05). Conclusions: Our finding suggested that patients with cataracts are at an increased risk of subsequent IHD development. PMID:27428198

  8. Increased Risk Taking in Relation to Chronic Stress in Adults.

    PubMed

    Ceccato, Smarandita; Kudielka, Brigitte M; Schwieren, Christiane

    2015-01-01

    Chronic stress is a public health problem that affects a significant part of the population. While the physiological damage it causes is under ongoing scrutiny, its behavioral effects have been overlooked. This is one of the first studies to examine the relation between chronic stress and decision-making, using a standard lottery paradigm. We measured risk taking in the gain domain through binary choices between financially incentivized lotteries. We then measured self-reported chronic stress with the Trier Inventory for the Assessment of Chronic Stress (TICS). We additionally collected hair samples in a subsample of volunteers, in order to quantify accumulation of the stress hormone cortisol. We discovered a significant positive, though modest, correlation between self-reported chronic stress and risk taking that is stronger for women than for men. This confirms part of the findings in acute stress research that show a connection between higher stress and increased risk taking. However, unlike the biologically-based results from acute stress research, we did not identify a significant relation between hair cortisol and behavior. In line with previous literature, we found a clear gender difference in risk taking and self-reports: women generally take less risk and report slightly higher stress levels than men. We conclude that perceived chronic stress can impact behavior in risky situations. PMID:26858663

  9. Increased Risk Taking in Relation to Chronic Stress in Adults

    PubMed Central

    Ceccato, Smarandita; Kudielka, Brigitte M.; Schwieren, Christiane

    2016-01-01

    Chronic stress is a public health problem that affects a significant part of the population. While the physiological damage it causes is under ongoing scrutiny, its behavioral effects have been overlooked. This is one of the first studies to examine the relation between chronic stress and decision-making, using a standard lottery paradigm. We measured risk taking in the gain domain through binary choices between financially incentivized lotteries. We then measured self-reported chronic stress with the Trier Inventory for the Assessment of Chronic Stress (TICS). We additionally collected hair samples in a subsample of volunteers, in order to quantify accumulation of the stress hormone cortisol. We discovered a significant positive, though modest, correlation between self-reported chronic stress and risk taking that is stronger for women than for men. This confirms part of the findings in acute stress research that show a connection between higher stress and increased risk taking. However, unlike the biologically-based results from acute stress research, we did not identify a significant relation between hair cortisol and behavior. In line with previous literature, we found a clear gender difference in risk taking and self-reports: women generally take less risk and report slightly higher stress levels than men. We conclude that perceived chronic stress can impact behavior in risky situations. PMID:26858663

  10. Increased Risk of Herpes Zoster Following Dermatomyositis and Polymyositis

    PubMed Central

    Tsai, Shin-Yi; Lin, Cheng-Li; Wong, Ying-Chi; Yang, Tse-Yen; Kuo, Chien-Feng; Cheng, Jiung-Mou; Wang, Jyh-Seng; Kao, Chia-Hung

    2015-01-01

    Abstract This study explored the possible association between dermatomyositis or polymyositis (DM or PM) and the subsequent risk of herpes zoster (HZ). We used data from the Taiwan National Health Insurance (NHI) system to address the research topic. The exposure cohort comprised 2023 patients with new diagnoses of DM or PM. Each patient was frequency matched according to age, sex, index year, and comorbidities including diabetes, renal disease, obesity, malignancy, rheumatoid arthritis, immunodeficiency virus infection, autoimmune disease not elsewhere classified, mixed connective tissue disease, or vasculitis with 4 participants from the general population who did not have a history of HZ (control cohort). Cox proportional hazards regression analysis was conducted to estimate the relationship between DM or PM and the risk of subsequent HZ. The incidence of HZ in the exposure and control cohorts was 35.8 and 7.01 per 1000 person-years, respectively. The exposure cohort had a significantly higher overall risk of subsequent HZ than did the control cohort (adjusted hazard ratio [HR] = 3.90, 95% confidence interval [CI] = 3.18–4.77). The risk of HZ in patients with DM or PM in whichever stratification (including sex, age, and comorbidity) was also higher than that of the control cohort. The findings from this population-based retrospective cohort study suggest that DM or PM is associated with an increased risk of subsequent HZ. A synergistic effect was observed between DM or PM and one of the comorbidities. PMID:26181551

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

    Cancer.gov

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

  12. Metabolic syndrome is associated with increased risk of Barrett esophagus

    PubMed Central

    He, Qiong; Li, Jian-dong; Huang, Wei; Zhu, Wen-chang; Yang, Jian-quan

    2016-01-01

    Abstract Background: Barrett esophagus (BE) is considered precursor condition of esophageal adenocarcinoma. Its incidence and prevalence are increasing in general population. Studies reported that metabolic syndrome (MS) or diabetes mellitus (DM) is related to increased risk of BE. Current study was to assess and better understand the relationship between MS /DM and BE. Methods: Electronic search was conducted in the database Pubmed/Medline (-December, 2015), Embase (-December, 2015), Cochrane Library (-December, 2015), and Web of Knowledge (-December, 2015). Studies included were assessed with summary odds ratios (ORs) with 95% confidence intervals (CIs) and compared exposure group with control group. The heterogeneity was examined by the funnel plot and the Egger's test. Subgroup analyses and sensitive analyses were performed for the detection of possible heterogeneity and impact on stability of analysis results. Results: Twelve publications met the criteria and included 355,311 subjects were analyzed. The pooled results showed MS was closely associated with increased risk of BE (OR = 1.23; 95%CI 1.03–1.47; P = 0.024), and yet DM did not significantly increase the risk of BE (OR = 1.07; 95%CI 0.82–1.38; P = 0.627). Substantial heterogeneities were detected. No significant publication bias was detected by Egger's test (P = 0.23). Conclusions: Based on the results of current meta-analysis, MS is associated with increased risk of BE. Further long-term follow-up prospective study needs to verify the current results, and definite pathophysiological mechanism needs to be further investigated and clearly elucidated. PMID:27495039

  13. Family history of esophageal cancer increases the risk of esophageal squamous cell carcinoma.

    PubMed

    Chen, Tiantian; Cheng, Hongwei; Chen, Xingdong; Yuan, Ziyu; Yang, Xiaorong; Zhuang, Maoqiang; Lu, Ming; Jin, Li; Ye, Weimin

    2015-01-01

    A population-based case-control was performed to explore familial aggregation of esophageal squamous cell carcinoma (ESCC). Family history of cancer was assessed by a structured questionnaire, and from which 2 cohorts of relatives of cases and controls were reconstructed. Unconditional logistic regression and Cox proportional hazards regression were applied for case-control design and reconstructed cohort design, respectively. We observed a close to doubled risk of ESCC associated with a positive family history of esophageal cancer among first degree relatives (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.42-2.41), after adjusting age, sex, family size and other confounders. The excess risks of ESCC increased with the increasing of first-degree relatives affected by esophageal cancer (p < 0.001). In particular, those individuals whose both parents with esophageal cancer had an 8-fold excess risk of ESCC (95% CI: 1.74-36.32). The reconstructed cohort analysis showed that the cumulative risk of esophageal cancer to age 75 was 12.2% in the first-degree relatives of cases and 7.0% in those of controls (hazard ratio = 1.91, 95% CI: 1.54-2.37). Our results suggest family history of esophageal cancer significantly increases the risk for ESCC. Future studies are needed to understand how the shared genetic susceptibility and/or environmental exposures contribute to the observed excess risk.

  14. Extreme Geohazards: Reducing the Disaster Risk and Increasing Resilience

    NASA Astrophysics Data System (ADS)

    Plag, Hans-Peter; Stein, Seth; Brocklebank, Sean; Jules-Plag, Shelley; Marsh, Stuart; Campus, Paola

    2013-04-01

    Extreme geohazards have the potential to escalate the global sustainability crisis and put us close to the boundaries of the safe operating space for humanity. Exposure of human assets to geohazards has increased dramatically in recent decades, and the sensitivity of the built environment and the embedded socio-economic fabric have changed. We are putting the urban environment, including megacities, in harm's way. Paradoxically, innovation during recent decades, in particular, urban innovation, has increased the disaster risk and coupled this risk to the sustainability crisis. Only more innovation can reduce disaster risk and lead us out of the sustainability crisis. Extreme geohazards (volcanic eruptions, earthquakes, tsunamis) that occurred regularly throughout the last few millennia mostly did not cause major disasters because population density was low and the built environment was not sprawling into hazardous areas to the same extent as today. Similar extreme events today would cause unparalleled damage on a global scale and could worsen the sustainability crisis. Simulation of these extreme hazards under present conditions can help to assess the disaster risk. The Geohazards Community of Practice of the Group on Earth Observations (GEO) with support from the European Science Foundation is preparing a white paper assessing the contemporary disaster risks associated with extreme geohazards and developing a vision for science and society to engage in deliberations addressing this risk (see http://www.geohazcop.org/projects/extgeowp). Risk awareness and monitoring is highly uneven across the world, and this creates two kinds of problems. Firstly, potential hazards are much more closely monitored in wealthy countries than in the developing world. But the largest hazards are global in nature, and it is critical to get as much forewarning as possible to develop an effective response. The disasters and near-misses of the past show that adherence to scientific

  15. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

    SciTech Connect

    Hsieh, Yi-Chen; Lien, Li-Ming; Chung, Wen-Ting; Hsieh, Fang-I; Hsieh, Pei-Fan; Wu, Meei-Maan; Tseng, Hung-Pin; Chiou, Hung-Yi; Chen, Chien-Jen

    2011-08-15

    Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis. {yields

  16. The Increased Risk of Joint Venture Promotes Social Cooperation

    PubMed Central

    Wu, Te; Fu, Feng; Zhang, Yanling; Wang, Long

    2013-01-01

    The joint venture of many members is common both in animal world and human society. In these public enterprizes, highly cooperative groups are more likely to while low cooperative groups are still possible but not probable to succeed. Existent literature mostly focuses on the traditional public goods game, in which cooperators create public wealth unconditionally and benefit all group members unbiasedly. We here institute a model addressing this public goods dilemma with incorporating the public resource foraging failure risk. Risk-averse individuals tend to lead a autarkic life, while risk-preferential ones tend to participate in the risky public goods game. For participants, group's success relies on its cooperativeness, with increasing contribution leading to increasing success likelihood. We introduce a function with one tunable parameter to describe the risk removal pattern and study in detail three representative classes. Analytical results show that the widely replicated population dynamics of cyclical dominance of loner, cooperator and defector disappear, while most of the time loners act as savors while eventually they also disappear. Depending on the way that group's success relies on its cooperativeness, either cooperators pervade the entire population or they coexist with defectors. Even in the later case, cooperators still hold salient superiority in number as some defectors also survive by parasitizing. The harder the joint venture succeeds, the higher level of cooperation once cooperators can win the evolutionary race. Our work may enrich the literature concerning the risky public goods games. PMID:23750204

  17. The Increasing Risk of Poverty Across the American Life Course

    PubMed Central

    SANDOVAL, DANIEL A.; RANK, MARK R.; HIRSCHL, THOMAS A.

    2009-01-01

    This article extends the emerging body of life course research on poverty by empirically identifying the incidence, chronicity, and age pattern of American poverty and how these dimensions have changed during the period 1968–2000. Using the Panel Study of Income Dynamics, we construct a series of life tables that estimate the risk of poverty for adults during their 20s, 30s, 40s, 50s, 60s, and 70s, and compare these estimates for Americans in the 1970s, 1980s, and 1990s. Our empirical results suggest that the risk of acute poverty increased substantially, particularly in the 1990s. This observed increase was especially pronounced for individuals in their 20s, 30s, and 40s; for all age groups with respect to extreme poverty; and for white males. On the other hand, the risk of chronic poverty declined during the 1990s (as measured by the percentage of the poor who experienced five or more years of poverty within a 10-year interval). The results in this article tell a very different story than the Census Bureau’s yearly cross-sectional rates, which have shown little overall change in the U.S. poverty rate during this 30-year period. In contrast, a life course approach reveals a rising economic risk of acute poverty for individuals, one that is consistent with recent observations and research suggesting that a growing number of Americans will eventually find themselves in an economically precarious position. PMID:20084826

  18. The increased risk of joint venture promotes social cooperation.

    PubMed

    Wu, Te; Fu, Feng; Zhang, Yanling; Wang, Long

    2013-01-01

    The joint venture of many members is common both in animal world and human society. In these public enterprizes, highly cooperative groups are more likely to while low cooperative groups are still possible but not probable to succeed. Existent literature mostly focuses on the traditional public goods game, in which cooperators create public wealth unconditionally and benefit all group members unbiasedly. We here institute a model addressing this public goods dilemma with incorporating the public resource foraging failure risk. Risk-averse individuals tend to lead a autarkic life, while risk-preferential ones tend to participate in the risky public goods game. For participants, group's success relies on its cooperativeness, with increasing contribution leading to increasing success likelihood. We introduce a function with one tunable parameter to describe the risk removal pattern and study in detail three representative classes. Analytical results show that the widely replicated population dynamics of cyclical dominance of loner, cooperator and defector disappear, while most of the time loners act as savors while eventually they also disappear. Depending on the way that group's success relies on its cooperativeness, either cooperators pervade the entire population or they coexist with defectors. Even in the later case, cooperators still hold salient superiority in number as some defectors also survive by parasitizing. The harder the joint venture succeeds, the higher level of cooperation once cooperators can win the evolutionary race. Our work may enrich the literature concerning the risky public goods games.

  19. Increased extinction potential of insular fish populations with reduced life history variation and low genetic diversity.

    PubMed

    Hellmair, Michael; Kinziger, Andrew P

    2014-01-01

    Theoretical work has shown that reduced phenotypic heterogeneity leads to population instability and can increase extinction potential, yet few examples exist of natural populations that illustrate how varying levels expressed diversity may influence population persistence, particularly during periods of stochastic environmental fluctuation. In this study, we assess levels of expressed variation and genetic diversity among demographically independent populations of tidewater goby (Eucyclogobius newberryi), show that reductions in both factors typically coincide, and describe how low levels of diversity contribute to the extinction risk of these isolated populations. We illustrate that, for this annual species, continuous reproduction is a safeguard against reproductive failure by any one population segment, as natural, stochastically driven salinity increases frequently result in high mortality among juvenile individuals. Several study populations deviated from the natural pattern of year-round reproduction typical for the species, rendering those with severely truncated reproductive periods vulnerable to extinction in the event of environmental fluctuation. In contrast, demographically diverse populations are more likely to persist through such periods through the continuous presence of adults with broader physiological tolerance to abrupt salinity changes. Notably, we found a significant correlation between genetic diversity and demographic variation in the study populations, which could be the result of population stressors that restrict both of these diversity measures simultaneously, or suggestive of a causative relationship between these population characteristics. These findings demonstrate the importance of biocomplexity at the population level, and assert that the maintenance of diversity contributes to population resilience and conservation of this endangered species.

  20. Increased Extinction Potential of Insular Fish Populations with Reduced Life History Variation and Low Genetic Diversity

    PubMed Central

    Hellmair, Michael; Kinziger, Andrew P.

    2014-01-01

    Theoretical work has shown that reduced phenotypic heterogeneity leads to population instability and can increase extinction potential, yet few examples exist of natural populations that illustrate how varying levels expressed diversity may influence population persistence, particularly during periods of stochastic environmental fluctuation. In this study, we assess levels of expressed variation and genetic diversity among demographically independent populations of tidewater goby (Eucyclogobius newberryi), show that reductions in both factors typically coincide, and describe how low levels of diversity contribute to the extinction risk of these isolated populations. We illustrate that, for this annual species, continuous reproduction is a safeguard against reproductive failure by any one population segment, as natural, stochastically driven salinity increases frequently result in high mortality among juvenile individuals. Several study populations deviated from the natural pattern of year-round reproduction typical for the species, rendering those with severely truncated reproductive periods vulnerable to extinction in the event of environmental fluctuation. In contrast, demographically diverse populations are more likely to persist through such periods through the continuous presence of adults with broader physiological tolerance to abrupt salinity changes. Notably, we found a significant correlation between genetic diversity and demographic variation in the study populations, which could be the result of population stressors that restrict both of these diversity measures simultaneously, or suggestive of a causative relationship between these population characteristics. These findings demonstrate the importance of biocomplexity at the population level, and assert that the maintenance of diversity contributes to population resilience and conservation of this endangered species. PMID:25409501

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

    PubMed

    Zuradzki, Tomasz

    2014-11-01

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

  2. Delivering chaplaincy services to veterans at increased risk of suicide.

    PubMed

    Kopacz, Marek S; Pollitt, Michael J

    2015-01-01

    The present study quantitatively examines the delivery of chaplaincy services to Veterans at increased risk of suicide as well as how chaplains collaborate with other healthcare providers. An on-line survey was distributed to the nationwide network of U.S. Department of Veterans Affairs chaplains, yielding a response rate of 11.91% (N = 118). Most chaplains reported some form of training in suicide prevention, approximately half were involved in safety planning, and the majority reported not engaging in firearm safety counseling. Chaplaincy services were usually delivered through in-person, group, and phone consultations. Respondents were generally satisfied with their collaboration with other healthcare providers, most often collaborating with psychologists, social workers, and counselors. As a descriptive study, the findings serve to inform the delivery of chaplaincy services to at-risk Veterans. Recommendations include expanding service delivery options, developing competency in safety planning and counseling, as well as increasing institutional awareness of chaplaincy services.

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  5. Increasing Public Awareness of Direct-to-Consumer Genetic Tests: Health Care Access, Internet Use, and Population Density Correlates

    PubMed Central

    Finney Rutten, Lila J.; Gollust, Sarah E.; Naveed, Sana; Moser, Richard P.

    2012-01-01

    Uncertainty around the value of and appropriate regulatory models for direct-to-consumer (DTC) genetic testing underscores the importance of tracking public awareness of these services. We analyzed nationally representative, cross-sectional data from the Health Information National Trends Survey in 2008 (n = 7, 674) and 2011 (n = 3, 959) to assess population-level changes in awareness of DTC genetic testing in the U.S. and to explore sociodemographic, health care, Internet use, and population density correlates. Overall, awareness increased significantly from 29% in 2008 to 37% in 2011. The observed increase in awareness from 2008 to 2011 remained significant (OR = 1.39) even when adjusted for sociodemographic variables, health care access, Internet use, and population density. Independent of survey year, the odds of awareness of DTC genetic tests were significantly higher for those aged 50–64 (OR = 1.64), and 65–74 (OR = 1.60); college graduates (OR = 2.02); those with a regular source of health care (OR = 1.27); those with a prior cancer diagnosis (OR = 1.24); those who use the Internet (OR = 1.27); and those living in urban areas (OR = 1.25). Surveillance of awareness—along with empirical data on use of and response to genetic risk information—can inform public health and policy efforts to maximize benefits and minimize risks of DTC genetic testing. PMID:22899921

  6. Clothing increases the risk of indirect ballistic fractures

    PubMed Central

    2013-01-01

    Background Current literature has shown the mechanism of how indirect fractures occur but has not determined what factors increase the risks of such fractures. The objective of this study is thus to determine the effect of clothing and soft tissue thickness on the risk of indirect fracture formation. Methods Twenty-five fresh red deer femora embedded in ballistic gelatine were shot with varying distances off their medial cortex with a 5.56 × 45 mm North Atlantic Treaty Organization (NATO) bullet while being filmed with a slow-motion video. We compared the effect of two different gelatine depths and the effect of denim cloth laid onto the impact surface of the moulds. Results Bullet passage in thinner moulds failed to cause fracture because the bullet exited the mould before a large expanding temporary cavity was produced. Clothing dramatically altered the size and depth of the expanding cavity, as well as increased lateral pressures, resulting in more severe fractures with greater bullet distances from the bone that can cause fracture. Conclusions Clothing increases the risk of indirect fracture and results in larger, more superficial temporary cavities, with greater lateral pressures than are seen in unclothed specimens, resulting in more comminuted fractures. Greater tissue depth affords the 5.56 × 45 mm NATO a chance to yaw and thus develop an enlarging temporary cavity that is sufficient to cause fracture. PMID:24267379

  7. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.

    PubMed

    Vilhjálmsson, Bjarni J; Yang, Jian; Finucane, Hilary K; Gusev, Alexander; Lindström, Sara; Ripke, Stephan; Genovese, Giulio; Loh, Po-Ru; Bhatia, Gaurav; Do, Ron; Hayeck, Tristan; Won, Hong-Hee; Kathiresan, Sekar; Pato, Michele; Pato, Carlos; Tamimi, Rulla; Stahl, Eli; Zaitlen, Noah; Pasaniuc, Bogdan; Belbin, Gillian; Kenny, Eimear E; Schierup, Mikkel H; De Jager, Philip; Patsopoulos, Nikolaos A; McCarroll, Steve; Daly, Mark; Purcell, Shaun; Chasman, Daniel; Neale, Benjamin; Goddard, Michael; Visscher, Peter M; Kraft, Peter; Patterson, Nick; Price, Alkes L

    2015-10-01

    Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

  8. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

    PubMed Central

    Vilhjálmsson, Bjarni J.; Yang, Jian; Finucane, Hilary K.; Gusev, Alexander; Lindström, Sara; Ripke, Stephan; Genovese, Giulio; Loh, Po-Ru; Bhatia, Gaurav; Do, Ron; Hayeck, Tristan; Won, Hong-Hee; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T.R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberly D.; Chan, Raymond C.K.; Chen, Ronald Y.L.; Chen, Eric Y.H.; Cheng, Wei; Cheung, Eric F.C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; DeLisi, Lynn E.; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodrguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; Grove, Jakob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julia, Antonio; Kahn, Rene S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kahler, Anna K.; Laurent, Claudine; Keong, Jimmy Lee Chee; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lnnqvist, Jouko; Macek, Milan; Magnusson, Patrik K.E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Mller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O’Callaghan, Eadbhard; O’Dushlaine, Colm; O’Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietilinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C.A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Sderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tooney, Paul A.; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H.M.; Wormley, Brandon K.; Wu, Jing Qin; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H.R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tonu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jonsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Nthen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St. Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O’Donovan, Michael C.; Kraft, Peter; Hunter, David J.; Adank, Muriel; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Berndt, Sonja; Blomquist, Carl; Canzian, Federico; Chang-Claude, Jenny; Chanock, Stephen J.; Crisponi, Laura; Czene, Kamila; Dahmen, Norbert; Silva, Isabel dos Santos; Easton, Douglas; Eliassen, A. Heather; Figueroa, Jonine; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Gibson, Lorna; Haiman, Christopher A.; Hall, Per; Hazra, Aditi; Hein, Rebecca; Henderson, Brian E.; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Lindström, Sara; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Meijers-Heijboer, Hanne; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sánchez, María José; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth; Turnbull, Clare; Uitterlinden, Andre G.; van der Luijt, Rob B.; Waisfisz, Quinten; Wang, Zhaoming; Whittemore, Alice S.; Yang, Rose; Zheng, Wei; Kathiresan, Sekar; Pato, Michele; Pato, Carlos; Tamimi, Rulla; Stahl, Eli; Zaitlen, Noah; Pasaniuc, Bogdan; Belbin, Gillian; Kenny, Eimear E.; Schierup, Mikkel H.; De Jager, Philip; Patsopoulos, Nikolaos A.; McCarroll, Steve; Daly, Mark; Purcell, Shaun; Chasman, Daniel; Neale, Benjamin; Goddard, Michael; Visscher, Peter M.; Kraft, Peter; Patterson, Nick; Price, Alkes L.

    2015-01-01

    Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. PMID:26430803

  9. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.

    PubMed

    Vilhjálmsson, Bjarni J; Yang, Jian; Finucane, Hilary K; Gusev, Alexander; Lindström, Sara; Ripke, Stephan; Genovese, Giulio; Loh, Po-Ru; Bhatia, Gaurav; Do, Ron; Hayeck, Tristan; Won, Hong-Hee; Kathiresan, Sekar; Pato, Michele; Pato, Carlos; Tamimi, Rulla; Stahl, Eli; Zaitlen, Noah; Pasaniuc, Bogdan; Belbin, Gillian; Kenny, Eimear E; Schierup, Mikkel H; De Jager, Philip; Patsopoulos, Nikolaos A; McCarroll, Steve; Daly, Mark; Purcell, Shaun; Chasman, Daniel; Neale, Benjamin; Goddard, Michael; Visscher, Peter M; Kraft, Peter; Patterson, Nick; Price, Alkes L

    2015-10-01

    Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. PMID:26430803

  10. Increasing prevalence, changes in diagnostic criteria, and nutritional risk factors for autism spectrum disorders.

    PubMed

    Neggers, Yasmin H

    2014-01-01

    The frequency of autism spectrum disorders (ASD) diagnoses has been increasing for decades, but researchers cannot agree on whether the trend is a result of increased awareness, improved detection, expanding definition, or an actual increase in incidence or a combination of these factors. Though both genetic and multiple environmental risk factors have been studied extensively, many potentially modifiable risk factors including nutritional and immune function related risk factors such as vitamin D, folic acid, and metabolic syndrome have not received sufficient attention. Several recent studies have put forward hypotheses to explain the mechanism of association between both folic acid and vitamin D and autism. A continuous rise in the prevalence of autism in the USA has coincided with a significant enhancement of maternal folate status with FDA mandated folic acid fortification of certain foods starting in 1998. There is also a growing body of research that suggests that vitamin D status either in utero or early in life may be a risk for autism. In this communication, controversies regarding increase in estimate of prevalence, implications of changes in definition, and possible association between some modifiable nutritional risk factors such as folic acid and vitamin D and ASD will be discussed.

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

    PubMed

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

    2009-01-01

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

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

    PubMed

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

    2009-01-01

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

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

    PubMed

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

    2016-03-04

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

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

    ERIC Educational Resources Information Center

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

    2009-01-01

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

  15. Increased Cardiometabolic Risk and Worsening Hypoxemia at High Altitude.

    PubMed

    Miele, Catherine H; Schwartz, Alan R; Gilman, Robert H; Pham, Luu; Wise, Robert A; Davila-Roman, Victor G; Jun, Jonathan C; Polotsky, Vsevolod Y; Miranda, J Jaime; Leon-Velarde, Fabiola; Checkley, William

    2016-06-01

    Miele, Catherine H., Alan R. Schwartz, Robert H. Gilman, Luu Pham, Robert A. Wise, Victor G. Davila-Roman, Jonathan C. Jun, Vsevolod Y. Polotsky, J. Jaime Miranda, Fabiola Leon-Velarde, and William Checkley. Increased cardiometabolic risk and worsening hypoxemia at high altitude. High Alt Med Biol. 17:93-100, 2016.-Metabolic syndrome, insulin resistance, diabetes, and dyslipidemia are associated with an increased risk of cardiovascular disease. While excessive erythrocytosis is associated with cardiovascular complications, it is unclear how worsening hypoxemia of any degree affects cardiometabolic risk factors in high-altitude populations. We studied the relationship between daytime resting oxyhemoglobin saturation and cardiometabolic risk factors in adult participants living in Puno, Peru (3825 m above sea level). We used multivariable logistic regression models to study the relationship between having a lower oxyhemoglobin saturation and markers of cardiometabolic risk. Nine hundred and fifty-four participants (mean age 55 years, 52% male) had information available on pulse oximetry and markers of cardiometabolic risk. Average oxyhemoglobin saturation was 90% (interquartile range 88%-92%) and 43 (4.5%) had excessive erythrocytosis. Older age, decreased height-adjusted lung function, and higher body mass index (BMI) were associated with having an oxyhemoglobin saturation ≤85%. When adjusting for age, sex, socioeconomic status, having excessive erythrocytosis, and site, we found that each 5% decrease in oxyhemoglobin saturation was associated with a higher adjusted odds of metabolic syndrome (OR = 1.35, 95% CI: 1.07-1.72, p < 0.04), insulin resistance as defined by homeostasis model assessment-insulin resistance (HOMA-IR) >2 mass units (OR = 1.29, 95% CI: 1.00-1.67, p < 0.05), hemoglobin A1c ≥6.5% (OR = 1.66, 95% CI: 1.09-2.51, p < 0.04), and high sensitivity C-reactive protein (hs-CRP) ≥3 mg/L (OR = 1.46, 95% CI: 1.09-1.96, p

  16. Increased Long-Term Cardiovascular Risk After Total Hip Arthroplasty

    PubMed Central

    Gordon, Max; Rysinska, Agata; Garland, Anne; Rolfson, Ola; Aspberg, Sara; Eisler, Thomas; Garellick, Göran; Stark, André; Hailer, Nils P.; Sköldenberg, Olof

    2016-01-01

    Abstract Total hip arthroplasty is a common and important treatment for osteoarthritis patients. Long-term cardiovascular effects elicited by osteoarthritis or the implant itself remain unknown. The purpose of the present study was to determine if there is an increased risk of late cardiovascular mortality and morbidity after total hip arthroplasty surgery. A nationwide matched cohort study with data on 91,527 osteoarthritis patients operated on, obtained from the Swedish Hip Arthroplasty Register. A control cohort (n = 270,688) from the general Swedish population was matched 1:3 to each case by sex, age, and residence. Mean follow-up time was 10 years (range, 7–21). The exposure was presence of a hip replacement for more than 5 years. The primary outcome was cardiovascular mortality after 5 years. Secondary outcomes were total mortality and re-admissions due to cardiovascular events. During the first 5 to 9 years, the arthroplasty cohort had a lower cardiovascular mortality risk compared with the control cohort. However, the risk in the arthroplasty cohort increased over time and was higher than in controls after 8.8 years (95% confidence interval [CI] 7.0–10.5). Between 9 and 13 years postoperatively, the hazard ratio was 1.11 (95% CI 1.05–1.17). Arthroplasty patients were also more frequently admitted to hospital for cardiovascular reasons compared with controls, with a rate ratio of 1.08 (95% CI 1.06–1.11). Patients with surgically treated osteoarthritis of the hip have an increased risk of cardiovascular morbidity and mortality many years after the operation when compared with controls. PMID:26871792

  17. Genetic bottlenecks, perceived racism, and hypertension risk among African Americans and first-generation African immigrants.

    PubMed

    Poston, W S; Pavlik, V N; Hyman, D J; Ogbonnaya, K; Hanis, C L; Haddock, C K; Hyder, M L; Foreyt, J P

    2001-05-01

    The complexity of factors influencing the development of hypertension (HTN) in African Americans has given rise to theories suggesting that genetic changes occurred due to selection pressures/genetic bottleneck effects (ie, constriction of existing genetic variability) over the course of the slave trade. Ninety-nine US-born and 86 African-born health professionals were compared in a cross-sectional survey examining genetic and psychosocial predictors of HTN. We examined the distributions of three genetic loci (G-protein, AGT-235, and ACE I/D) that have been associated with increased HTN risk. There were no significant differences between US-born African Americans and African-born immigrants in the studied genetic loci or biological variables (eg, plasma renin and angiotensin converting enzyme activity), except that the AGT-235 homozygous T genotype was somewhat more frequent among African-born participants than US-born African Americans. Only age, body mass index, and birthplace consistently demonstrated associations with HTN status. Thus, there was no evidence of a genetic bottleneck in the loci studied, ie, that US-born African Americans have different genotype distributions that increase their risk for HTN. In fact, some of the genotypic distributions evidenced lower frequencies of HTN-related alleles among US-born African Americans, providing evidence of European admixture. The consistent finding that birthplace (ie, US vs Africa) was associated with HTN, even though it was not always significant, suggests potential and unmeasured cultural, lifestyle, and environmental differences between African immigrants and US-born African Americans that are protective against HTN.

  18. eNOS Genetic Polymorphisms and Cancer Risk

    PubMed Central

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

    2015-01-01

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

  19. An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity

    PubMed Central

    Simopoulos, Artemis P.

    2016-01-01

    In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity. Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity. PMID:26950145

  20. An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity.

    PubMed

    Simopoulos, Artemis P

    2016-03-02

    In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity. Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity.

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

    PubMed Central

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

    2009-01-01

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

  2. Hair keratin mutations in tooth enamel increase dental decay risk.

    PubMed

    Duverger, Olivier; Ohara, Takahiro; Shaffer, John R; Donahue, Danielle; Zerfas, Patricia; Dullnig, Andrew; Crecelius, Christopher; Beniash, Elia; Marazita, Mary L; Morasso, Maria I

    2014-12-01

    Tooth enamel is the hardest substance in the human body and has a unique combination of hardness and fracture toughness that protects teeth from dental caries, the most common chronic disease worldwide. In addition to a high mineral content, tooth enamel comprises organic material that is important for mechanical performance and influences the initiation and progression of caries; however, the protein composition of tooth enamel has not been fully characterized. Here, we determined that epithelial hair keratins, which are crucial for maintaining the integrity of the sheaths that support the hair shaft, are expressed in the enamel organ and are essential organic components of mature enamel. Using genetic and intraoral examination data from 386 children and 706 adults, we found that individuals harboring known hair disorder-associated polymorphisms in the gene encoding keratin 75 (KRT75), KRT75(A161T) and KRT75(E337K), are prone to increased dental caries. Analysis of teeth from individuals carrying the KRT75(A161T) variant revealed an altered enamel structure and a marked reduction of enamel hardness, suggesting that a functional keratin network is required for the mechanical stability of tooth enamel. Taken together, our results identify a genetic locus that influences enamel structure and establish a connection between hair disorders and susceptibility to dental caries.

  3. Hair keratin mutations in tooth enamel increase dental decay risk

    PubMed Central

    Duverger, Olivier; Ohara, Takahiro; Shaffer, John R.; Donahue, Danielle; Zerfas, Patricia; Dullnig, Andrew; Crecelius, Christopher; Beniash, Elia; Marazita, Mary L.; Morasso, Maria I.

    2014-01-01

    Tooth enamel is the hardest substance in the human body and has a unique combination of hardness and fracture toughness that protects teeth from dental caries, the most common chronic disease worldwide. In addition to a high mineral content, tooth enamel comprises organic material that is important for mechanical performance and influences the initiation and progression of caries; however, the protein composition of tooth enamel has not been fully characterized. Here, we determined that epithelial hair keratins, which are crucial for maintaining the integrity of the sheaths that support the hair shaft, are expressed in the enamel organ and are essential organic components of mature enamel. Using genetic and intraoral examination data from 386 children and 706 adults, we found that individuals harboring known hair disorder–associated polymorphisms in the gene encoding keratin 75 (KRT75), KRT75A161T and KRT75E337K, are prone to increased dental caries. Analysis of teeth from individuals carrying the KRT75A161T variant revealed an altered enamel structure and a marked reduction of enamel hardness, suggesting that a functional keratin network is required for the mechanical stability of tooth enamel. Taken together, our results identify a genetic locus that influences enamel structure and establish a connection between hair disorders and susceptibility to dental caries. PMID:25347471

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed Central

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

    2016-01-01

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

  7. Delayed diagnosis of coeliac disease increases cancer risk

    PubMed Central

    Silano, Marco; Volta, Umberto; Mecchia, Anna Maria; Dessì, Mariarita; Di Benedetto, Rita; De Vincenzi, Massimo

    2007-01-01

    Background The association between coeliac disease (CD) and neoplasms has been long established, but few data are available about the risk factors. The aim of this paper is to estimate the risk of developing a neoplasm among non diagnosed coeliac patients and to evaluate if this risk correlates with the age of patients at diagnosis of coeliac disease. Methods The study population consists of patients (n = 1968) diagnosed with CD at 20 Italian gastroenterology referral Centers between 1st January 1982 and 31st March 2005. Results The SIR for all cancers resulted to be 1.3; 95% CI = 1.0–1.7 p < 0.001. The specific SIRs for non Hodgkin lymphoma was 4.7; 95% CI = 2.9–7.3 p < 0.001, for the small bowel carcinoma 25; 95% CI = 8.5–51.4 p < 0.001, for non Hodgkin lymphoma 10; 95% CI = 2.7–25 p = 0.01, finally for the stomach carcinoma 3; 95% CI = 1.3–4.9 p < 0.08. The mean age at diagnosis of CD of patients that developed sooner or later a neoplasm was 47,6 ± 10.2 years versus 28.6 ± 18.2 years of patients who did not. Conclusion Coeliac patients have an increased risk of developing cancer in relation to the age of diagnosis of CD. This risk results higher for malignancies of the gastro-intestinal sites. An accurate screening for tumors should be performed in patients diagnosed with CD in adulthood and in advancing age. PMID:17349035

  8. Schooling Increases Risk Exposure for Fish Navigating Past Artificial Barriers

    PubMed Central

    Lemasson, Bertrand H.; Haefner, James W.; Bowen, Mark D.

    2014-01-01

    Artificial barriers have become ubiquitous features in freshwater ecosystems and they can significantly impact a region's biodiversity. Assessing the risk faced by fish forced to navigate their way around artificial barriers is largely based on assays of individual swimming behavior. However, social interactions can significantly influence fish movement patterns and alter their risk exposure. Using an experimental flume, we assessed the effects of social interactions on the amount of time required for juvenile palmetto bass (Morone chrysops × M. saxatilis) to navigate downstream past an artificial barrier. Fish were released either individually or in groups into the flume using flow conditions that approached the limit of their expected swimming stamina. We compared fish swimming behaviors under solitary and schooling conditions and measured risk as the time individuals spent exposed to the barrier. Solitary fish generally turned with the current and moved quickly downstream past the barrier, while fish in groups swam against the current and displayed a 23-fold increase in exposure time. Solitary individuals also showed greater signs of skittish behavior than those released in groups, which was reflected by larger changes in their accelerations and turning profiles. While groups displayed fission-fusion dynamics, inter-individual positions were highly structured and remained steady over time. These spatial patterns align with theoretical positions necessary to reduce swimming exertion through either wake capturing or velocity sheltering, but diverge from any potential gains from channeling effects between adjacent neighbors. We conclude that isolated performance trials and projections based on individual behaviors can lead to erroneous predictions of risk exposure along engineered structures. Our results also suggest that risk perception and behavior may be more important than a fish's swimming stamina in artificially modified systems. PMID:25268736

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

    Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4 rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4 rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4 rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA. PMID:27570521

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

    PubMed Central

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

    2016-01-01

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

  12. Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett’s Esophagus, and Gastroesophageal Reflux

    PubMed Central

    2013-01-01

    Background Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett’s esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA. Methods We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2 g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used. Results We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10−9) and for EA (h2 g = 25 %; SE = 5%; one-sided P = 2 × 10−7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10−6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD. Conclusions We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases. PMID:24168968

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  15. Linking genetic counseling content to short-term outcomes in individuals at elevated breast cancer risk.

    PubMed

    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.

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

    PubMed Central

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

    2014-01-01

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

  17. Topiramate increases the risk of valproic acid-induced encephalopathy.

    PubMed

    Noh, Young; Kim, Dong Wook; Chu, Kon; Lee, Soon-Tae; Jung, Keun-Hwa; Moon, Hye-Jin; Lee, Sang Kun

    2013-01-01

    Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA-induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA-induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA-induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA-induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA-induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment.

  18. Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers

    PubMed Central

    Hartz, Sarah M.; Short, Susan E.; Saccone, Nancy L.; Culverhouse, Robert; Chen, LiShiun; Schwantes-An, Tae-Hwi; Coon, Hilary; Han, Younghun; Stephens, Sarah H.; Sun, Juzhong; Chen, Xiangning; Ducci, Francesca; Dueker, Nicole; Franceschini, Nora; Frank, Josef; Geller, Frank; Guđbjartsson, Daniel; Hansel, Nadia N.; Jiang, Chenhui; Keskitalo-Vuokko, Kaisu; Liu, Zhen; Lyytikäinen, Leo-Pekka; Michel, Martha; Rawal, Rajesh; Hum, Sc; Rosenberger, Albert; Scheet, Paul; Shaffer, John R.; Teumer, Alexander; Thompson, John R.; Vink, Jacqueline M.; Vogelzangs, Nicole; Wenzlaff, Angela S.; Wheeler, William; Xiao, Xiangjun; Yang, Bao-Zhu; Aggen, Steven H.; Balmforth, Anthony J.; Baumeister, Sebastian E.; Beaty, Terri; Bennett, Siiri; Bergen, Andrew W.; Boyd, Heather A.; Broms, Ulla; Campbell, Harry; Chatterjee, Nilanjan; Chen, Jingchun; Cheng, Yu-Ching; Cichon, Sven; Couper, David; Cucca, Francesco; Dick, Danielle M.; Foroud, Tatiana; Furberg, Helena; Giegling, Ina; Gu, Fangyi; Hall, Alistair S.; Hällfors, Jenni; Han, Shizhong; Hartmann, Annette M.; Hayward, Caroline; Heikkilä, Kauko; Lic, Phil; Hewitt, John K.; Hottenga, Jouke Jan; Jensen, Majken K.; Jousilahti, Pekka; Kaakinen, Marika; Kittner, Steven J.; Konte, Bettina; Korhonen, Tellervo; Landi, Maria-Teresa; Laatikainen, Tiina; Leppert, Mark; Levy, Steven M.; Mathias, Rasika A.; McNeil, Daniel W.; Medland, Sarah E.; Montgomery, Grant W.; Muley, Thomas; Murray, Tanda; Nauck, Matthias; North, Kari; Pergadia, Michele; Polasek, Ozren; Ramos, Erin M.; Ripatti, Samuli; Risch, Angela; Ruczinski, Ingo; Rudan, Igor; Salomaa, Veikko; Schlessinger, David; Styrkársdóttir, Unnur; Terracciano, Antonio; Uda, Manuela; Willemsen, Gonneke; Wu, Xifeng; Abecasis, Goncalo; Barnes, Kathleen; Bickeböller, Heike; Boerwinkle, Eric; Boomsma, Dorret I.; Caporaso, Neil; Duan, Jubao; Edenberg, Howard J.; Francks, Clyde; Gejman, Pablo V.; Gelernter, Joel; Grabe, Hans Jörgen; Hops, Hyman; Jarvelin, Marjo-Riitta; Viikari, Jorma; Kähönen, Mika; Kendler, Kenneth S.; Lehtimäki, Terho; Levinson, Douglas F.; Marazita, Mary L.; Marchini, Jonathan; Melbye, Mads; Mitchell, Braxton D.; Murray, Jeffrey C.; Nöthen, Markus M.; Penninx, Brenda W.; Raitakari, Olli; Rietschel, Marcella; Rujescu, Dan; Samani, Nilesh J.; Sanders, Alan R.; Schwartz, Ann G.; Shete, Sanjay; Shi, Jianxin; Spitz, Margaret; Stefansson, Kari; Swan, Gary E.; Thorgeirsson, Thorgeir; Völzke, Henry; Wei, Qingyi; Wichmann, H.-Erich; Amos, Christopher I.; Breslau, Naomi; Cannon, Dale S.; Ehringer, Marissa; Grucza, Richard; Hatsukami, Dorothy; Heath, Andrew; Johnson, Eric O.; Kaprio, Jaakko; Madden, Pamela; Martin, Nicholas G.; Stevens, Victoria L.; Stitzel, Jerry A.; Weiss, Robert B.; Kraft, Peter; Bierut, Laura J.

    2012-01-01

    Context Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. Objective To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. Data Sources Primary data. Study Selection Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. Data Extraction Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. Data Synthesis Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01). Conclusion These results highlight an increased genetic vulnerability to smoking in early-onset smokers. PMID:22868939

  19. [Risk of genetic transformation of multipotent mesenchymal stromal cells in vitro].

    PubMed

    Nikitina, V A; Chausheva, A I

    2014-01-01

    Proof of the efficacy of cell therapy by numerous studies and clinical trials inevitably has raised the question of improving the regulatory framework that governs its use. Particular attention should be paid to the genetic safety of cell preparations. The immune, genetic, and pharmacological modification and expansion of cells in vitro can lead to an undesired effect, which not only has reduced the healing, recovery, and regulatory potential of cell therapy, but also increased the risk of accumulating genetically aberrant cells and the oncogenic transformation of cell preparations. The article has presented the estimation of the parameters of the genetic stability of cultured multipotent mesenchymal stromal cells (MSCs) derived from bone marrow and adipose tissue. The study was conducted using classic methods of genotoxicology, i.e., the individual cells gel-electrophoresis (DNA comets) and the micronucleus test. We described a basic level of DNA damage and the frequency of micronucleus, identified genetically instable cultures, and conducted the comparison of genetic variability of MSCs isolated from different tissues. PMID:25711017

  20. Low Serum Testosterone Increases Mortality Risk among Male Dialysis Patients

    PubMed Central

    Carrero, Juan Jesús; Qureshi, Abdul Rashid; Parini, Paolo; Arver, Stefan; Lindholm, Bengt; Bárány, Peter; Heimbürger, Olof; Stenvinkel, Peter

    2009-01-01

    Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease. PMID:19144759

  1. Low serum testosterone increases mortality risk among male dialysis patients.

    PubMed

    Carrero, Juan Jesús; Qureshi, Abdul Rashid; Parini, Paolo; Arver, Stefan; Lindholm, Bengt; Bárány, Peter; Heimbürger, Olof; Stenvinkel, Peter

    2009-03-01

    Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease.

  2. Genetic variants associated with celiac disease and the risk for coronary artery disease.

    PubMed

    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 < 5 × 10(-08)). These SNPs were evaluated for their association with CAD in the Coronary ARtery 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.

  3. Lack of Association between Genetic Risk Loci for Restless Legs Syndrome and Multimorbidity

    PubMed Central

    Szentkirályi, András; Völzke, Henry; Hoffmann, Wolfgang; Winkelmann, Julianne; Berger, Klaus

    2016-01-01

    Study Objectives: Multimorbidity is a risk factor for incident restless legs syndrome (RLS). In this relationship, the potential role of known genetic risk loci for RLS has not been studied. Our aim was to evaluate whether carriers of specific RLS risk alleles have higher comorbidity burden than noncarriers. Methods: The Dortmund Health Study (DHS) and the Study of Health in Pomerania (SHIP) are two independent cohort studies in Germany based on agestratified, random samples drawn from the respective population registers. DHS included 1,312 subjects and SHIP included 4,308 subjects. RLS status was assessed according to the RLS standard minimal criteria. A comorbidity index was calculated by summing the scores of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. Thirteen single nucleotide polymorphisms (SNP) previously associated with elevated risk of RLS were genotyped. Analyses were carried out on the pooled sample of the two studies. Results: The mean age was 50.4 ± 15.9 y, and the proportion of women was 51.4%. The mean number of comorbid conditions was 1.5 ± 1.3. In multivariable regression, the mean number of comorbidities was not significantly different between carriers of any of the RLS risk alleles and noncarriers either in the total pooled sample or in those having RLS symptoms. Conclusions: Based on these results it is unlikely that known genetic risk factors for RLS would lead to increased multimorbidity. Citation: Szentkirályi A, Völzke H, Hoffmann W, Winkelmann J, Berger K. Lack of association between genetic risk loci for restless legs syndrome and multimorbidity. SLEEP 2016;39(1):111–115. PMID:26350469

  4. Alcohol Use Disorder Increases the Risk of Irritable Bowel Disease

    PubMed Central

    Hsu, Tai-Yi; He, Guan-Yi; Wang, Yu-Chiao; Chen, Chih-Yu; Wang, Shih-Hao; Chen, Wei-Kung; Kao, Chia-Hung

    2015-01-01

    Abstract Alcohol use disorder (AUD) is considered a possible risk factor for irritable bowel syndrome (IBS); however, previous studies investigating the association between AUD and IBS have yielded inconsistent results. The study investigated whether AUD increases the risk of IBS by using a population-based database in Taiwan. This retrospective matched-cohort study included the health insurance claims data of 56,355 AUD inpatients and 225,420 randomly selected controls by frequency-matched for sex, age, and index year. Cox proportional hazards regression analysis was performed to measure the risk of IBS among AUD patients compared with non-AUD patients. During the follow-up period, the incidence rate ratio (IRR) of IBS had 12.3-fold (95% CI: 11.9–12.7) in the AUD patients than non-AUD patients and the adjusted hazard ratio (aHR) for IBS in the AUD patients was 5.51 (95% CI: 4.36–6.96). For several comorbidities, the risk of IBS was significantly higher in the AUD patients than in non-AUD patients, with aHRs of 2.14 (95% confidence interval [CI]: 1.19–3.84), 2.05 (95% CI: 1.06–3.96), and 2.91 (95% CI: 1.26–6.72) for sleep disorders, acute pancreatitis, and hepatitis B, respectively. When we stratified the severity of AUD according to the length of hospital stay, the aHRs exhibited a significant correlation (P < 0.001) with severity, yielding aHRs of 3.24 (95% CI: 2.49–4.22), 11.9 (95% CI: 8.96–15.9), and 26.1 (95% CI: 19.4–35.2) for mild, moderate, and severe AUD, respectively. The risk of IBS was higher among AUD patients, and increased with the length of hospital stay. PMID:26705226

  5. Pneumoconiosis increases the risk of congestive heart failure

    PubMed Central

    Yen, Chia-Ming; Lin, Cheng-Li; Lin, Ming-Chia; Chen, Huei-Yong; Lu, Nan-Han; Kao, Chia-Hung

    2016-01-01

    Abstract The purpose of the study was to determine the relationship between pneumoconiosis and congestive heart failure (CHF). We collected data from the National Health Insurance Research Database in Taiwan. The study sample comprised 8923 patients with pneumoconiosis and 35,692 nonpneumoconiosis controls enrolled from 2000 to 2011. Patients were followed up until the end of 2011 to evaluate the incidence of CHF. The risk of CHF was analyzed using Cox proportional hazard regression models, and the analysis accounted for factors such as sex, age, comorbidities, and air pollutants (μg/m3). The overall incidence of CHF was higher in the pneumoconiosis cohort (15.7 per 1000 person-y) than in the nonpneumoconiosis cohort (11.2 per 1000 person-y), with a crude hazard ratio (HR) of 1.40 (P < 0.001). The HR for CHF was 1.38-fold greater in the pneumoconiosis cohort than in the nonpneumoconiosis cohort (P < 0.001) after the model was adjusted for age, sex, various comorbidities, and air pollutants (μg/m3). The relative risk for CHF in the sex-specific pneumoconiosis cohort compared with the nonpneumoconiosis cohort was significant for men (adjusted HR = 1.40, 95% confidence interval = 1.21–1.62, P < 0.001). The incidence density rates of CHF increased with age; pneumoconiosis patients had a higher relative risk of CHF for all age group. Patients with pneumoconiosis were at higher risk for developing CHF than patients in the nonpneumoconiosis cohort, particularly in cases with coexisting coronary artery disease, hypertension, and chronic obstructive pulmonary disease. PMID:27336897

  6. Nocturnal indicators of increased cardiovascular risk in depressed adolescent girls.

    PubMed

    Waloszek, Joanna M; Woods, Michael J; Byrne, Michelle L; Nicholas, Christian L; Bei, Bei; Murray, Greg; Raniti, Monika; Allen, Nicholas B; Trinder, John

    2016-04-01

    Depression is an independent risk factor for cardiovascular disease in adults, and recent literature suggests preclinical signs of cardiovascular risk are also present in depressed adolescents. No study has examined the effect of clinical depression on cardiovascular factors during sleep. This study examined the relationship between clinical depression and nocturnal indicators of cardiovascular risk in depressed adolescent girls from the general community (13-18 years old; 11 clinically depressed, eight healthy control). Continuous beat-to-beat finger arterial blood pressure and heart rate were monitored via Portapres and electrocardiogram, respectively. Cardiovascular data were averaged over each hour for the first 6 h of sleep, as well as in 2-min epochs of stable sleep that were then averaged within sleep stages. Data were also averaged across 2-min epochs of pre-sleep wakefulness and the first 5 min of continuous non-rapid eye movement sleep to investigate the blood pressure dipping response over the sleep-onset period. Compared with controls, depressed adolescents displayed a similar but significantly elevated blood pressure profile across sleep. Depressed adolescents had significantly higher systolic and diastolic blood pressure and mean arterial pressures across the entire night (P < 0.01), as well as during all sleep stages (P < 0.001). Depressed adolescents also had higher blood pressure across the sleep-onset period, but the groups did not differ in the rate of decline across the period. Higher blood pressure during sleep in depressed adolescent females suggests that depression has a significant association with cardiovascular functioning during sleep in adolescent females, which may increase risk for future cardiovascular pathology. PMID:26543013

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

    PubMed

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

    2014-04-11

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

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

    PubMed Central

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

    2014-01-01

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

  9. Strengthening the reporting of genetic risk prediction studies: the GRIPS statement.

    PubMed

    Janssens, A Cecile J W; Ioannidis, John P A; van Duijn, Cornelia M; Little, Julian; Khoury, Muin J

    2011-09-01

    • The rapid and continuing progress in gene discovery for complex diseases is fuelling 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 vary. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. • A detailed Explanation and Elaboration document is published as an accompanying article [1].

  10. Strengthening the reporting of genetic risk prediction studies: the GRIPS statement.

    PubMed

    Janssens, A Cecile J W; Ioannidis, John P A; van Duijn, Cornelia M; Little, Julian; Khoury, Muin J

    2011-04-01

    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 of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published.

  11. Traditional marijuana, high‐potency cannabis and synthetic cannabinoids: increasing risk for psychosis

    PubMed Central

    Murray, Robin M.; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta

    2016-01-01

    Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose‐response relationship between the level of use and the risk of later psychosis. High‐potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co‐administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high‐potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high‐potency cannabis and synthetic cannabinoids. PMID:27717258

  12. Traditional marijuana, high‐potency cannabis and synthetic cannabinoids: increasing risk for psychosis

    PubMed Central

    Murray, Robin M.; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta

    2016-01-01

    Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose‐response relationship between the level of use and the risk of later psychosis. High‐potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co‐administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high‐potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high‐potency cannabis and synthetic cannabinoids.

  13. ABO Blood Groups and Genetic Risk Factors for Thrombosis in Croatian Population

    PubMed Central

    Jukić, Irena; Bingulac-Popović, Jasna; Đogić, Vesna; Babić, Ivana; Culej, Jelena; Tomičić, Maja; Vuk, Tomislav; Šarlija, Dorotea; Balija, Melita

    2009-01-01

    Aim To assess the association between ABO blood group genotypes and genetic risk factors for thrombosis (FV Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations) in the Croatian population and to determine whether genetic predisposition to thrombotic risk is higher in non-OO blood group genotypes than in OO blood group genotypes. Methods The study included 154 patients with thrombosis and 200 asymptomatic blood donors as a control group. Genotyping to 5 common alleles of ABO blood groups was performed by polymerase chain reaction with sequence specific primers (PCR-SSP). FV Leiden was determined by PCR-SSP, while prothrombin and methylenetetrahydrofolate reductase were determined by PCR and restriction fragment length polymorphism (PCR-RFLP). Results There was an association between non-OO blood group genotypes and the risk of thrombosis (odds ratio [OR] 2.08, 95% confidence interval [CI], 1.32-3.27). The strongest association with thrombotic risk was recorded for A1B/A2B blood group genotypes (OR, 2.73; 95% CI, 1.10-6.74), followed by BB/O1B/O2B (OR, 2.29; 95% CI, 1.25-4.21) and O1A1/O2A1 (OR, 1.95; 95% CI, 1.15-3.31). FV Leiden increased the risk of thrombosis 31-fold in the group of OO carriers and fourfold in the group of non-OO carriers. There was no significant difference in the risk of thrombosis between OO and non-OO blood groups associated with prothrombin mutation. Non-OO carriers positive for methylenetetrahydrofolate reductase had a 5.7 times greater risk of thrombosis than that recorded in OO carriers negative for methylenetetrahydrofolate reductase. Conclusion Study results confirmed the association of non-OO blood group genotypes with an increased risk of thrombosis in Croatia. PMID:20017223

  14. Does the use of a stentless bioprosthesis increase surgical risk?

    PubMed

    Westaby, S; Jönson, A; Payne, N; Saito, S; Jin, X Y; Del Rizzo, D F; Grunkemeier, G

    2001-10-01

    Stentless aortic bioprostheses (SBPs) convey hemodynamic and perhaps survival benefit over stented counterparts. The aim of this study was to determine whether the more taxing operation increases surgical risk. We studied contemporary multicenter (USA) data submitted to the Food and Drug Administration (FDA) for Freestyle stentless (group I, n = 583) and Mosaic stented xenograft approval (group II, n = 1260). The study compared 30-day mortality for the two groups overall, then for isolated aortic valve replacement (AVR) and for AVR and coronary bypass (CABG). Because the USA Freestyle valves were used in selected patients (pts) we included SBP data (group III) from Oxford, where Freestyle valves were used consecutively within the same time frame. We also reviewed hospital mortality in the stentless bioprosthesis literature and compared this with the Society of Thoracic Surgery Database. There were no differences in age, NYHA, or incidence of CABG between the groups. There was no significant difference in operative mortality between stented (group II) and exclusive (group III) SBP patient groups (P =.233 for AVR and P =.478 for AVR + CABG), or between selective (group I) and exclusive (P =.929 for AVR and P =.390 for AVR + CABG) groups, after adjustment for risk factors. However, there was a significantly higher mortality both for isolated AVR (P =.026) and AVR + CABG (P =.001) in the selected stentless group compared with stented. This was partly attributed to greater mortality when the Freestyle was used in elderly patients by the full root replacement method, and to the higher proportion of females, and subjects with intra-aortic balloon pump insertion in this group. A meta-analysis of published stentless valve series, showed mortality rates to be lower than those of the STS National Database average. During the learning curve selective use of SBPs increased hospital mortality for AVR +/- CABG. Consecutive use dispelled the difference and the literature now

  15. Modifiable Risk Factors for Increased Arterial Stiffness in Outpatient Nephrology

    PubMed Central

    Elewa, Usama; Fernandez-Fernandez, Beatriz; Alegre, Raquel; Sanchez-Niño, Maria D.; Mahillo-Fernández, Ignacio; Perez-Gomez, Maria Vanessa; El-Fishawy, Hussein; Belal, Dawlat; Ortiz, Alberto

    2015-01-01

    Arterial stiffness, as measured by pulse wave velocity (PWV), is an independent predictor of cardiovascular events and mortality. Arterial stiffness increases with age. However, modifiable risk factors such as smoking, BP and salt intake also impact on PWV. The finding of modifiable risk factors may lead to the identification of treatable factors, and, thus, is of interest to practicing nephrologist. We have now studied the prevalence and correlates of arterial stiffness, assessed by PWV, in 191 patients from nephrology outpatient clinics in order to identify modifiable risk factors for arterial stiffness that may in the future guide therapeutic decision-making. PWV was above normal levels for age in 85/191 (44.5%) patients. Multivariate analysis showed that advanced age, systolic BP, diabetes mellitus, serum uric acid and calcium polystyrene sulfonate therapy or calcium-containing medication were independent predictors of PWV. A new parameter, Delta above upper limit of normal PWV (Delta PWV) was defined to decrease the weight of age on PWV values. Delta PWV was calculated as (measured PWV) - (upper limit of the age-adjusted PWV values for the general population). Mean±SD Delta PWV was 0.76±1.60 m/sec. In multivariate analysis, systolic blood pressure, active smoking and calcium polystyrene sulfonate therapy remained independent predictors of higher delta PWV, while age, urinary potassium and beta blocker therapy were independent predictors of lower delta PWV. In conclusion, arterial stiffness was frequent in nephrology outpatients. Systolic blood pressure, smoking, serum uric acid, calcium-containing medications, potassium metabolism and non-use of beta blockers are modifiable factors associated with increased arterial stiffness in Nephrology outpatients. PMID:25880081

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

    PubMed Central

    2012-01-01

    Introduction Clinicians use different breast cancer risk models for patients considered at average and above-average risk, based largely on their family histories and genetic factors. We used longitudinal cohort data from women whose breast cancer risks span the full spectrum to determine the genetic and nongenetic covariates that differentiate the performance of two commonly used models that include nongenetic factors - BCRAT, also called Gail model, generally used for patients with average risk and IBIS, also called Tyrer Cuzick model, generally used for patients with above-average risk. Methods We evaluated the performance of the BCRAT and IBIS models as currently applied in clinical settings for 10-year absolute risk of breast cancer, using prospective data from 1,857 women over a mean follow-up length of 8.1 years, of whom 83 developed cancer. This cohort spans the continuum of breast cancer risk, with some subjects at lower than average population risk. Therefore, the wide variation in individual risk makes it an interesting population to examine model performance across subgroups of women. For model calibration, we divided the cohort into quartiles of model-assigned risk and compared differences between assigned and observed risks using the Hosmer-Lemeshow (HL) chi-squared statistic. For model discrimination, we computed the area under the receiver operator curve (AUC) and the case risk percentiles (CRPs). Results The 10-year risks assigned by BCRAT and IBIS differed (range of difference 0.001 to 79.5). The mean BCRAT- and IBIS-assigned risks of 3.18% and 5.49%, respectively, were lower than the cohort's 10-year cumulative probability of developing breast cancer (6.25%; 95% confidence interval (CI) = 5.0 to 7.8%). Agreement between assigned and observed risks was better for IBIS (HL X42 = 7.2, P value 0.13) than BCRAT (HL X42 = 22.0, P value <0.001). The IBIS model also showed better discrimination (AUC = 69.5%, CI = 63.8% to 75.2%) than did the BCRAT model

  17. Challenges in testing genetically modified crops for potential increases in endogenous allergen expression for safety.

    PubMed

    Panda, R; Ariyarathna, H; Amnuaycheewa, P; Tetteh, A; Pramod, S N; Taylor, S L; Ballmer-Weber, B K; Goodman, R E

    2013-02-01

    Premarket, genetically modified (GM) plants are assessed for potential risks of food allergy. The major risk would be transfer of a gene encoding an allergen or protein nearly identical to an allergen into a different food source, which can be assessed by specific serum testing. The potential that a newly expressed protein might become an allergen is evaluated based on resistance to digestion in pepsin and abundance in food fractions. If the modified plant is a common allergenic source (e.g. soybean), regulatory guidelines suggest testing for increases in the expression of endogenous allergens. Some regulators request evaluating endogenous allergens for rarely allergenic plants (e.g. maize and rice). Since allergic individuals must avoid foods containing their allergen (e.g. peanut, soybean, maize, or rice), the relevance of the tests is unclear. Furthermore, no acceptance criteria are established and little is known about the natural variation in allergen concentrations in these crops. Our results demonstrate a 15-fold difference in the major maize allergen, lipid transfer protein between nine varieties, and complex variation in IgE binding to various soybean varieties. We question the value of evaluating endogenous allergens in GM plants unless the intent of the modification was production of a hypoallergenic crop. PMID:23205714

  18. Challenges in testing genetically modified crops for potential increases in endogenous allergen expression for safety.

    PubMed

    Panda, R; Ariyarathna, H; Amnuaycheewa, P; Tetteh, A; Pramod, S N; Taylor, S L; Ballmer-Weber, B K; Goodman, R E

    2013-02-01

    Premarket, genetically modified (GM) plants are assessed for potential risks of food allergy. The major risk would be transfer of a gene encoding an allergen or protein nearly identical to an allergen into a different food source, which can be assessed by specific serum testing. The potential that a newly expressed protein might become an allergen is evaluated based on resistance to digestion in pepsin and abundance in food fractions. If the modified plant is a common allergenic source (e.g. soybean), regulatory guidelines suggest testing for increases in the expression of endogenous allergens. Some regulators request evaluating endogenous allergens for rarely allergenic plants (e.g. maize and rice). Since allergic individuals must avoid foods containing their allergen (e.g. peanut, soybean, maize, or rice), the relevance of the tests is unclear. Furthermore, no acceptance criteria are established and little is known about the natural variation in allergen concentrations in these crops. Our results demonstrate a 15-fold difference in the major maize allergen, lipid transfer protein between nine varieties, and complex variation in IgE binding to various soybean varieties. We question the value of evaluating endogenous allergens in GM plants unless the intent of the modification was production of a hypoallergenic crop.

  19. Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.

    PubMed

    Maier, Robert; Moser, Gerhard; Chen, Guo-Bo; Ripke, Stephan; Coryell, William; Potash, James B; Scheftner, William A; Shi, Jianxin; Weissman, Myrna M; Hultman, Christina M; Landén, Mikael; Levinson, Douglas F; Kendler, Kenneth S; Smoller, Jordan W; Wray, Naomi R; Lee, S Hong

    2015-02-01

    Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.

  20. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

    PubMed Central

    Maier, Robert; Moser, Gerhard; Chen, Guo-Bo; Ripke, Stephan; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayés, Mònica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H.R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breen, Gerome; Breuer, René; Bruggeman, Richard; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Cormican, Paul; Corvin, Aiden; Coryell, William H.; Craddock, Nicholas; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Daly, Mark J.; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Devlin, Bernie; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Faraone, Stephen V.; Farmer, Anne E.; Ferrier, I. Nicol; Flickinger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisén, Louise; Gallagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Geschwind, Daniel H.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holmans, Peter A.; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andrés; Ising, Marcus; Jamain, Stéphane; Jones, Ian; Jones, Lisa; Kähler, Anna K.; Kahn, René S.; Kandaswamy, Radhika; Keller, Matthew C.; Kelsoe, John R.; Kendler, Kenneth S.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landén, Mikael; Långström, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lee, Phil H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A.F.; Maestrini, Elena; Magnusson, Patrik K.E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Mattheisen, Manuel; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Mowry, Bryan J.; Muglia, Pierandrea; Mühleisen, Thomas W.; Müller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Benjamin M.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Nöthen, Markus M.; Nurnberger, John I.; Nwulia, Evaristus A.; Nyholt, Dale R.; O’Donovan, Michael C.; O’Dushlaine, Colm; Oades, Robert D.; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A.; Osby, Urban; Owen, Michael J.; Palotie, Aarno; Parr, Jeremy R.; Paterson, Andrew D.; Pato, Carlos N.; Pato, Michele T.; Penninx, Brenda W.; Pergadia, Michele L.; Pericak-Vance, Margaret A.; Perlis, Roy H.; Pickard, Benjamin S.; Pimm, Jonathan; Piven, Joseph; Posthuma, Danielle; Potash, James B.; Poustka, Fritz; Propping, Peter; Purcell, Shaun M.; Puri, Vinay; Quested, Digby J.; Quinn, Emma M.; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Raychaudhuri, Soumya; Rehnström, Karola; Reif, Andreas; Ribasés, Marta; Rice, John P.; Rietschel, Marcella; Ripke, Stephan; Roeder, Kathryn; Roeyers, Herbert; Rossin, Lizzy; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R.; Sanders, Stephan J.; Santangelo, Susan L.; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F.; Scheftner, William A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J.; Sergeant, Joseph A.; Shi, Jianxin; Shilling, Paul D.; Shyn, Stanley I.; Silverman, Jeremy M.; Sklar, Pamela; Slager, Susan L.; Smalley, Susan L.; Smit, Johannes H.; Smith, Erin N.; Smoller, Jordan W.; Sonuga-Barke, Edmund J.S.; St Clair, David; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S.; Strohmaier, Jana; Stroup, T. Scott; Sullivan, Patrick F.; Sutcliffe, James; Szatmari, Peter; Szelinger, Szabocls; Thapar, Anita; Thirumalai, Srinivasa; Thompson, Robert C.; Todorov, Alexandre A.; Tozzi, Federica; Treutlein, Jens; Tzeng, Jung-Ying; Uhr, Manfred; van den Oord, Edwin J.C.G.; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M.; Vieland, Veronica J.; Vincent, John B.; Visscher, Peter M.; Walsh, Christopher A.; Wassink, Thomas H.; Watson, Stanley J.; Weiss, Lauren A.; Weissman, Myrna M.; Werge, Thomas; Wienker, Thomas F.; Wiersma, Durk; Wijsman, Ellen M.; Willemsen, Gonneke; Williams, Nigel; Willsey, A. Jeremy; Witt, Stephanie H.; Wray, Naomi R.; Xu, Wei; Young, Allan H.; Yu, Timothy W.; Zammit, Stanley; Zandi, Peter P.; Zhang, Peng; Zitman, Frans G.; Zöllner, Sebastian; Coryell, William; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Hultman, Christina M.; Landén, Mikael; Levinson, Douglas F.; Kendler, Kenneth S.; Smoller, Jordan W.; Wray, Naomi R.; Lee, S. Hong

    2015-01-01

    Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk. PMID:25640677

  1. Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.

    PubMed

    Maier, Robert; Moser, Gerhard; Chen, Guo-Bo; Ripke, Stephan; Coryell, William; Potash, James B; Scheftner, William A; Shi, Jianxin; Weissman, Myrna M; Hultman, Christina M; Landén, Mikael; Levinson, Douglas F; Kendler, Kenneth S; Smoller, Jordan W; Wray, Naomi R; Lee, S Hong

    2015-02-01

    Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk. PMID:25640677

  2. Increased risk of hepatitis E virus infection in schizophrenia.

    PubMed

    Xue, Yong; Sun, Xiaohua; Li, Yinghui; Liu, Xin; Dong, Chen

    2013-02-01

    Until now, the risk of HEV infection in schizophrenia was unknown. The present results showed that the seroprevalence of anti-HEV IgG and anti-HEV IgM in schizophrenia were significantly higher than that in healthy controls. Anti-HEV IgG positivity increased with age and with the duration of disease in schizophrenia patients. Moreover, schizophrenia patients with increased CD4(+)/CD8(+) T-cell ratios (>2.03) had higher anti-HEV IgG detection rates than those with normal ratios (1.05-2.03). Compared with the schizophrenia patients who tested anti-HEV IgG negative, the levels of interleukin-4 and interleukin-10 (Th2 cytokines) were significantly higher, while the interleukin-12 (Th1 cytokine) level was significantly lower, in those with anti-HEV IgG positivity. Of five schizophrenia patients who were anti-HEV IgM positive, four had elevated CD4(+)/CD8(+) T-cell ratios. HEV RNA was isolated from one of these four patients and classified as genotype 4. Anti-HEV IgM positivity was not detected among healthy controls. Therefore, schizophrenia patients exhibited a higher risk of HEV infection than controls. PMID:23053523

  3. Geometrical factors as predictors of increased growth rate or increased rupture risk in small aortic aneurysms.

    PubMed

    Georgakarakos, Efstratios; Ioannou, Christos V

    2012-07-01

    Abdominal Aortic Aneurysms (AAAs) are focal dilation of the aorta that can lead to excessive enlargement and rupture over time. Current practice suggests intervention when the maximum diameter exceeds 5.5 cm, since in this diameter range the annual rupture risk outweighs the operative mortality. However, small AAA (<5.5 cm), though infrequently, may rupture or produce symptoms. Evidence from large randomized studies of small AAAs support the heterogeneity in patterns of growth and rupture potential among small AAAs. Elevated wall stress values have been implicated in AAAs rupture and rapid enlargement. Additionally, many studies have identified a strong correlation between certain geometric factors and elevated stress values. In this article we discuss the possibility that geometrical factors may have a predictive value to identify those small AAAs that have an increased risk of rupture or growth rate either during initial examination or during follow-up, making them amenable for early repair. PMID:22541859

  4. Genetic risk prediction and neurobiological understanding of alcoholism.

    PubMed

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

    2014-05-20

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

  5. Genetic evidence that culling increases badger movement: implications for the spread of bovine tuberculosis.

    PubMed

    Pope, Lisa C; Butlin, Roger K; Wilson, Gavin J; Woodroffe, Rosie; Erven, Kristien; Conyers, Chris M; Franklin, Tanya; Delahay, Richard J; Cheeseman, Chris L; Burke, Terry

    2007-12-01

    The Eurasian badger (Meles meles) has been implicated in the transmission of bovine tuberculosis (TB, caused by Mycobacterium bovis) to cattle. However, evidence suggests that attempts to reduce the spread of TB among cattle in Britain by culling badgers have mixed effects. A large-scale field experiment (the randomized badger culling trial, RBCT) showed that widespread proactive badger culling reduced the incidence of TB in cattle within culled areas but that TB incidence increased in adjoining areas. Additionally, localized reactive badger culling increased the incidence of TB in cattle. It has been suggested that culling-induced perturbation of badger social structure may increase individual movements and elevate the risk of disease transmission between badgers and cattle. Field studies support this hypothesis, by demonstrating increases in badger group ranges and the prevalence of TB infection in badgers following culling. However, more evidence on the effect of culling on badger movements is needed in order to predict the epidemiological consequences of this control strategy. Here, analysis of the genetic signatures of badger populations in the RBCT revealed increased dispersal following culling. While standard tests provided evidence for greater dispersal after culling, a novel method indicated that this was due to medium- and long-distance dispersal, in addition to previously reported increases in home-range size. Our results also indicated that, on average, badgers infected with M. bovis moved significantly farther than did uninfected badgers. A disease control strategy that included culling would need to take account of the potentially negative epidemiological consequences of increased badger dispersal. PMID:17944854

  6. Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach

    PubMed Central

    Lee, Eunjung; Hsu, Chris; Haiman, Christopher A.; Razavi, Pedram; Horn-Ross, Pamela L.; Van Den Berg, David; Bernstein, Leslie; Le Marchand, Loic; Henderson, Brian E.; Setiawan, V. Wendy; Ursin, Giske

    2010-01-01

    Background: It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. The PROGINS allele of the progesterone receptor (PGR) gene reduces the function of PGR and has been associated with increased risk of the endometrioid type ovarian cancer. We investigated whether genetic variation in PGR is also associated with endometrial cancer risk using a haplotype-based approach. Methods: We pooled data from two endometrial cancer case–control studies that were nested within two prospective cohorts, the Multiethnic Cohort Study and the California Teachers Study. Seventeen haplotype-tagging single nucleotide polymorphisms (SNPs) across four linkage disequilibrium (LD) blocks spanning the PGR locus were genotyped in 583 incident cases and 1936 control women. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each haplotype were estimated using conditional logistic regression, stratified by age and ethnicity. Results: Genetic variation in LD block 3 of the PGR locus was associated with endometrial cancer risk (Pglobal test = 0.002), with haplotypes 3C, 3D and 3F associated with 31–34% increased risk. Among whites (383 cases/840 controls), genetic variation in all four blocks was associated with increased endometrial cancer risk (Pglobal test = 0.010, 0.013, 0.005 and 0.020). Haplotypes containing the PROGINS allele and several haplotypes in blocks 1, 3 and 4 were associated with 34–77% increased risk among whites. SNP analyses for whites suggested that rs608995, partially linked to the PROGINS allele (r2 = 0.6), was associated with increased risk (OR = 1.30, 95% CI = 1.06–1.59). Conclusions: Our results suggest that genetic variation in the PGR region is associated with endometrial cancer risk. PMID:20547493

  7. Dopamine and serotonin genetic risk scores predicting substance and nicotine use in attention deficit/hyperactivity disorder.

    PubMed

    Groenman, Annabeth P; Greven, Corina U; van Donkelaar, Marjolein M J; Schellekens, Arnt; van Hulzen, Kimm J E; Rommelse, Nanda; Hartman, Catharina A; Hoekstra, Pieter J; Luman, Marjolein; Franke, Barbara; Faraone, Stephen V; Oosterlaan, Jaap; Buitelaar, Jan K

    2016-07-01

    Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders. PMID:25752199

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

    PubMed

    Wootton, J Timothy; Pfister, Catherine A

    2013-10-01

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

  9. Comorbidity increases the risk of hospitalizations in multiple sclerosis

    PubMed Central

    Elliott, Lawrence; Marriott, James; Cossoy, Michael; Tennakoon, Aruni; Yu, Nancy

    2015-01-01

    Objective: We aimed to evaluate the association between comorbidity and rates of hospitalization in the multiple sclerosis (MS) population as compared to a matched cohort from the general population. Methods: Using population-based administrative data from the Canadian province of Manitoba, we identified 4,875 persons with MS and a matched general population cohort of 24,533 persons. We identified all acute care hospitalizations in the period 2007–2011. Using general linear models, we evaluated the association between comorbidity status and hospitalization rates (all-cause, non-MS-related, MS-related) in the 2 populations, adjusting for age, sex, and socioeconomic status. Results: Comorbidity was common in both cohorts. Over the 5-year study period, the MS population had a 1.5-fold higher hospitalization rate (adjusted rate ratio [aRR] 1.56; 95% confidence interval [CI] 1.44–1.68) than the matched population. Any comorbidity was associated with a 2-fold increased risk of non-MS-related hospitalization rates (aRR 2.21; 95% CI 1.73–2.82) in the MS population, but a nearly 4-fold increase in hospitalization rates in the matched population (aRR 3.85; 95% CI 3.40–4.35). Comorbidity was not associated with rates of hospitalization for MS-related reasons, regardless of how comorbidity status was defined. Conclusions: In the MS population, comorbidity is associated with an increased risk of all-cause hospitalizations, suggesting that the prevention and management of comorbidity may reduce hospitalizations. PMID:25540309

  10. BRCA genetic counseling among at-risk Latinas in New York City: new beliefs shape new generation.

    PubMed

    Sussner, Katarina M; Edwards, Tiffany; Villagra, Cristina; Rodriguez, M Carina; Thompson, Hayley S; Jandorf, Lina; Valdimarsdottir, Heiddis B

    2015-02-01

    Despite the life-saving information that genetic counseling can provide for women at hereditary breast and/or ovarian cancer (HBOC) risk, Latinas disproportionately underuse such services. Understanding Latinas' beliefs and attitudes about BRCA genetic counseling may be the key to better health promotion within this underserved, at-risk group. We conducted 12 focus groups (N = 54) with at-risk Latina women in New York City, followed by 30 in-depth interviews among a subset of the focus group women. Both were professionally transcribed, translated where applicable and data analysis was completed by two coders trained in qualitative methods. Results revealed personal and community knowledge about BRCA genetic counseling was relatively low, although women felt largely positive about counseling. The main motivator to undergo genetic counseling was concerns about learning family members' cancer status, while the main barrier was competing demands. Generational differences were apparent, with younger women (approximately <55 years) reporting that they were more interested in educating themselves about counseling and other ways to prevent cancer. Younger women were also less likely to ascribe to traditionally Latino-centered cultural beliefs which could serve as barriers (e.g. machismo, fatalismo, destino) to undergoing genetic counseling. Participants were largely enthusiastic about educational efforts to increase awareness of genetic counseling among Latinos. Revealing the beliefs and attitudes of underserved Latinas may help shape culturally appropriate educational materials and promotion programs to increase BRCA genetic counseling uptake within this underrepresented community.

  11. BRCA Genetic Counseling Among At-Risk Latinas in New York City: New Beliefs Shape New Generation

    PubMed Central

    Edwards, Tiffany; Villagra, Cristina; Rodriguez, M. Carina; Thompson, Hayley S.; Jandorf, Lina; Valdimarsdottir, Heiddis B.

    2015-01-01

    Despite the life-saving information that genetic counseling can provide for women at hereditary breast and/or ovarian cancer (HBOC) risk, Latinas disproportionately underuse such services. Understanding Latinas’ beliefs and attitudes about BRCA genetic counseling may be the key to better health promotion within this underserved, at-risk group. We conducted 12 focus groups (N=54) with at-risk Latina women in New York City, followed by 30 in-depth interviews among a subset of the focus group women. Both were professionally transcribed, translated where applicable and data analysis was completed by two coders trained in qualitative methods. Results revealed personal and community knowledge about BRCA genetic counseling was relatively low, although women felt largely positive about counseling. The main motivator to undergo genetic counseling was concerns about learning family members’ cancer status, while the main barrier was competing demands. Generational differences were apparent, with younger women (approximately <55 years) reporting that they were more interested in educating themselves about counseling and other ways to prevent cancer. Younger women were also less likely to ascribe to traditionally Latino-centered cultural beliefs which could serve as barriers (e.g. machismo, fatalismo, destino) to undergoing genetic counseling. Participants were largely enthusiastic about educational efforts to increase awareness of genetic counseling among Latinos. Revealing the beliefs and attitudes of underserved Latinas may help shape culturally appropriate educational materials and promotion programs to increase BRCA genetic counseling uptake within this under-represented community. PMID:25120034

  12. Calcium intake increases risk of prostate cancer among Singapore Chinese

    PubMed Central

    Butler, Lesley M.; Wong, Alvin S.; Koh, Woon-Puay; Wang, Renwei; Yuan, Jian-Min; Yu, Mimi C.

    2010-01-01

    Consumption of dairy products, the primary source of calcium in Western diets, has been found to be positively associated with prostate cancer. In an Asian diet, non-dairy foods are the major contributors of calcium. Thus, a study of dietary calcium and prostate cancer in Asians can better inform on whether calcium, as opposed to other dairy components is responsible for the dairy foods-prostate cancer association. We examined calcium intake and prostate cancer risk among 27,293 men of the Singapore Chinese Health Study that was established between 1993 and 1998. As of December 31, 2007, 298 incident prostate cancer cases had been diagnosed among the cohort members. Diet was assessed at baseline with a validated 165-item food frequency questionnaire. It is hypothesized that there is greater net absorption of calcium in smaller individuals. Therefore, the calcium-prostate cancer association was also assessed in stratified analyses by median body mass index (BMI). Vegetables were the largest contributor of daily calcium intake in the study population. Overall, we observed a modest, statistically nonsignificant 25% increase in prostate cancer risk for the 4th (median = 659 mg/day) versus 1st (median=211 mg/day) quartiles of calcium intake after adjustment for potential confounders. The association became considerably stronger and achieved statistical significance (hazard ratio=2.03; 95% confidence interval: 1.23, 3.34; P for trend=0.01) for men with below median (22.9 kg/m2) BMI. Dietary calcium may be a risk factor for prostate cancer even at relatively low intake. PMID:20516117

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

    PubMed Central

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

    2016-01-01

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

  14. Genetic Addiction Risk Score (GARS): molecular neurogenetic evidence for predisposition to Reward Deficiency Syndrome (RDS).

    PubMed

    Blum, Kenneth; Oscar-Berman, Marlene; Demetrovics, Zsolt; Barh, Debmalya; Gold, Mark S

    2014-12-01

    We have published extensively on the neurogenetics of brain reward systems with reference to the genes related to dopaminergic function in particular. In 1996, we coined "Reward Deficiency Syndrome" (RDS), to portray behaviors found to have gene-based association with hypodopaminergic function. RDS as a useful concept has been embraced in many subsequent studies, to increase our understanding of Substance Use Disorder (SUD), addictions, and other obsessive, compulsive, and impulsive behaviors. Interestingly, albeit others, in one published study, we were able to describe lifetime RDS behaviors in a recovering addict (17 years sober) blindly by assessing resultant Genetic Addiction Risk Score (GARS™) data only. We hypothesize that genetic testing at an early age may be an effective preventive strategy to reduce or eliminate pathological substance and behavioral seeking activity. Here, we consider a select number of genes, their polymorphisms, and associated risks for RDS whereby, utilizing GWAS, there is evidence for convergence to reward candidate genes. The evidence presented serves as a plausible brain-print providing relevant genetic information that will reinforce targeted therapies, to improve recovery and prevent relapse on an individualized basis. The primary driver of RDS is a hypodopaminergic trait (genes) as well as epigenetic states (methylation and deacetylation on chromatin structure). We now have entered a new era in addiction medicine that embraces the neuroscience of addiction and RDS as a pathological condition in brain reward circuitry that calls for appropriate evidence-based therapy and early genetic diagnosis and that requires further intensive investigation.

  15. Increased risk of ischemic stroke in patients with pneumoconiosis.

    PubMed

    Cheng, Yuan-Yang; Hsu, Kuo-Hsuan; Chen, Yi-Huei; Lin, Ching-Heng

    2015-02-01

    Although past studies have confirmed that chronic dust exposure is a risk factor for cardiovascular disease, the relationship between it and cerebrovascular disease is still unclear. We aimed to determine whether pneumoconiosis is related to increased incidence of ischemic stroke in the following 5 to 11 years. We selected 1238 patients with pneumoconiosis from Taiwan's National Health Insurance database as our study cohort. After matching for age, sex and the date of ambulatory care visit, another 4952 patients without pneumoconiosis were selected as the comparison cohort. Each patient was individually followed up until the end of 2010 to track the incidence of stroke, and Cox proportional hazard regression analysis was performed to compute the relative hazard ratio of stroke. Our results showed 19.6% of pneumoconiosis patients and 15.8% of non-pneumoconiosis patients developed stroke. After statistically adjusting for age, sex, and medical comorbidities, the hazard of developing stroke was 1.36 times greater for those with pneumoconiosis compared to those without. Even in those with pneumoconiosis excluding chronic obstructive pulmonary disease, the hazard of developing stroke was still 1.31 times greater than those without pneumoconiosis. Our study revealed that pneumoconiosis patients are at a higher risk of ischemic stroke, and primary prevention of stroke is particularly important in this group of patients.

  16. Risk Factors Associated with Increased Morbidity in Living Liver Donation

    PubMed Central

    Candido, Helry L.; da Fonseca, Eduardo A.; Feier, Flávia H.; Pugliese, Renata; Benavides, Marcel A.; Silva, Enis D.; Gordon, Karina; de Abreu, Marcelo Gama; Canet, Jaume; Chapchap, Paulo; Neto, Joao Seda

    2015-01-01

    Living donor liver donation (LDLD) is an alternative to cadaveric liver donation. We aimed at identifying risk factors and developing a score for prediction of postoperative complications (POCs) after LDLD in donors. This is a retrospective cohort study in 688 donors between June 1995 and February 2014 at Hospital Sírio-Libanês and A.C. Camargo Cancer Center, in São Paulo, Brazil. Primary outcome was POC graded ≥III according to the Clavien-Dindo classification. Left lateral segment (LLS), left lobe (LL), and right lobe resections (RL) were conducted in 492 (71.4%), 109 (15.8%), and 87 (12.6%) donors, respectively. In total, 43 (6.2%) developed POCs, which were more common after RL than LLS and LL (14/87 (16.1%) versus 23/492 (4.5%) and 6/109 (5.5%), resp., p < 0.001). Multivariate analysis showed that RL resection (OR: 2.81, 95% CI: 1.32 to 3.01; p = 0.008), smoking status (OR: 3.2, 95% CI: 1.35 to 7.56; p = 0.012), and blood transfusion (OR: 3.15, 95% CI: 1.45 to 6.84; p = 0.004) were independently associated with POCs. RL resection, intraoperative blood transfusion, and smoking were associated with increased risk for POCs in donors. PMID:26788361

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

    PubMed

    Bawa, A S; Anilakumar, K R

    2013-12-01

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

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

    PubMed

    Bawa, A S; Anilakumar, K R

    2013-12-01

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

  19. [Genetics of late-onset Alzheimer's disease: vascular risk and beta-amyloid metabolism].

    PubMed

    Panza, Francesco; Solfrizzi, Vincenzo; D'Introno, Alessia; Capurso, Cristiano; Colacicco, Anna Maria; Torres, Francesco; Altomare, Emanuele; Capurso, Antonio

    2002-09-01

    Progress in clinical and basic research of Alzheimer's disease (AD) suggested theoretical models of possible pathogenetic mechanisms, with a primary role of the genetic factors that have been implicated in AD. These can be divided into two main categories. First, the three genes in which mutations are known to result in early onset autosomal dominant familial AD (presenilins 1 and 2, and amyloid beta protein precursor [APP]): well characterized but that account for only a small proportion of AD cases. Secondly, late onset, sporadic AD is more common and evidence suggests that there is a genetic component to this type of disease. A number of genetic risk factors have been implicated that might increase the risk of developing sporadic disease: particularly, apolipoprotein E (apo E) polymorphism and many others suggested by linkage studies [alpha-macroglobulin, low density receptor protein (LRP1), bleomycin hydrolase], with a precise role in beta-amyloid metabolism and deposition. Many of these are controversial and studies have shown conflicting results, but apoE polymorphism seems to be only one of the possible genetic factors suggested to play a role in the multifactoral pathogenesis of AD. Regional and ethnic differences may affect the strength of association between apoE epsilon 4 allele and the disease, and we reported evidences of the decreasing frequency of epsilon 4 allele in AD patients and centenarians from Northern to Southern European regions. Finally, several genetic risk factors of vascular origin (angiotensin converting enzyme, methyltetrahydropholate-reductase, and NOS3 gene polymorphisms) have been implicated in the development of both vascular dementia and AD with conflicting results.

  20. Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis

    PubMed Central

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

    2015-01-01

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

  1. Extinction risk and eco-evolutionary dynamics in a variable environment with increasing frequency of extreme events

    PubMed Central

    Vincenzi, Simone

    2014-01-01

    One of the most dramatic consequences of climate change will be the intensification and increased frequency of extreme events. I used numerical simulations to understand and predict the consequences of directional trend (i.e. mean state) and increased variability of a climate variable (e.g. temperature), increased probability of occurrence of point extreme events (e.g. floods), selection pressure and effect size of mutations on a quantitative trait determining individual fitness, as well as the their effects on the population and genetic dynamics of a population of moderate size. The interaction among climate trend, variability and probability of point extremes had a minor effect on risk of extinction, time to extinction and distribution of the trait after accounting for their independent effects. The survival chances of a population strongly and linearly decreased with increasing strength of selection, as well as with increasing climate trend and variability. Mutation amplitude had no effects on extinction risk, time to extinction or genetic adaptation to the new climate. Climate trend and strength of selection largely determined the shift of the mean phenotype in the population. The extinction or persistence of the populations in an ‘extinction window’ of 10 years was well predicted by a simple model including mean population size and mean genetic variance over a 10-year time frame preceding the ‘extinction window’, although genetic variance had a smaller role than population size in predicting contemporary risk of extinction. PMID:24920116

  2. Extinction risk and eco-evolutionary dynamics in a variable environment with increasing frequency of extreme events.

    PubMed

    Vincenzi, Simone

    2014-08-01

    One of the most dramatic consequences of climate change will be the intensification and increased frequency of extreme events. I used numerical simulations to understand and predict the consequences of directional trend (i.e. mean state) and increased variability of a climate variable (e.g. temperature), increased probability of occurrence of point extreme events (e.g. floods), selection pressure and effect size of mutations on a quantitative trait determining individual fitness, as well as the their effects on the population and genetic dynamics of a population of moderate size. The interaction among climate trend, variability and probability of point extremes had a minor effect on risk of extinction, time to extinction and distribution of the trait after accounting for their independent effects. The survival chances of a population strongly and linearly decreased with increasing strength of selection, as well as with increasing climate trend and variability. Mutation amplitude had no effects on extinction risk, time to extinction or genetic adaptation to the new climate. Climate trend and strength of selection largely determined the shift of the mean phenotype in the population. The extinction or persistence of the populations in an 'extinction window' of 10 years was well predicted by a simple model including mean population size and mean genetic variance over a 10-year time frame preceding the 'extinction window', although genetic variance had a smaller role than population size in predicting contemporary risk of extinction.

  3. Genetic Factors That Increase Male Facial Masculinity Decrease Facial Attractiveness of Female Relatives

    PubMed Central

    Lee, Anthony J.; Mitchem, Dorian G.; Wright, Margaret J.; Martin, Nicholas G.; Keller, Matthew C.; Zietsch, Brendan P.

    2014-01-01

    For women, choosing a facially masculine man as a mate is thought to confer genetic benefits to offspring. Crucial assumptions of this hypothesis have not been adequately tested. It has been assumed that variation in facial masculinity is due to genetic variation and that genetic factors that increase male facial masculinity do not increase facial masculinity in female relatives. We objectively quantified the facial masculinity in photos of identical (n = 411) and nonidentical (n = 782) twins and their siblings (n = 106). Using biometrical modeling, we found that much of the variation in male and female facial masculinity is genetic. However, we also found that masculinity of male faces is unrelated to their attractiveness and that facially masculine men tend to have facially masculine, less-attractive sisters. These findings challenge the idea that facially masculine men provide net genetic benefits to offspring and call into question this popular theoretical framework. PMID:24379153

  4. Genetic factors that increase male facial masculinity decrease facial attractiveness of female relatives.

    PubMed

    Lee, Anthony J; Mitchem, Dorian G; Wright, Margaret J; Martin, Nicholas G; Keller, Matthew C; Zietsch, Brendan P

    2014-02-01

    For women, choosing a facially masculine man as a mate is thought to confer genetic benefits to offspring. Crucial assumptions of this hypothesis have not been adequately tested. It has been assumed that variation in facial masculinity is due to genetic variation and that genetic factors that increase male facial masculinity do not increase facial masculinity in female relatives. We objectively quantified the facial masculinity in photos of identical (n = 411) and nonidentical (n = 782) twins and their siblings (n = 106). Using biometrical modeling, we found that much of the variation in male and female facial masculinity is genetic. However, we also found that masculinity of male faces is unrelated to their attractiveness and that facially masculine men tend to have facially masculine, less-attractive sisters. These findings challenge the idea that facially masculine men provide net genetic benefits to offspring and call into question this popular theoretical framework.

  5. Analysis of factors that increase motorcycle rider risk compared to car driver risk.

    PubMed

    Keall, Michael D; Newstead, Stuart

    2012-11-01

    As in other parts of the Western world, there is concern in New Zealand about increasing popularity of motorcycles because of potential increases in road trauma. This study sought to identify important factors associated with increased risk for motorcyclists to inform potential policy approaches to reduce motorcyclist injury, such as changes to motorcyclist licensing, training and education. Using data extracted from a register of all New Zealand licensed motor vehicles that were matched to crash data, statistical models were fitted to examine patterns of motorcycle risk in comparison with small cars. These showed generally elevated risks for motorcyclists compared to cars, but particularly elevated risks for motorcycle owners aged in their 20s or who lived in more urbanised settings. In crashes, motorcyclists have little protection from injury, putting the motorcyclist at high risk of injury. When comparing new motorcycles with new cars, the odds of fatal or serious injury to a motorcycle rider involved in an injury crash were almost eight times the odds for a car driver.

  6. Increasing water temperature and disease risks in aquatic systems: climate change increases the risk of some, but not all, diseases.

    PubMed

    Karvonen, Anssi; Rintamäki, Päivi; Jokela, Jukka; Valtonen, E Tellervo

    2010-11-01

    Global warming may impose severe risks for aquatic animal health if increasing water temperature leads to an increase in the incidence of parasitic diseases. Essentially, this could take place through a temperature-driven effect on the epidemiology of the disease. For example, higher temperature may boost the rate of disease spread through positive effects on parasite fitness in a weakened host. Increased temperature may also lengthen the transmission season leading to higher total prevalence of infection and more widespread epidemics. However, to date, general understanding of these relationships is limited due to scarcity of long-term empirical data. Here, we present one of the first long-term multi-pathogen data sets on the occurrence of pathogenic bacterial and parasitic infections in relation to increasing temperatures in aquatic systems. We analyse a time-series of disease dynamics on two fish farms in northern Finland from 1986 to 2006. We first demonstrate that the annual mean water temperature increased significantly on both farms over the study period and that the increase was most pronounced in the late summer (July-September). Second, we show that the prevalence of infection (i.e. proportion of fish tanks infected each year) increased with temperature. Interestingly, this pattern was observed in some of the diseases (Ichthyophthirius multifiliis, Flavobacterium columnare), whereas in the other diseases, the pattern was the opposite (Ichthyobodo necator) or absent (Chilodonella spp.). These results demonstrate the effect of increasing water temperature on aquatic disease dynamics, but also emphasise the importance of the biology of each disease, as well as the role of local conditions, in determining the direction and magnitude of these effects.

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

    PubMed

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

    2016-01-01

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

  8. Risk factors for increased BTEX exposure in four Australian cities.

    PubMed

    Hinwood, Andrea L; Rodriguez, Clemencia; Runnion, Tina; Farrar, Drew; Murray, Frank; Horton, Anthony; Glass, Deborah; Sheppeard, Vicky; Edwards, John W; Denison, Lynnette; Whitworth, Tom; Eiser, Chris; Bulsara, Max; Gillett, Rob W; Powell, Jenny; Lawson, S; Weeks, Ian; Galbally, Ian

    2007-01-01

    Benzene, toluene, ethylbenzene and xylenes (BTEX) are common volatile organic compounds (VOCs) found in urban airsheds. Elevated levels of VOCs have been reported in many airsheds at many locations, particularly those associated with industrial activity, wood heater use and heavy traffic. Exposure to some VOCs has been associated with health risks. There have been limited investigations into community exposures to BTEX using personal monitoring to elucidate the concentrations to which members of the community may be exposed and the main contributors to that exposure. In this cross sectional study we investigated BTEX exposure of 204 non-smoking, non-occupationally exposed people from four Australian cities. Each participant wore a passive BTEX sampler over 24h on five consecutive days in both winter and summer and completed an exposure source questionnaire for each season and a diary for each day of monitoring. The geometric mean (GM) and range of daily BTEX concentrations recorded for the study population were benzene 0.80 (0.04-23.8 ppb); toluene 2.83 (0.03-2120 ppb); ethylbenzene 0.49 (0.03-119 ppb); and xylenes 2.36 (0.04-697 ppb). A generalised linear model was used to investigate significant risk factors for increased BTEX exposure. Activities and locations found to increase personal exposure included vehicle repair and machinery use, refuelling of motor vehicles, being in an enclosed car park and time spent undertaking arts and crafts. A highly significant difference was found between the mean exposures in each of the four cities, which may be explained by differences in fuel composition, differences in the mix and density of industry, density of motor vehicles and air pollution meteorology. PMID:16837022

  9. Increased Risk of Postthoracotomy Pain Syndrome in Patients with Prolonged Hospitalization and Increased Postoperative Opioid Use

    PubMed Central

    Jacob, Adam K.; Passe, Melissa A.; Mantilla, Carlos B.

    2016-01-01

    Background. Postthoracotomy pain syndrome (PTPS) is unfortunately very common following thoracotomy and results in decreased quality of life. The purpose of this retrospective study was to determine perioperative patient, surgical, and analgesic characteristics associated with the development of PTPS. Methods. Sixty-six patients who presented to the Mayo Clinic Rochester Pain Clinic were diagnosed with PTPS 2 months or more after thoracotomy with postoperative epidural analgesia. These patients were matched with sixty-six control patients who underwent thoracotomy with postoperative epidural analgesia and were never diagnosed with PTPS. Results. Median (IQR) hospital stay was significantly different between control patients (5 days (4, 6)) compared with PTPS patients (6 days (5, 8)), P < 0.02. The total opioid equivalent utilized in oral morphine equivalents in milligrams for the first three days postoperatively was significantly different between control patients and PTPS patients. The median (IQR) total opioid equivalent utilized was 237 (73, 508) for controls and 366 (116, 874) for PTPS patients (P < 0.005). Conclusion. Patients with a prolonged hospital stay after thoracotomy were at an increased risk of developing PTPS, and this is a novel finding. Patients who utilize higher oral morphine equivalents for the first 3 days were also at increased risk for PTPS. PMID:27340565

  10. Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors.

    PubMed

    Jaju, Prajakta D; Ransohoff, Katherine J; Tang, Jean Y; Sarin, Kavita Y

    2016-03-01

    Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease.

  11. Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors.

    PubMed

    Jaju, Prajakta D; Ransohoff, Katherine J; Tang, Jean Y; Sarin, Kavita Y

    2016-03-01

    Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease. PMID:26892653

  12. Celtic ancestry, HLA phenotype and increased risk of skin cancer.

    PubMed

    Long, C C; Darke, C; Marks, R

    1998-04-01

    Individuals of Celtic ancestry are claimed to be at greater risk of skin cancer than non-Celts, and various positive and negative associations between certain human leucocyte antigen (HLA) phenotypes and the development of skin cancer have been described. The aims of this study were to determine whether any HLA phenotypes are associated either with Celtic or non-Celtic ancestry, or skin type. One thousand and ten members of the Welsh Bone Marrow Donor Registry (WBMDR), whose HLA phenotypes are known, were asked to complete a questionnaire which enquired as to their family origins and their 'Index of Celtic Ancestry' scored out of 12. Three groups were identified: non-Celts (score < 3), Celts (score > 9), and a subset of the Celts--'high scoring' Celts (score > 10). Details of hair and eye colour and skin type were also requested. Skin type and HLA-A, -B, -DR and -DQ frequencies were compared between the three groups (Celts, non-Celts and 'high scoring' Celts), and a random indigenous population of 9196 members of the WBMDR. Seven hundred and thirty-six replies were received (279 male, 457 female, mean age 31 years). One hundred and forty-four Celts, 51 'high scoring' Celts and 170 non-Celts were identified. Forty-six (32%) Celts had skin type I or II compared with 36 (21%) non-Celts (P = 0.039), and 37 (73%) 'high scoring' Celts had skin type I or II (P < 0.0001). However, there were no significant differences between the groups with regard to hair colour, eye colour or number of episodes of painful sunburn. The frequency of HLA-DR4 was 32% in the non-Celtic group, 44% in the Celtic group (not significant), and 53% in the 'high scoring' Celts (P = 0.008). However, the difference was not significant after correction. There were no significant associations between skin type and HLA phenotype. HLA-DR4 is known to be associated with an increased risk of both basal cell carcinoma and malignant melanoma and its increased frequency in Celts may be an independent risk

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

    PubMed

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

    2015-09-01

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

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

    PubMed

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

    2003-08-01

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

  15. Increased Flooding Risk - Accelerating Threat and Stakeholder Response

    NASA Astrophysics Data System (ADS)

    Atkinson, L. P.; Ezer, T.; De Young, R.; McShane, M. K.; McFarlane, B.

    2012-12-01

    projects, and "…subsidence …. is not well-documented". Studies sponsored by the City of Norfolk for example suggest massive tidal barriers. Flood insurance - Flood insurance is available only from the National Flood Insurance Program (NFIP), not from private insurers. NFIP has a current deficit of about 18B, which is estimated to increase by about 2B annually. The rates are subsidized and do not reflect the true risk of coastal flooding and do not incorporate the likelihood of future sea-level rise. In effect, the subsidy promotes increased building on the coast, leading to increased deficits in the tax-payer financed program. Risk-based flood insurance pricing would lead to less coastal development, therefore decreasing the tax base of the community. Stakeholder needs - Planning for increased flooding due to sea level rise extends 50 to 100 years given the lifetime of infrastructure. Planners need guidance and error estimates. To make adequate predictions for users we must understand the various components of sea level rise including subsidence, global sea level rise and regional and local dynamic sea level rise. Predictions of regional sea level rise will be presented in the context of existing infrastructure such as NASA research facilities and the city of Norfolk, Virginia.

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

    PubMed Central

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

    2009-01-01

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

  17. Genetic principles and methods in high-risk studies of schizophrenia.

    PubMed

    Cloninger, C R

    1987-01-01

    Recent advances in genetic epidemiology present excellent opportunities for future high-risk studies of schizophrenia. Improved methods are now available for specifying the natural boundaries of the schizophrenia spectrum and evaluating the mode of inheritance of schizophrenia and its biosocial risk factors. Path-analytic techniques permit the derivation of multifactor indices of both biological and social antecedents of schizophrenia. Powerful advances have been made in segregation analysis of pedigree data and in the power of linkage tests with DNA markers to confirm the presence of putative major loci that influence susceptibility to complex phenotypes like schizophrenia. The yield of information from high-risk samples is greatly increased when both longitudinal and pedigree analyses are combined.

  18. Extreme Geohazards: Reducing Disaster Risk and Increasing Resilience

    NASA Astrophysics Data System (ADS)

    Plag, Hans-Peter; Stein, Seth; Brocklebank, Sean; Jules-Plag, Shelley; Campus, Paola

    2014-05-01

    Extreme natural hazards have the potential to cause global disasters and to lead to an escalation of the global sustainability crisis. Floods and droughts pose threats that could reach planetary extent, particularly through secondary economic and social impacts. Earthquakes and tsunamis cause disasters that could exceed the immediate coping capacity of the global economy, particularly in hazardous areas containing megacities, that can be particularly vulnerable to natural hazards if proper emergency protocols and infrastructures are not set in place. Recent events illustrate the destruction extreme hazards can inflict, both directly and indirectly, through domino effects resulting from the interaction with the built environment. Unfortunately, the more humanity learns to cope with relatively frequent (50 to 100 years) natural hazard events, the less concerns remain about the low-probability (one in a few hundred or more years) high-impact events. As a consequence, threats from low-probability extreme floods, droughts, and volcanic eruptions are not appropriately accounted for in Disaster Risk Reduction (DRR) discussions. With the support of the European Science Foundation (ESF), the Geohazards Community of Practice (GHCP) of the Group on Earth Observations (GEO) has developed a White Paper (WP) on the risk associated with low-probability, high-impact geohazards. These events are insufficiently addressed in risk management, although their potential impacts are comparable to those of a large asteroid impact, a global pandemic, or an extreme drought. The WP aims to increase awareness of the risk associated with these events as a basis for a comprehensive risk management. Extreme geohazards have occurred regularly throughout the past, but mostly did not cause major disasters because the exposure of human assets to such hazards and the global population density were much lower than today. The most extreme events during the last 2,000 years would cause today unparalleled

  19. Genetic risk prediction and neurobiological understanding of alcoholism

    PubMed Central

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

    2014-01-01

    We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse

  20. Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

    PubMed Central

    Jansen, Henning; Loley, Christina; Lieb, Wolfgang; Pencina, Michael J; Nelson, Christopher P; Kathiresan, Sekar; Peloso, Gina M; Voight, Benjamin F; Reilly, Muredach P; Assimes, Themistocles L; Boerwinkle, Eric; Hengstenberg, Christian; Laaksonen, Reijo; McPherson, Ruth; Roberts, Robert; Thorsteinsdottir, Unnur; Peters, Annette; Gieger, Christian; Rawal, Rajesh; Thompson, John R; König, Inke R; Vasan, Ramachandran S; Erdmann, Jeanette; Samani, Nilesh J; Schunkert, Heribert

    2015-01-01

    Background The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. Methods and Results We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p<5*10−8) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p<0.05), more than expected by chance (p=5.0*10−5). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973–1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p=7.2*10−10 vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. Conclusions Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting. PMID:26074316

  1. Genetics, Genomics and Cancer Risk Assessment: State of the art and future directions in the era of personalized medicine

    PubMed Central

    Weitzel, Jeffrey N.; Blazer, Kathleen R.; MacDonald, Deborah J.; Culver, Julie O.; Offit, Kenneth

    2012-01-01

    Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently-discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease-risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine. PMID:21858794

  2. Plant genetic resources: what can they contribute toward increased crop productivity?

    PubMed

    Hoisington, D; Khairallah, M; Reeves, T; Ribaut, J M; Skovmand, B; Taba, S; Warburton, M

    1999-05-25

    To feed a world population growing by up to 160 people per minute, with >90% of them in developing countries, will require an astonishing increase in food production. Forecasts call for wheat to become the most important cereal in the world, with maize close behind; together, these crops will account for approximately 80% of developing countries' cereal import requirements. Access to a range of genetic diversity is critical to the success of breeding programs. The global effort to assemble, document, and utilize these resources is enormous, and the genetic diversity in the collections is critical to the world's fight against hunger. The introgression of genes that reduced plant height and increased disease and viral resistance in wheat provided the foundation for the "Green Revolution" and demonstrated the tremendous impact that genetic resources can have on production. Wheat hybrids and synthetics may provide the yield increases needed in the future. A wild relative of maize, Tripsacum, represents an untapped genetic resource for abiotic and biotic stress resistance and for apomixis, a trait that could provide developing world farmers access to hybrid technology. Ownership of genetic resources and genes must be resolved to ensure global access to these critical resources. The application of molecular and genetic engineering technologies enhances the use of genetic resources. The effective and complementary use of all of our technological tools and resources will be required for meeting the challenge posed by the world's expanding demand for food.

  3. Plant genetic resources: What can they contribute toward increased crop productivity?

    PubMed Central

    Hoisington, David; Khairallah, Mireille; Reeves, Timothy; Ribaut, Jean-Marcel; Skovmand, Bent; Taba, Suketoshi; Warburton, Marilyn

    1999-01-01

    To feed a world population growing by up to 160 people per minute, with >90% of them in developing countries, will require an astonishing increase in food production. Forecasts call for wheat to become the most important cereal in the world, with maize close behind; together, these crops will account for ≈80% of developing countries’ cereal import requirements. Access to a range of genetic diversity is critical to the success of breeding programs. The global effort to assemble, document, and utilize these resources is enormous, and the genetic diversity in the collections is critical to the world’s fight against hunger. The introgression of genes that reduced plant height and increased disease and viral resistance in wheat provided the foundation for the “Green Revolution” and demonstrated the tremendous impact that genetic resources can have on production. Wheat hybrids and synthetics may provide the yield increases needed in the future. A wild relative of maize, Tripsacum, represents an untapped genetic resource for abiotic and biotic stress resistance and for apomixis, a trait that could provide developing world farmers access to hybrid technology. Ownership of genetic resources and genes must be resolved to ensure global access to these critical resources. The application of molecular and genetic engineering technologies enhances the use of genetic resources. The effective and complementary use of all of our technological tools and resources will be required for meeting the challenge posed by the world’s expanding demand for food. PMID:10339521

  4. Evidences of increasing risk of dirofilarioses in southern Italy.

    PubMed

    Giangaspero, A; Marangi, M; Latrofa, M S; Martinelli, D; Traversa, D; Otranto, D; Genchi, C

    2013-03-01

    Given the spread of Aedes albopictus from northern to southern Italy, and the lack of updated data on Dirofilaria infections, this study was carried out to assess the infection risk for dogs and cats in Apulia region. During a 2-year study, 175 A. albopictus female specimens and samples of blood from 427 dogs (309 privately owned dogs and 118 shelter dogs) and 12 cats were collected. All blood samples were subjected to a modified Knott method, to a test for the detection of circulating Dirofilaria immitis antigen, and to a Dirofilaria species-specific real-time PCR for the simultaneous detection of D. immitis and Dirofilaria repens, targeting on partial cytochrome oxidase subunit 1 and internal transcribed spacer-2, respectively. Two abdomen and one thorax pools from A. albopictus were positive for D. immitis, with minimum infection rates of 1.14 and 0.51, respectively, and a probability of a single positive specimen to be infected of P = 0.6 % (95 % confidence interval (CI) = 0.12-1.73). Out of 439 examined subjects, 22 (5.0 %) tested positive for Dirofilaria spp. in at least one diagnostic test. A specific D. immitis infestation rate of 3.5 % was found among the privately owned dogs, while shelter dogs tested positive only for D. repens with a prevalence of 3.4 %; one cat tested molecularly positive for D. immitis. There was a significantly higher rate of positivity among guard dogs for D. immitis (odds ratio, 6.24, 95 % CI, 1.26-25.28; P < 0.05). The increasing risk of D. immitis infection in southern Italy is supported by the noteworthy positivity of A. albopictus populations and the cat. Our data highlight the usefulness to include filarioid infestation in routine diagnosis. PMID:23224639

  5. Acute Kidney Injury Increases Risk of ESRD among Elderly

    PubMed Central

    Ishani, Areef; Xue, Jay L.; Himmelfarb, Jonathan; Eggers, Paul W.; Kimmel, Paul L.; Molitoris, Bruce A.; Collins, Allan J.

    2009-01-01

    Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged ≥67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for ≥2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease. PMID:19020007

  6. Appendectomy correlates with increased risk of pyogenic liver abscess

    PubMed Central

    Liao, Kuan-Fu; Lai, Shih-Wei; Lin, Cheng-Li; Chien, Sou-Hsin

    2016-01-01

    Abstract Little is known on the association between appendectomy and pyogenic liver abscess. The objective of this study was to investigate the association between appendectomy and the risk of pyogenic liver abscess in Taiwan. This population-based retrospective cohort study was conducted using the hospitalization dataset of the Taiwan National Health Insurance Program. There were 212,530 subjects age 20 to 84 years with newly diagnosed appendectomy as the appendectomy group since 1998 to 2010, and 850,099 randomly selected subjects without appendectomy as the nonappendectomy group. Both appendectomy and nonappendectomy groups were matched with sex, age, comorbidities, and index year of diagnosing appendectomy. The incidence of pyogenic liver abscess at the end of 2011 was estimated in both groups. The multivariable Cox proportional hazards regression model was applied to investigate the hazard ratio (HR) and 95% confidence interval (CI) for risk of pyogenic liver abscess associated with appendectomy and other comorbidities including alcoholism, biliary stone, chronic kidney disease, chronic liver diseases, and diabetes mellitus. The overall incidence of pyogenic liver abscess was 1.73-fold greater in the appendectomy group than that in the nonappendectomy group (3.85 vs 2.22 per 10,000 person-years, 95% CI 1.71, 1.76). The multivariable regression analysis disclosed that the adjusted HR of pyogenic liver abscess was 1.77 for the appendectomy group (95% CI 1.59, 1.97), when compared with the nonappendectomy group. Appendectomy is associated with increased hazard of pyogenic liver abscess. Further studies remain necessary to confirm our findings. PMID:27368018

  7. Acute kidney injury increases risk of ESRD among elderly.

    PubMed

    Ishani, Areef; Xue, Jay L; Himmelfarb, Jonathan; Eggers, Paul W; Kimmel, Paul L; Molitoris, Bruce A; Collins, Allan J

    2009-01-01

    Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged > or = 67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for > or = 2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease.

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

  9. Evaluation of a Brief Web-Based Genetic Feedback Intervention for Reducing Alcohol-Related Health Risks Associated with ALDH2

    PubMed Central

    Otto, Jacqueline M.; Collins, Susan E.; Liang, Tiebing; Wall, Tamara L.

    2010-01-01

    There is increasing interest in health interventions that incorporate genetic risk information. Although genetic feedback has been evaluated as an adjunct to smoking cessation interventions, its efficacy for reducing alcohol-related risks is unknown. The purpose of this study was to evaluate the feasibility, acceptability, and efficacy of a web-based alcohol intervention incorporating genetic feedback and risk information specific to ALDH2 genotype. The ALDH2*2 variant is associated with partial protection against alcohol dependence but confers significantly increased risk for alcohol-related cancers as a function of alcohol exposure. Two hundred Asian-American young adults were randomly assigned to receive web-based personalized genetic feedback or attention-control feedback. Genetic feedback included health risk information specific to alcohol-related cancer or alcohol dependence, depending on genotype. Outcomes included postintervention drinking behavior and theoretical correlates of behavior change. Genetic feedback and risk information resulted in significant reductions in 30-day drinking frequency and quantity among participants with the ALDH2*1/*2 genotype. Genetic feedback was rated highly by participants and also showed some effects on theoretical correlates of behavior change. Results provide initial evidence of the feasibility, acceptability, and brief efficacy of web-based genetic feedback for reducing alcohol-related health risks associated with ALDH2 genotype. PMID:20652463

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

    PubMed Central

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

    2015-01-01

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

  11. Increased Dietary Inflammatory Index (DII) Is Associated With Increased Risk of Prostate Cancer in Jamaican Men

    PubMed Central

    Shivappa, Nitin; Jackson, Maria D.; Bennett, Franklyn; Hébert, James R.

    2015-01-01

    Purpose Prostate cancer is the most common non-skin malignancy; and it accounts for the most cancer deaths among Jamaican males. Diet has been implicated in the etiology of prostate cancer, including through its effects on inflammation. Method We examined the association between a newly developed dietary inflammatory index (DII) and prostate cancer in a case-control study of 40-80 year-old Jamaican males. A total of 229 incident cases and 250 controls attended the same urology out-patient clinics at 2 major hospitals and private practitioners in the Kingston, Jamaica Metropolitan area between March 2005 and July 2007. The DII was computed based on dietary intake assessed using a previously validated food frequency questionnaire (FFQ) that was expanded to assess diet and cancer in this Jamaican population. Multivariable logistic regression was used to estimate odds ratios, with DII as continuous and expressed as quartiles. Logistic regression analysis adjusted for age, total energy intake, education, body mass index (BMI), smoking status, physical activity and family history of prostate cancer. Results Men in the highest quartile of the DII were at higher risk of prostate cancer [odds ratio (OR) = 2.39; 95% confidence interval (CI) =1.14–5.04 (Ptrend = 0.08)] compared to men in the lowest DII quartile. Conclusion These data suggest a pro-inflammatory diet, as indicated by increasing DII score, may be a risk factor for prostate cancer in Jamaican men. PMID:26226289

  12. Anthropogenic Warming Has Increased Drought Risk In California

    NASA Astrophysics Data System (ADS)

    Diffenbaugh, N. S.; Swain, D. L.; Touma, D. E.

    2015-12-01

    California is currently in the midst of a record-setting drought. The drought began in 2012 and now includes the lowest calendar-year and 12-mo precipitation, the highest annual temperature, and the most extreme drought indicators on record. The extremely warm and dry conditions have led to acute water shortages, groundwater overdraft, critically low streamflow, and enhanced wildfire risk. Analyzing historical climate observations from California, we find that precipitation deficits in California were more than twice as likely to yield drought years if they occurred when conditions were warm. We find that although there has not been a substantial change in the probability of either negative or moderately negative precipitation anomalies in recent decades, the occurrence of drought years has been greater in the past two decades than in the preceding century. In addition, the probability that precipitation deficits co-occur with warm conditions and the probability that precipitation deficits produce drought have both increased. Climate model experiments with and without anthropogenic forcings reveal that human activities have increased the probability that dry precipitation years are also warm. Further, a large ensemble of climate model realizations reveals that additional global warming over the next few decades is very likely to create ˜100% probability that any annual-scale dry period is also extremely warm. We therefore conclude that anthropogenic warming is increasing the probability of co-occurring warm-dry conditions like those that have created the acute human and ecosystem impacts associated with the "exceptional" 2012-2014 drought in California.

  13. Anthropogenic warming has increased drought risk in California

    PubMed Central

    Diffenbaugh, Noah S.; Swain, Daniel L.; Touma, Danielle

    2015-01-01

    California is currently in the midst of a record-setting drought. The drought began in 2012 and now includes the lowest calendar-year and 12-mo precipitation, the highest annual temperature, and the most extreme drought indicators on record. The extremely warm and dry conditions have led to acute water shortages, groundwater overdraft, critically low streamflow, and enhanced wildfire risk. Analyzing historical climate observations from California, we find that precipitation deficits in California were more than twice as likely to yield drought years if they occurred when conditions were warm. We find that although there has not been a substantial change in the probability of either negative or moderately negative precipitation anomalies in recent decades, the occurrence of drought years has been greater in the past two decades than in the preceding century. In addition, the probability that precipitation deficits co-occur with warm conditions and the probability that precipitation deficits produce drought have both increased. Climate model experiments with and without anthropogenic forcings reveal that human activities have increased the probability that dry precipitation years are also warm. Further, a large ensemble of climate model realizations reveals that additional global warming over the next few decades is very likely to create ∼100% probability that any annual-scale dry period is also extremely warm. We therefore conclude that anthropogenic warming is increasing the probability of co-occurring warm–dry conditions like those that have created the acute human and ecosystem impacts associated with the “exceptional” 2012–2014 drought in California. PMID:25733875

  14. Anthropogenic warming has increased drought risk in California.

    PubMed

    Diffenbaugh, Noah S; Swain, Daniel L; Touma, Danielle

    2015-03-31

    California is currently in the midst of a record-setting drought. The drought began in 2012 and now includes the lowest calendar-year and 12-mo precipitation, the highest annual temperature, and the most extreme drought indicators on record. The extremely warm and dry conditions have led to acute water shortages, groundwater overdraft, critically low streamflow, and enhanced wildfire risk. Analyzing historical climate observations from California, we find that precipitation deficits in California were more than twice as likely to yield drought years if they occurred when conditions were warm. We find that although there has not been a substantial change in the probability of either negative or moderately negative precipitation anomalies in recent decades, the occurrence of drought years has been greater in the past two decades than in the preceding century. In addition, the probability that precipitation deficits co-occur with warm conditions and the probability that precipitation deficits produce drought have both increased. Climate model experiments with and without anthropogenic forcings reveal that human activities have increased the probability that dry precipitation years are also warm. Further, a large ensemble of climate model realizations reveals that additional global warming over the next few decades is very likely to create ∼ 100% probability that any annual-scale dry period is also extremely warm. We therefore conclude that anthropogenic warming is increasing the probability of co-occurring warm-dry conditions like those that have created the acute human and ecosystem impacts associated with the "exceptional" 2012-2014 drought in California.

  15. Anthropogenic warming has increased drought risk in California.

    PubMed

    Diffenbaugh, Noah S; Swain, Daniel L; Touma, Danielle

    2015-03-31

    California is currently in the midst of a record-setting drought. The drought began in 2012 and now includes the lowest calendar-year and 12-mo precipitation, the highest annual temperature, and the most extreme drought indicators on record. The extremely warm and dry conditions have led to acute water shortages, groundwater overdraft, critically low streamflow, and enhanced wildfire risk. Analyzing historical climate observations from California, we find that precipitation deficits in California were more than twice as likely to yield drought years if they occurred when conditions were warm. We find that although there has not been a substantial change in the probability of either negative or moderately negative precipitation anomalies in recent decades, the occurrence of drought years has been greater in the past two decades than in the preceding century. In addition, the probability that precipitation deficits co-occur with warm conditions and the probability that precipitation deficits produce drought have both increased. Climate model experiments with and without anthropogenic forcings reveal that human activities have increased the probability that dry precipitation years are also warm. Further, a large ensemble of climate model realizations reveals that additional global warming over the next few decades is very likely to create ∼ 100% probability that any annual-scale dry period is also extremely warm. We therefore conclude that anthropogenic warming is increasing the probability of co-occurring warm-dry conditions like those that have created the acute human and ecosystem impacts associated with the "exceptional" 2012-2014 drought in California. PMID:25733875

  16. Genetic Risk Factors in Recurrent Venous Thromboembolism: A Multilocus, Population-Based, Prospective Approach

    PubMed Central

    Zee, Robert YL; Bubes, Vadim; Shrivastava, Sanjay; Ridker, Paul M; Glynn, Robert J

    2009-01-01

    Background Recurrent venous thromboembolism (VTE) is a common, complex disorder; however, genetic factors have been suggested to play a role in the disease development. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in inflammation, thrombosis, coagulation, and lipid metabolism pathways, individually or interactively, with risk of recurrent VTE. Methods Using DNA samples collected at baseline in the Prevention of Recurrent Venous Thromboembolism trial (PREVENT), we genotyped 86 candidate genes polymorphisms among 43 individuals who subsequently developed recurrent VTE and among 396 individuals who remained free of recurrent event over a mean follow-up period of 2.1 years to prospectively determine whether these gene polymorphisms contribute to the risk of recurrent VTE. Results Using a single-marker ‘uncorrected’ analysis, CCR5 A(-2459)G [rs1799864], MMP3 5A(-1171)6A [rs3025058] and PON1 gln192arg [rs662] gene variants were associated with increased risk, and CETP C(-629)A [rs1800775] gene variant with reduced risk of recurrent VTE, respectively. Furthermore, potentially important gene-gene-interactions were detected by the Monte Carlo Markov chain Logic Regression method. Conclusions Although the present findings are hypothesis-generating and require confirmation in an independent investigation, our study provides a practical example of detecting epistasis in common, complex diseases. PMID:19263529

  17. N-acetyltransferase 2 genetic polymorphism: Effects of carcinogen and haplotype on urinary bladder cancer risk

    PubMed Central

    Hein, David W.

    2006-01-01

    A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and aryldiamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications. PMID:16550165

  18. Association of the XRCC1 c.1178G>A genetic polymorphism with lung cancer risk in Chinese.

    PubMed

    Wang, Lei; Lin, Yong; Qi, Cong-Cong; Sheng, Bao-Wei; Fu, Tian

    2014-01-01

    The X-ray repair cross-complementing group 1 protein (XRCC1) plays important roles in the DNA base excision repair pathway which may influence the development of lung cancer. This study aimed to evaluate the potential association of the XRCC1 c.1178G>A genetic polymorphism with lung cancer risk. The created restriction site-polymerase chain reaction (CRS-PCR) and DNA sequencing methods were utilized to evaluate the XRCC1 c.1178G>A genetic polymorphism among 376 lung cancer patients and 379 controls. Associations between the genetic polymorphism and lung cancer risk were determined with an unconditional logistic regression model. Our data suggested that the distribution of allele and genotype in lung cancer patients was significantly different from that of controls. The XRCC1 c.1178G>A genetic polymorphism was associated with an increased risk of lung cancer (AA vs GG: OR=2.91, 95%CI 1.70-4.98, p<0.001; A vs G: OR=1.52, 95%CI 1.22-1.90, p<0.001). The allele A and genotype AA may contribute to risk of lung cancer. These preliminary results suggested that the XRCC1 c.1178G>A genetic polymorphism is statistically associated with lung cancer risk in the Chinese population.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2008-01-01

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

  1. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

    PubMed Central

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

    2015-01-01

    Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. PMID:25855707

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

    PubMed Central

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

    2016-01-01

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

  3. Loss of genetic diversity and increased embryonic mortality in non-native lizard populations.

    PubMed

    Michaelides, Sozos N; While, Geoffrey M; Zajac, Natalia; Aubret, Fabien; Calsbeek, Brittny; Sacchi, Roberto; Zuffi, Marco A L; Uller, Tobias

    2016-09-01

    Many populations are small and isolated with limited genetic variation and high risk of mating with close relatives. Inbreeding depression is suspected to contribute to extinction of wild populations, but the historical and demographic factors that contribute to reduced population viability are often difficult to tease apart. Replicated introduction events in non-native species can offer insights into this problem because they allow us to study how genetic variation and inbreeding depression are affected by demographic events (e.g. bottlenecks), genetic admixture and the extent and duration of isolation. Using detailed knowledge about the introduction history of 21 non-native populations of the wall lizard Podarcis muralis in England, we show greater loss of genetic diversity (estimated from microsatellite loci) in older populations and in populations from native regions of high diversity. Loss of genetic diversity was accompanied by higher embryonic mortality in non-native populations, suggesting that introduced populations are sufficiently inbred to jeopardize long-term viability. However, there was no statistical correlation between population-level genetic diversity and average embryonic mortality. Similarly, at the individual level, there was no correlation between female heterozygosity and clutch size, infertility or hatching success, or between embryo heterozygosity and mortality. We discuss these results in the context of human-mediated introductions and how the history of introductions can play a fundamental role in influencing individual and population fitness in non-native species. PMID:27393416

  4. Increased risk of type 2 diabetes in Alzheimer disease.

    PubMed

    Janson, Juliette; Laedtke, Thomas; Parisi, Joseph E; O'Brien, Peter; Petersen, Ronald C; Butler, Peter C

    2004-02-01

    Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid beta protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively. Given these similarities, we questioned whether there may be a common underlying mechanism predisposing to islet and cerebral amyloid. To address this, we first examined the prevalence of type 2 diabetes in a community-based controlled study, the Mayo Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease versus control subjects without Alzheimer disease. In addition to this clinical study, we performed a pathological study of autopsy cases from this same community to determine whether there is an increased prevalence of islet amyloid in patients with Alzheimer disease and increased prevalence of cerebral amyloid in patients with type 2 diabetes. Patients who were enrolled in the ADPR (Alzheimer disease n = 100, non-Alzheimer disease control subjects n = 138) were classified according to fasting glucose concentration (FPG) as nondiabetic (FPG <110 mg/dl), impaired fasting glucose (IFG, FPG 110-125 mg/dl), and type 2 diabetes (FPG >126 mg/dl). The mean slope of FPG over 10 years in each case was also compared between Alzheimer disease and non-Alzheimer disease control subjects. Pancreas and brain were examined from autopsy specimens obtained from 105 humans (first, 28 cases of Alzheimer disease disease vs. 21 non-Alzheimer disease control subjects and, second, 35 subjects with type 2 diabetes vs. 21 non-type 2 diabetes control subjects) for the presence of islet and brain amyloid. Both type 2 diabetes (35% vs. 18%; P < 0

  5. Factors associated with perceived risk in automotive employees at increased risk of colorectal cancer.

    PubMed

    Vernon, S W; Myers, R E; Tilley, B C; Li, S

    2001-01-01

    Risk perception may be an important motivator of health-related behaviors. To develop effective risk communication messages, it is important to understand both the patterns of association between perceived risk and health-related behaviors as well as the correlates of risk perception. Very little is known about whether correlates of risk perception are similar in cross-sectional data compared with prospective data. Furthermore, there are scant data on consistency of correlates of risk perception across groups who vary in objective medical risk. If correlates differ, it would underscore the need to tailor intervention messages based on subgroup characteristics as well as increase awareness of the limitations of basing intervention messages only on cross-sectional data. We analyzed data on a subset of 5042 employees who participated in The Next Step Trial, a randomized health promotion trial to encourage colorectal cancer screening and dietary change. We restricted our analysis to only those automotive workers who were white, male, and did not have colorectal cancer (4477/5042) and who returned surveys both at baseline (2,684/4,477) and at year 2 of follow-up (1955/2684). Initial analyses detected interactions between a history of polyps and several of the other covariates. Therefore, univariate and multivariable analyses were conducted separately for men with and without a personal history of colorectal polyps. Within each of the four subgroups (those with or without polyps in the baseline or follow-up analyses), we examined associations between perceived risk measured at baseline (cross-sectional analyses) and at year 2 of follow-up (prospective analyses) in relation to intervention group status, demographic, medical history, psychosocial, and worksite characteristics measured at baseline. To assess the predictive ability of the models, we computed sensitivity and specificity as measures of each model's ability to correctly classify men into their respective

  6. Framing recommendations to promote prevention behaviors among people at high risk: A simulation study of responses to melanoma genetic test reporting.

    PubMed

    Taber, Jennifer M; Aspinwall, Lisa G

    2015-10-01

    A CDKN2A/p16 mutation confers 76 % lifetime risk of developing melanoma to US residents, and high-risk individuals are counseled to use sunscreen. Generally, for patients at population risk, gain framing more effectively promotes prevention behaviors; however, it is unknown whether loss frames might more effectively promote behavioral intentions and perceived control over disease risk among high-risk patients. Undergraduates (N = 146) underwent a simulated genetic counseling and test reporting session for hereditary melanoma. Participants watched a video of a genetic counselor providing information in which genetic risk of melanoma (Low: 15 %; High: 76 %) and framed recommendations to use sunscreen (Loss: Risk may increase by 15 % if don't use sunscreen; Gain: Risk may decrease by 15 % if use sunscreen) were manipulated. Controlling for baseline sunscreen use, high-risk participants given loss frames reported greater beliefs that sunscreen would reduce risk than high-risk participants given gain frames. Further, high-risk participants with fair skin tended to report greater intentions to use sunscreen when given loss frames versus gain frames. Perceived control over risk mediated the effect of message frame and disease risk on intentions to use sunscreen. When counseling patients with elevated cancer risk, genetic counselors may consider framing prevention behavioral recommendations in terms of potential losses. PMID:25582532

  7. GENETIC CONTRIBUTIONS TO POPULATION LEVEL ECOLOGICAL RISK ASSESSMENT

    EPA Science Inventory

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

  8. Acute Exercise Increases Sex Differences in Amateur Athletes' Risk Taking.

    PubMed

    Pighin, S; Savadori, L; Bonini, N; Andreozzi, L; Savoldelli, A; Schena, F

    2015-10-01

    The research presented here investigates the interaction between acute exercise, biological sex and risk-taking behavior. The study involved 20 amateur athletes (19-33 years old), 10 males and 10 females, who were asked to undergo subsequent experimental sessions designed to compare their risky behaviors on the Balloon Analogue Risk Task (BART) 34 at rest and while exercising at moderate intensity (60% of their maximal aerobic power). Results showed that physical exercise affected male and female participants differently: Whereas males became more risk seeking, females became more risk averse during exercise. PMID:26090877

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

    PubMed

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

    2014-05-15

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

  10. Therapy for triggered acute risk prevention in subjects at increased cardiovascular risk.

    PubMed

    Tofler, Geoffrey H; Spinaze, Monica; Shaw, Elizabeth; Buckley, Thomas

    2013-06-15

    Heavy physical exertion, emotional stress, heavy meals, and respiratory infection transiently increase the risk of myocardial infarction, sudden cardiac death, and stroke; however, it remains uncertain how to use this information for disease prevention. We determined whether it was feasible for those with either risk factors for cardiovascular disease (CVD) or known CVD to take targeted medication for the hazard duration of the triggering activity to reduce their risk. After a run-in of 1 month, 20 subjects (12 women and 8 men) aged 68.6 years (range 58 to 83) recorded for 2 months all episodes of physical and emotional stress, heavy meal consumption, and respiratory infection. For each episode, the subjects were instructed to take either aspirin 100 mg and propranolol 10 mg (for physical exertion and emotional stress) or aspirin 100 mg alone (for respiratory infection and heavy meal consumption) and to record their adherence. Adherence with taking the appropriate medication was 86% according to the diary entries, with 15 of 20 subjects (75%) achieving ≥80% adherence. Propranolol taken before exertion reduced the peak heart rate compared with similar exercise during the run-in period (118 ± 21 vs 132 ± 16 beats/min, p = 0.016). Most subjects (85%) reported that it was feasible to continue taking the medication in this manner. In conclusion, it is feasible for those with increased CVD risk to identify potential triggers of acute CVD and to take targeted therapy at the time of these triggers.

  11. Does arsenic exposure increase the risk for liver cancer?

    PubMed

    Chiu, Hui-Fen; Ho, Shu-Chen; Wang, Li-Yu; Wu, Trong-Neng; Yang, Chun-Yuh

    2004-10-01

    Arsenic has been well documented as the major risk factor for development of blackfoot disease (BFD), a unique peripheral vascular disease that was once endemic to the southwestern coast of Taiwan, where residents imbibed artesian well water containing high concentrations of arsenic for more than 50yr. Long-term arsenic exposure has also been reported to be associated with increased incidence of liver cancer in a dose-responsive manner. A tap-water supply system was implemented in the early 1960s in the BFD endemic areas. Artesian well water was no longer used for drinking and cooking after the mid-1970s. The objective of this study was to examine whether liver cancer mortality rates were altered after the consumption of high-arsenic artesian well water ceased and, if so, when the reduction occurred. Standardized mortality ratios (SMRs) for liver cancer were calculated for the BFD endemic area for the years 1971-2000. Cumulative-sum techniques were used to detect the occurrence of changes in the SMRs. The study results show that mortality from liver cancer in females declined starting 9yr after the cessation of consumption of high-arsenic artesian well water. However, data show fluctuations in male liver cancer mortality rates. Based on the reversibility criterion, the association between arsenic exposure and liver cancer mortality is likely to be causal for females but not in males.

  12. Global risk of big earthquakes has not recently increased.

    PubMed

    Shearer, Peter M; Stark, Philip B

    2012-01-17

    The recent elevated rate of large earthquakes has fueled concern that the underlying global rate of earthquake activity has increased, which would have important implications for assessments of seismic hazard and our understanding of how faults interact. We examine the timing of large (magnitude M≥7) earthquakes from 1900 to the present, after removing local clustering related to aftershocks. The global rate of M≥8 earthquakes has been at a record high roughly since 2004, but rates have been almost as high before, and the rate of smaller earthquakes is close to its historical average. Some features of the global catalog are improbable in retrospect, but so are some features of most random sequences--if the features are selected after looking at the data. For a variety of magnitude cutoffs and three statistical tests, the global catalog, with local clusters removed, is not distinguishable from a homogeneous Poisson process. Moreover, no plausible physical mechanism predicts real changes in the underlying global rate of large events. Together these facts suggest that the global risk of large earthquakes is no higher today than it has been in the past.

  13. Placental Cadmium Levels Are Associated with Increased Preeclampsia Risk

    PubMed Central

    Laine, Jessica E.; Ray, Paul; Bodnar, Wanda; Cable, Peter H.; Boggess, Kim; Offenbacher, Steven; Fry, Rebecca C.

    2015-01-01

    Environmental exposure to heavy metals is a potentially modifiable risk factor for preeclampsia (PE). Toxicologically, there are known interactions between the toxic metal cadmium (Cd) and essential metals such as selenium (Se) and zinc (Zn), as these metals can protect against the toxicity of Cd. As they relate to preeclampsia, the interaction between Cd and these essential metals is unknown. The aims of the present study were to measure placental levels of Cd, Se, and Zn in a cohort of 172 pregnant women from across the southeast US and to examine associations of metals levels with the odds of PE in a nested case-control design. Logistic regressions were performed to assess odds ratios (OR) for PE with exposure to Cd controlling for confounders, as well as interactive models with Se or Zn. The mean placental Cd level was 3.6 ng/g, ranging from 0.52 to 14.5 ng/g. There was an increased odds ratio for PE in relationship to placental levels of Cd (OR = 1.5; 95% CI: 1.1–2.2). The Cd-associated OR for PE increased when analyzed in relationship to lower placental Se levels (OR = 2.0; 95% CI: 1.1–3.5) and decreased with higher placental Se levels (OR = 0.98; 95% CI: 0.5–1.9). Similarly, under conditions of lower placental Zn, the Cd-associated OR for PE was elevated (OR = 1.8; 95% CI: 0.8–3.9), whereas with higher placental Zn it was reduced (OR = 1.3; 95% CI: 0.8–2.0). Data from this pilot study suggest that essential metals may play an important role in reducing the odds of Cd-associated preeclampsia and that replication in a larger cohort is warranted. PMID:26422011

  14. Obesity but not overweight is associated with increased mortality risk.

    PubMed

    Faeh, David; Braun, Julia; Tarnutzer, Silvan; Bopp, Matthias

    2011-08-01

    The association between body mass index (BMI) and survival has been described in various populations. However, the results remain controversial and information from low-prevalence Western countries is sparse. Our aim was to examine this association and its public health impact in Switzerland, a country with internationally low mortality rate and obesity prevalence. We included 9,853 men and women aged 25-74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CArdiovscular disease) study (1983-1992) and could be followed up for survival until 2008 by using anonymous record linkage. Cox regression models were used to calculate mortality hazard ratios (HRs) and to estimate excess deaths. Independent variables were age, sex, survey wave, diet, physical activity, smoking, educational class. After adjustment for age and sex the association between BMI and all-cause mortality was J shaped (non-smokers) or U shaped (smokers). Compared to BMI 18.5-24.9, among those with BMI ≥ 30 (obesity) HR for all-cause mortality was 1.41 (95% confidence interval: 1.23-1.62), for cardiovascular disease (CVD) 2.05 (1.60-2.62), for cancer 1.29 (1.04-1.60). Further adjustment attenuated the obesity-mortality relationship but the associations remained statistically significant. No significant increase was found for overweight (BMI 25-29.9). Between 4 and 6.5% of all deaths, 8.8-13.7% of CVD deaths and 2.4-3.9% of cancer deaths could be attributed to obesity. Obesity, but not overweight was associated with excess mortality, mainly because of an increased risk of death from CVD and cancer. Public health interventions should focus on preventing normal- and overweight persons from becoming obese.

  15. Smoking increases risk of pain chronification through shared corticostriatal circuitry.

    PubMed

    Petre, Bogdan; Torbey, Souraya; Griffith, James W; De Oliveira, Gildasio; Herrmann, Kristine; Mansour, Ali; Baria, Alex T; Baliki, Marwan N; Schnitzer, Thomas J; Apkarian, Apkar Vania

    2015-02-01

    Smoking is associated with increased incidence of chronic pain. However, the evidence is cross-sectional in nature, and underlying mechanisms remain unclear. In a longitudinal observational study, we examined the relationship between smoking, transition to chronic pain, and brain physiology. In 160 subjects with subacute back pain (SBP: back pain lasting 4-12 weeks, and no prior back pain [BP] for at least 1 year) pain characteristics, smoking status, and brain functional properties were measured repeatedly over 1 year. Sixty-eight completed the study, subdivided into recovering (SBPr, n = 31) and persisting (SBPp, n = 37), based on >20% decrease in BP over the year. Thirty-two chronic back pain (CBP: duration > 5 years) and 35 healthy controls were similarly monitored. Smoking prevalence was higher in SBP and CBP but not related to intensity of BP. In SBP, smoking status at baseline was predictive of persistence of BP 1 year from symptom onset (differentiating SBPp and SBPr with 0.62 accuracy). Smoking status combined with affective properties of pain and medication use improved prediction accuracy (0.82). Mediation analysis indicated the prediction of BP persistence by smoking was largely due to synchrony of fMRI activity between two brain areas (nucleus accumbens and medial prefrontal cortex, NAc-mPFC). In SBP or CBP who ceased smoking strength of NAc-mPFC decreased from precessation to postcessation of smoking. We conclude that smoking increases risk of transitioning to CBP, an effect mediated by corticostriatal circuitry involved in addictive behavior and motivated learning.

  16. Increased polysomy of chromosome 7 in bronchial epithelium from patients at high risk for lung cancer

    SciTech Connect

    Belinsky, S.A.; Neft, R.E.; Lechner, J.F.

    1995-12-01

    Current models of carcinogenesis suggest that tissues progress through multiple genetic and epigenetic changes which ultimately lead to development of invasive cancer. Epidemiologic studies of Peto, R.R. and J.A. Doll indicate that the accumulation of these genetic changes over time, rather than any single unique genetic change, is probably responsible for development of the malignant phenotype. The bronchial epithelium of cigarette smokers is diffusely exposed to a broad spectrum of carcinogens, toxicants, and tumor promoters contained in tobacco smoke. This exposure increases the risk of developing multiple, independent premalignant foci throughout the lower respiratory tract that may contain independent gene aberrations. This {open_quotes}field cancerization{close_quotes} theory is supported by studies that have demonstrated progressive histologic changes distributed throughout the lower respiratory tract of smokers. A series of autopsy studies demonstrated that cigarette smokers exhibit premalignant histologic changes ranging from hyperplasia and metaplasia to severe dysplasia and carcinoma in situ diffusely throughout the bronchial mucosa. The proximal bronchi appear to exhibit the greatest number of changes, particularly at bifurcations. The results described are the first to quantitate the frequency for a chromosome aberration in {open_quotes}normal{close_quotes} bronchial epithelial cells.

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

    PubMed

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

    2014-05-01

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

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

    PubMed

    Stilgenbauer, S; Hallek, M

    2013-02-01

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

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

    PubMed

    Caiata-Zufferey, Maria

    2015-05-01

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

  20. Genetic Polymorphisms Involved in Folate Metabolism and Maternal Risk for Down Syndrome: A Meta-Analysis

    PubMed Central

    Balduino Victorino, Daniella; de Godoy, Moacir Fernandes; Goloni-Bertollo, Eny Maria; Pavarino, Érika Cristina

    2014-01-01

    Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I2 statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS. PMID:25544792

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

    PubMed Central

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

    2014-01-01

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

  2. Reducing the Risk, Increasing the Promise: Strategies for Student Success

    ERIC Educational Resources Information Center

    Bergmann, Sherrel; Brough, Judith Allen

    2012-01-01

    In their new book, Bergmann and Brough provide a clear path to follow for helping your at-risk students achieve success in and out of the classroom. Packed with classroom-tested, practical strategies and lesson plans for teaching respect, responsibility, resilience, reading, and other essential skills to at-risk students, this is a must-have book…

  3. Genetic risks and environmental surveillance: epidemiological aspects of monitoring industrial populations for environmental mutagens

    SciTech Connect

    Buffler, P.A.; Aase, J.M.

    1982-04-01

    As industrial populations are exposed to new chemicals and other agents in their work environment, it becomes increasingly important to be able to ascertain any associated genetic risks. The characteristics of a desirable surveillance system for deleterious genetic effects are outlined and the existing or proposed surveillance systems for industrial populations are reviewed against these criteria. At present, monitoring for reproductive loss and infertility seems to be the technique best suited for surveillance of industrial populations. However, monitoring techniques based on these events do not directly assess mutagenicity. Since fetal death and infertility are strongly, but not exclusively, correlated with mutation, these methods can be considered as an early-warning system to indicate when and where more definitive studies are needed.

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

    PubMed Central

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

    2010-01-01

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

  5. Increased risk of muscle tears below physiological temperature ranges

    PubMed Central

    Scott, E. E. F.; Hamilton, D. F.; Wallace, R. J.; Muir, A. Y.

    2016-01-01

    Objectives Temperature is known to influence muscle physiology, with the velocity of shortening, relaxation and propagation all increasing with temperature. Scant data are available, however, regarding thermal influences on energy required to induce muscle damage. Methods Gastrocnemius and soleus muscles were harvested from 36 male rat limbs and exposed to increasing impact energy in a mechanical test rig. Muscle temperature was varied in 5°C increments, from 17°C to 42°C (to encompass the in vivo range). The energy causing non-recoverable deformation was recorded for each temperature. A measure of tissue elasticity was determined via accelerometer data, smoothed by low-pass fifth order Butterworth filter (10 kHz). Data were analysed using one-way analysis of variance (ANOVA) and significance was accepted at p = 0.05. Results The energy required to induce muscle failure was significantly lower at muscle temperatures of 17°C to 32°C compared with muscle at core temperature, i.e., 37°C (p < 0.01). During low-energy impacts there were no differences in muscle elasticity between cold and warm muscles (p = 0.18). Differences in elasticity were, however, seen at higher impact energies (p < 0.02). Conclusion Our findings are of particular clinical relevance, as when muscle temperature drops below 32°C, less energy is required to cause muscle tears. Muscle temperatures of 32°C are reported in ambient conditions, suggesting that it would be beneficial, particularly in colder environments, to ensure that peripheral muscle temperature is raised close to core levels prior to high-velocity exercise. Thus, this work stresses the importance of not only ensuring that the muscle groups are well stretched, but also that all muscle groups are warmed to core temperature in pre-exercise routines. Cite this article: Professor A. H. R. W. Simpson. Increased risk of muscle tears below physiological temperature ranges. Bone Joint Res 2016;5:61–65. DOI: 10

  6. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    PubMed

    Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

    2016-03-01

    The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

  7. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    PubMed

    Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

    2016-03-01

    The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress. PMID:26243271

  8. Do Polybrominated Diphenyl Ethers (PBDEs) Increase the Risk of Thyroid Cancer?

    PubMed Central

    Zhang, Yawei; Guo, Grace L.; Han, Xuesong; Zhu, Cairong; Kilfoy, Briseis A.; Zhu, Yong; Boyle, Peter; Zheng, Tongzhang

    2008-01-01

    An increased incidence of thyroid cancer has been reported in many parts of the world including the United States during the past several decades. Recently emerging evidence has demonstrated that polyhalogenated aromatic hydrocarbons (PHAHs), particularly polybrominated diphenyl ethers (PBDEs), alter thyroid hormone homeostasis and cause thyroid dysfunction. However, few studies have been conducted to test whether exposure to PBDEs and other PHAHs increases the risk of thyroid cancer. Here, we hypothesize that elevated exposure to PHAHs, particularly PBDEs, increases the risk of thyroid cancer and may explain part of the increase in incidence of thyroid cancer during the past several decades. In addition, genetic and epigenetic variations in metabolic pathway genes may alter the expression and function of metabolic enzymes which are involved in the metabolism of endogenous thyroid hormones and the detoxification of PBDEs and other PHAHs. Such variation may result in different individual susceptibilities to PBDEs and other PHAHs and the subsequent development of thyroid cancer. The investigation of this hypothesis will lead to an improved understanding of the role of PBDEs and other PHAHs in thyroid tumorigenesis and may provide a real means to prevent this deadly disease. PMID:19122824

  9. Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased Risk for Females.

    PubMed

    Blackmon, Karen; Bluvstein, Judith; MacAllister, William S; Avallone, Jennifer; Misajon, Jade; Hedlund, Julie; Goldberg, Rina; Bojko, Aviva; Mitra, Nirmala; Giridharan, Radha; Sultan, Richard; Keller, Seth; Devinsky, Orrin

    2016-02-01

    The male:female ratio in autism spectrum disorder (ASD) averages greater than 4:1 while the male:female ratio of ASD with epilepsy averages less than 3:1. This indicates an elevated risk of epilepsy in females with ASD; yet, it is unknown whether phenotypic features of epilepsy and ASD differ between males and females with this comorbidity. The goal of this study is to investigate sex differences in phenotypic features of epilepsy and ASD in a prospective sample of 130 children and young adults with an initial ASD diagnosis and subsequent epilepsy diagnosis. All participants were characterized by standardized diagnostic inventories, parent/caregiver completed questionnaires, and medical/academic record review. Diagnostic classifications of epilepsy, ASD, and intellectual disability were performed by board certified neurologists and a pediatric neuropsychologist. Results demonstrated a lower male:female ratio (1.8:1) in individuals with ASD and treatment-resistant epilepsy relative to those with ASD and treatment-responsive epilepsy (4.9:1), indicating a higher risk of treatment-resistant epilepsy in females. Mild neuroimaging abnormalities were more common in females than males and this was associated with increased risk of treatment-resistance. In contrast, ASD symptom severity was lower in females compared with males. Findings distinguish females with ASD and epilepsy as a distinct subgroup at higher risk for a more severe epilepsy phenotype in the context of a less severe ASD phenotype. Increased risk of anti-epileptic treatment resistance in females with ASD and epilepsy suggests that comprehensive genetic, imaging, and neurologic screening and enhanced treatment monitoring may be indicated for this subgroup. Autism Res 2016, 9: 311-320. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

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

    PubMed

    Stuckey, Ashley R; Onstad, Michaela A

    2015-08-01

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

  11. TRPM8 genetic variations associated with COPD risk in the Chinese Han population

    PubMed Central

    Xiong, Mingmei; Wang, Jian; Guo, Meihua; Zhou, Qipeng; Lu, Wenju

    2016-01-01

    TRPM8 plays a key role in COPD. The development of pulmonary hypertension (PH) in COPD adversely affects survival and exercise capacity. Thus, the aim of this study was to evaluate the possible association between single nucleotide polymorphisms (SNPs) in TRPM8 and COPD or PH in COPD among the Chinese Han population. A total of 513 COPD patients and 506 controls were enrolled in the study. Six tag SNPs (tSNPs) were genotyped. The relationship between COPD or PH in COPD and the six tSNPs was evaluated using the χ2 test and genetic model analysis. In the rs9789398 polymorphism, the T/C genotype was associated with an increased risk for COPD (P=0.005). Under the assumption of models of inheritance, there was an association between the rs9789398 polymorphism and COPD. In the rs9789675 polymorphism, the G/A genotype was associated with an increased risk for COPD (P=0.021). Furthermore, by the χ2 test, we found that the minor allele “A” of rs9789675 (odds ratio [OR] =0.63, 95% confidence interval [CI], 0.42–0.97, P=0.034) and the minor allele “C” of rs9789398 (OR =1.59, 95% CI, 1.03–2.44, P=0.034) were associated with a decreased risk of PH in COPD in allele models. In genetic models, the genotypes “GA” and “AA” of rs9789675 were associated with a decreased risk of PH in COPD. The genotypes “TC” and “CC” of rs9789398 were associated with a decreased risk of PH in COPD. Moreover, “CG” of rs1004478 was significantly associated with a decreased risk of PH in COPD. There was a significant association between the five SNPs (rs2362290, rs9789675, rs9789398, rs1003540, and rs104478) in the TRPM8 gene and the risk of PH in COPD. Our findings indicated that rs9789398 in the TRPM8 gene was significantly associated with the risk of COPD in the Chinese Han population. Moreover, rs9789675, rs9789398, and rs1004478 were significantly associated with the risk of PH in COPD. This study provides a novel insight into COPD and PH in the development of COPD

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

    PubMed

    Bando, Hiroko

    2014-11-01

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

  13. [Childhhood obesity, insulin resistance and increased cardiovascular risk].

    PubMed

    Carlone, Angela; Venditti, Chiara; Cipolloni, Laura; Zampetti, Simona; Spoletini, Marialuisa; Capizzi, Marco; Leto, Gaetano; Buzzetti, Raffaella

    2012-10-01

    Excess fat is one of the major risk factors for insulin resistance predisposing to the development of cardiovascular diseases in western countries. We know that obese patients are strongly at risk of cardiovascular diseases, like myocardial infarction or stroke. These diseases are the most frequent cause of death in the adult population, representing a social and economic problem. Today there are not available and useful markers for screening and diagnosis of insulin- resistance in young people. "Easy-to-detect" clinical markers must be found to identify young subjects at risk of cardiovascular diseases. Very interesting the relationship between wrist circumference, its bone composition and insulin resistance. PMID:23114400

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

    PubMed

    Powers, Jacquelyn; Stopfer, Jill Elise

    2014-01-01

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

  15. Linking genetic and environmental factors in amphibian disease risk

    PubMed Central

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

    2015-01-01

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

  16. Study finds increases in risk of leukemias related to treatment

    Cancer.gov

    A new study describes the pattern of risk for chemotherapy-related acute myeloid leukemia among adult cancer survivors over the past three decades who have previously been treated with chemotherapy for other cancers. These patterns coincide with major shi

  17. Do fatty breasts increase or decrease breast cancer risk?

    PubMed Central

    2012-01-01

    Few studies have investigated the association of non-dense area or fatty breasts in conjunction with breast density and breast cancer risk. Two articles in a recent issue of Breast Cancer Research investigate the role of absolute non-dense breast area measured on mammograms and find conflicting results: one article finds that non-dense breast area has a modest positive association with breast cancer risk, whereas the other finds that non-dense breast area has a strong protective effect to reduce breast cancer risk. Understanding the interplay of body mass index, menopause status, and measurement of non-dense breast area would help to clarify the contribution of non-dense breast area to breast cancer risk. PMID:22277587

  18. The LRP6 rs2302685 polymorphism is associated with increased risk of myocardial infarction

    PubMed Central

    2014-01-01

    Background Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI. Methods Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction–ligation detection reaction (PCR–LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software. Results Multivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects. Conclusions Our data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels. PMID:24906453

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

    PubMed

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

    2015-04-01

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

  20. An Unusual BRCA Mutation Distribution in a High Risk Cancer Genetics Clinic

    PubMed Central

    Nelson-Moseke, Anna C.; Jeter, Joanne M.; Cui, Haiyan; Roe, Denise J.; Chambers, Setsuko K.; Laukaitis, Christina M.

    2012-01-01

    The Database of Individuals at High Risk for Breast, Ovarian, or Other Hereditary Cancers at the Arizona Cancer Center in Tucson, Arizona, assesses cancer risk factors and outcomes in patients with a family history of cancer or a known genetic mutation. We analyzed the subset of clinic probands who carry deleterious BRCA gene mutations to identify factors that could explain why mutations in BRCA2 out number those in BRCA1. Medical, family, social, ethnic and genetic mutation histories were collected from consenting patients’ electronic medical records. Differences between BRCA1 and BRCA2 probands from this database were analyzed for statistical significance and compared to published analyses.. A significantly higher proportion of our clinic probands carry mutations in BRCA2 than BRCA1, compared with previous reports of mutation prevalence. This also holds true for the Hispanic sub-group. Probands with BRCA2 mutations were significantly more likely than their BRCA1 counterparts to present to the high risk clinic without adiagnosis of cancer. Other differences between the groups were not significant. Six previously unreported BRCA2 mutations appear in our clinic population. The increased proportion of probands carrying deleterious BRCA2 mutations is likely multifactorial, but may reflect aspects of Southern Arizona’s unique ethnic heritage. PMID:23179792

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

    PubMed Central

    Shaw, Alison

    2011-01-01

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

  2. Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

    PubMed Central

    2011-01-01

    Background Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population. Methods We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value. Results Three NOD2 SNPs, two IL23R SNPs, and one SNP each at IRGM and PTGER4 were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16). Conclusions CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches. PMID:21548950

  3. Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score.

    PubMed

    Eze, Ikenna C; Imboden, Medea; Kumar, Ashish; von Eckardstein, Arnold; Stolz, Daiana; Gerbase, Margaret W; Künzli, Nino; Pons, Marco; Kronenberg, Florian; Schindler, Christian; Probst-Hensch, Nicole

    2016-09-01

    Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma case-control study design. AP was estimated as 10-year mean residential particulate matter <10μm (PM10). We computed count-GRS and weighted-GRS, and applied PM10 interaction terms in mixed logistic regressions, on odds of diabetes. Analyses were stratified by pathways of diabetes pathology and by asthma status. Diabetes prevalence was 4.6% and mean exposure to PM10 was 22μg/m(3). Odds of diabetes increased by 8% (95% confidence interval: 2, 14%) per T2D risk allele and by 35% (-8, 97%) per 10μg/m(3) exposure to PM10. We observed a positive interaction between PM10 and count-GRS on diabetes [ORinteraction=1.10 (1.01, 1.20)], associations being strongest among participants at the highest quartile of count-GRS [OR: 1.97 (1.00, 3.87)]. Stronger interactions were observed with variants of the GRS involved in insulin resistance [(ORinteraction=1.22 (1.00, 1.50)] than with variants related to beta-cell function. Interactions with count-GRS were stronger among asthma cases. We observed similar results with weighted-GRS. Five single variants near GRB14, UBE2E2, PTPRD, VPS26A and KCNQ1 showed nominally significant interactions with PM10 (P<0.05). Our results suggest that genetic risk for T2D may modify susceptibility to air pollution through alterations in insulin sensitivity. These results need confirmation in diabetes cohort consortia.

  4. Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score.

    PubMed

    Eze, Ikenna C; Imboden, Medea; Kumar, Ashish; von Eckardstein, Arnold; Stolz, Daiana; Gerbase, Margaret W; Künzli, Nino; Pons, Marco; Kronenberg, Florian; Schindler, Christian; Probst-Hensch, Nicole

    2016-09-01

    Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma ca