Double trouble: T2DM genetic risk factors play a causal role in CAD

Abstract

Type 2 diabetes mellitus T2D T2DM Single nucleotide polymorphism SNP Genetic risk score Pathogenesis CommentaryCoronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide [1]. A major risk factor for CAD that has long been recognised is type 2 diabetes mellitus (T2DM). In addition, obesity, sedentary lifestyle and stress are common shared risk factors that contribute to the close association between T2DM and CAD. It is not yet obvious whether and to what degree this close association between the two conditions can be attributed to shared genetic risk factors. In contrast to other risk factors shared between T2DM and CAD, genetic risk factors offer the advantage of being unaffected by the various confounders affecting the association between these two conditions. T2DM and CAD both have polygenic inheritance and genetic studies have identified numerous distinct loci for both diseases. For CAD, over 50 single nucleotide polymorphisms (SNPs) have been identified in genome-wide association studies (GWAS), but only a few of these also associated with traditional CAD risk factors (lipid and blood pressure traits) and none of these were associated with glyco-metabolic traits at a genome-wide significant level (p < 5 Â 10 À8 ) [2e4]. In the setting of T2DM, some components of the genetic predisposition to CAD appear to differ from those found in the general population. A variant related to the g-glutamyl cycle of amino acid transport that had not been previously identified in the general population was found to be associated with CAD at a genome wide-level of significance in T2DM, representing a novel genetic risk factor for CAD in T2DM [5].In this issue of Atherosclerosis, Jansen and colleagues used genetic markers as proxies for diabetes status to investigate whether T2DM e associated SNPs are also associated with increased risk of CAD in Caucasians, using the CARDIoGRAM Consortium dataset comprising~22,000 CAD cases and~65,000 controls [2,6,7]. They argued that if T2DM is a causal risk factor for CAD, then genetic variants associated with T2DM would consequently be expected to be associated with CAD. They investigated whether the risk alleles of T2DM -associated SNPs previously identified in GWAS also increase the risk of CAD. A systematic literature search identified 48 variants currently known to be robustly associated with T2DM, of which 4 were excluded (on technical grounds or because of statistically e defined pleiotropy) and the remaining 44 were included in the study. For 29 of these variants, the T2DM risk allele gave an effect in the expected direction, (i.e. increased risk of CAD) and for ten SNPs this was statistically significant (p < 0.05). Of these, only the T2DM SNP at the chromosome 2q36.3 locus, which contains the insulin receptor substrate 1 (IRS1) and LOC64673 genes, remained significantly associated with CAD after correcting for multiple testing (p ¼ 3.4 Â 10 À5 , Bonferroni corrected threshold p value 0.0011). Interestingly, for two of the remaining 15 variants (CILP2 and ...

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“…Despite improvements in the diagnosis and treatment of T2DM, the specific mechanisms underlying the pathogenesis of this disorder remain unclear. The etiology of T2DM is generally considered to be critically dependent on genetic factors as well as aging and aspects of the modern Western lifestyle 19,20 including The American Diabetes Association and European Association for the Study of Diabetes recommend metformin as the first-line antihyperglycemic agent in the management of T2DM. This treatment has been used for over 50 years in Europe.…”

“…Despite improvements in the diagnosis and treatment of T2DM, the specific mechanisms underlying the pathogenesis of this disorder remain unclear. The etiology of T2DM is generally considered to be critically dependent on genetic factors as well as aging and aspects of the modern Western lifestyle 19,20 including reduced physical activity, high calorie food intake, and obesity. Therefore, strategies for the treatment of T2DM remain a significant challenge.…”

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