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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:BackgroundCoronary heart disease (CHD) and type 2 diabetes (T2D) are two complex diseases with complex interrelationships. However, the genetic architecture of the two diseases is often studied independently by the individual single-nucleotide polymorphism (SNP) approach. Here, we presented a genotypic-phenotypic framework for deciphering the genetic architecture underlying the disease patterns of CHD and T2D.MethodA data-driven SNP-set approach was performed in a genome-wide association study consisting of subpopulations with different disease patterns of CHD and T2D (comorbidity, CHD without T2D, T2D without CHD and all none). We applied nonsmooth nonnegative matrix factorization (nsNMF) clustering to generate SNP sets interacting the information of SNP and subject. Relationships between SNP sets and phenotype sets harboring different disease patterns were then assessed, and we further co-clustered the SNP sets into a genetic network to topologically elucidate the genetic architecture composed of SNP sets.ResultsWe identified 23 non-identical SNP sets with significant association with CHD or T2D (SNP-set based association test, P < 3.70 × [Formula: see text]). Among them, disease patterns involving CHD and T2D were related to distinct SNP sets (Hypergeometric test, P < 2.17 × [Formula: see text]). Accordingly, numerous genes (e.g., KLKs, GRM8, SHANK2) and pathways (e.g., fatty acid metabolism) were diversely implicated in different subtypes and related pathophysiological processes. Finally, we showed that the genetic architecture for disease patterns of CHD and T2D was composed of disjoint genetic networks (heterogeneity), with common genes contributing to it (pleiotropy).ConclusionThe SNP-set approach deciphered the complexity of both genotype and phenotype as well as their complex relationships. Different disease patterns of CHD and T2D share distinct genetic architectures, for which lipid metabolism related to fibrosis may be an atherogenic pathway that is specifically activated by diabetes. Our findings provide new insights for exploring new biological pathways.

Project description:BackgroundCar use has been associated with higher risk of coronary heart disease (CHD). However, whether the associations of transport modes with CHD vary by genetic susceptibility to CHD are unknown. This study aims to investigate the associations of genetic susceptibility and modes of transport with incidence of CHD.MethodsWe included 339,588 white British participants from UK Biobank with no history of CHD or stroke at baseline or within two years of follow-up (52.3% in work). Genetic susceptibility to CHD was quantified through weighted polygenic risk scores derived from 300 single-nucleotide polymorphisms related to CHD risk. Categories of transport mode included exclusive car use and alternatives to the car (e.g., walking, cycling and public transport), separately for non-commuting (e.g., getting about [n=339,588] excluding commuting for work), commuting (in the sub-set in work [n=177,370] who responded to the commuting question), and overall transport (transport mode for both commuting and non-commuting [n=177,370]). We used Cox regression with age as the underlying timescale to estimate hazard ratios (HR) of CHD (n=13,730; median 13.8-year follow-up) and tested the interaction between genetic susceptibility and travel modes with adjustment for confounders.ResultsCompared to those using alternatives to the car, hazards of CHD were higher for exclusive use of cars for overall transport (HR: 1.16, 95% confidence interval (CI): 1.08-1.25), non-commuting (HR: 1.08, 95% CI: 1.04-1.12) and commuting (HR: 1.16, 95% CI: 1.09-1.23), after adjusting for confounders plus genetic susceptibility. HRs of CHD were 1.45 (95% CI: 1.38-1.52) and 2.04 (95% CI: 1.95-2.12) for the second and third tertile of genetic susceptibility to CHD, respectively, compared to the first. There was, in general, no strong evidence of interactions between genetic susceptibility and categories of overall, non-commuting and commuting transport. Estimated 10-year absolute risk of CHD was lower for the alternatives to the car across strata of genetic susceptibility, compared with exclusive use of cars for overall, non-commuting and commuting transport.ConclusionExclusive use of cars was associated with a relatively higher risk of CHD across all strata of genetic susceptibility. Using alternatives to the car should be encouraged for prevention of CHD for the general population including individuals at high genetic risk.

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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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