Impact of Type 2 diabetes susceptibility loci on variation in multiple cardio-metabolic traits

Aims: Type 2 diabetes (T2D) is related to pathophysiological changes in metabolic and cardio-vascular traits. We aimed to uncover the mechanistic basis of T2D associations by exploring the pleiotropic effects of T2D risk variants on multiple cardio-metabolic traits. Methods: We evaluated the effects of 65 established T2D-associated common genetic variants (Sept 2012) on 22 quantitative anthropometric, glycaemic, lipid, blood pressure, obesity, fat distribution and hypertension traits. We analysed the multi-trait effects using two cluster analysis methods, k-means clustering and complete hierarchical agglomerative clustering. Clustering identified groups of loci with shared genetic effects on cardio-metabolic traits. We compared genetic associations with known epidemiological correlations. Results: Complete hierarchical cluster analysis grouped 65 T2D loci into five major clusters based on patterns of their associations with 24 cardio-metabolic traits. T2D risk-variants near GCKR and CILP2 were associated with lower LDL-cholesterol, total cholesterol and triglycerides, whilst those at FTO and MC4R were correlated with obesity-related traits. The group including ARAP1, GCK and MTNR1B were related to hyperglycaemia and decreased beta-cell function. K-means clustering distinguished two additional sub-groups of loci: (I) GRB14, IRS1, PPARG1, KLF14 and ADAMTS9; and (II) CDKAL1, ADCY5 and SLC30A8. In both sub-groups, the T2D risk-alleles were associated with “leanness” via an impaired metabolic profile. However, only in the second sub-group were T2D risk-alleles also associated with decreased beta-cell function. All other loci showed no clear-cut cardio-metabolic trait associations. Conclusions: Our findings indicate that T2D susceptibility variants exert their effects on multiple cardio-metabolic traits through a variety of mechanisms.