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Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies.

ABSTRACT: OBJECTIVES:The aim of this study was to evaluate whether coronary heart disease (CHD)-susceptibility loci identified by genome-wide association studies of the general population also contribute to CHD in type 2 diabetes. BACKGROUND:No study has examined the effects of these genetic variants on CHD in diabetic patients. METHODS:We genotyped 15 genetic markers of 12 loci in 3 studies of diabetic patients: the prospective Nurses' Health Study (309 CHD cases, and 544 control subjects) and Health Professional Follow-up Study (345 CHD cases, and 451 control subjects) and the cross-sectional Joslin Heart Study (422 CHD cases, and 435 control subjects). RESULTS:Five single-nucleotide polymorphisms, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the 3 studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p = 0.03 to 0.0002). None of the other single-nucleotide polymorphisms reached significance in individual or combined analyses. A genetic risk score (GRS) was created by combining the risk alleles of the 5 significantly associated loci. The OR of CHD/GRS unit was 1.19 (95% confidence interval: 1.13 to 1.26; p < 0.0001). Individuals with GRS ?8 (19% of diabetic subjects) had almost a 2-fold increase in CHD risk (OR: 1.94, 95% confidence interval: 1.60 to 2.35) as compared with individuals with GRS ?5 (30% of diabetic subjects). Prediction of CHD was significantly improved (p < 0.001) when the GRS was added to a model including clinical predictors in the combined samples. CONCLUSIONS:Our results illustrate the consistency and differences in the determinants of genetic susceptibility to CHD in diabetic patients and the general populations.

SUBMITTER: Qi L

PROVIDER: S-EPMC3240896 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies.

Qi Lu L Parast Layla L Cai Tianxi T Powers Christine C Gervino Ernest V EV Hauser Thomas H TH Hu Frank B FB Doria Alessandro A

Journal of the American College of Cardiology 20111201 25

<h4>Objectives</h4>The aim of this study was to evaluate whether coronary heart disease (CHD)-susceptibility loci identified by genome-wide association studies of the general population also contribute to CHD in type 2 diabetes.<h4>Background</h4>No study has examined the effects of these genetic variants on CHD in diabetic patients.<h4>Methods</h4>We genotyped 15 genetic markers of 12 loci in 3 studies of diabetic patients: the prospective Nurses' Health Study (309 CHD cases, and 544 control su ...[more]

PMID: 22152955

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Project description:BackgroundWhether the associations of time spent in screen-based sedentary activities with CHD vary by genetic susceptibility is currently unknown. The objective of this study was to examine the interplay of genetic susceptibility to CHD and two prevalent types of screen-based sedentary activities (television [TV] viewing and computer use) for CHD incidence.MethodsThis prospective cohort study included 373,026 individuals of European ancestry without prevalent CHD/stroke from UK Biobank data. Genetic susceptibility to CHD was assessed using weighted polygenic risk scores, calculated by summing the number of risk-increasing alleles among 300 single-nucleotide polymorphisms, multiplied by their corresponding effect estimates. TV viewing and computer use were assessed through touch-screen questionnaires. CHD incidence (n=9185) was adjudicated over a median 12.6-year follow-up.ResultsCompared with ≥4h/day of TV viewing, the hazard ratio of CHD was 0.84 (95% confidence interval [CI] 0.79-0.90) and 0.94 (0.90-0.99) for ≤1h/day and 2-3h/day of TV viewing, respectively, after adjusting for confounders including the genetic risk. CHD hazards were higher for medium and high genetic risk than for low genetic risk. Across all levels of genetic risk including high-genetic risk, ≤1h/day of TV viewing had lower CHD hazards, compared with ≥4h/day: no evidence of interaction between genetic risk and TV viewing (p value: 0.362). Estimates of the population attributable fraction (PAF) suggested that 10.9% (95% CI 6.1-15.3%) of CHD could be prevented if TV viewing time were reduced to ≤1h/day, assuming causality. The PAF values were relatively larger for medium-to-high genetic risk than for low genetic risk, although the CIs were wide and overlapping. No associations were observed for computer use.ConclusionsLess TV viewing time was associated with lower CHD risk independently of genetic risk. Clinical trials targeted at individuals with high genetic susceptibility should consider reducing TV viewing as as a behavioural target for prevention of an early onset of cardiovascular events.

Project description:Importance:In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain. Objective:To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes. Design, Setting, and Participants:A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322?154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111?986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149?821 individuals and 184?305 individuals, respectively, combined with individual-level data from the UK Biobank. Exposures:Genetic predisposition to increased WHR adjusted for BMI. Main Outcomes and Measures:Type 2 diabetes and CHD. Results:Among 111?986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58?845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1-mm Hg higher systolic blood pressure (each P?<?.001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40?530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66?440). Conclusions and Relevance:A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.

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Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies.

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Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies.

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