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Current Insights into the Joint Genetic Basis of Type 2 Diabetes and Coronary Heart Disease.

ABSTRACT: The large-scale genome-wide association studies conducted so far identified numerous allelic variants associated with type 2 diabetes (T2D), coronary heart disease (CHD) and related cardiometabolic traits. Many T2D- and some CHD-risk loci are also linked with metabolic traits that are hallmarks of insulin resistance (lipid profile, abdominal adiposity). Chromosome 9p21.3 and 2q36.3 are the most consistently replicated loci appearing to share genetic risk for both T2D and CHD. Although many glucose- or insulin-related trait variants are also linked with T2D risk, none of them is associated with CHD. Hence, while T2D and CHD are strongly clinically linked together, further ongoing analyses are needed to clarify the existence of a shared underlying genetic signature of these complex traits. The present review summarizes an updated picture of T2D-CHD genetics as of 2013, aiming to provide a platform for targeted studies dissecting the contribution of genetics to the phenotypic heterogeneity of T2D and CHD.

SUBMITTER: Dauriz M

PROVIDER: S-EPMC3981553 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Current Insights into the Joint Genetic Basis of Type 2 Diabetes and Coronary Heart Disease.

Dauriz Marco M Meigs James B JB

Current cardiovascular risk reports 20140101 1

The large-scale genome-wide association studies conducted so far identified numerous allelic variants associated with type 2 diabetes (T2D), coronary heart disease (CHD) and related cardiometabolic traits. Many T2D- and some CHD-risk loci are also linked with metabolic traits that are hallmarks of insulin resistance (lipid profile, abdominal adiposity). Chromosome 9p21.3 and 2q36.3 are the most consistently replicated loci appearing to share genetic risk for both T2D and CHD. Although many gluco ...[more]

PMID: 24729826

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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:ImportanceIn observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain.ObjectiveTo 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 participantsA 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.ExposuresGenetic predisposition to increased WHR adjusted for BMI.Main outcomes and measuresType 2 diabetes and CHD.ResultsAmong 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 relevanceA 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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Current Insights into the Joint Genetic Basis of Type 2 Diabetes and Coronary Heart Disease.

Publications

Current Insights into the Joint Genetic Basis of Type 2 Diabetes and Coronary Heart Disease.

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