Common variants in and near IRS1 and subclinical cardiovascular disease in the Framingham Heart Study

Abstract

Objective: Common variants at the 2q36.3-IRS1 locus are associated with insulin resistance (IR), type 2 diabetes (T2D) and coronary artery disease (CAD) in large-scale association studies. We tested the hypothesis that variants at this locus are associated with subclinical atherosclerosis traits.

Methods: We studied 2740 Framingham Heart Study participants (54.9% women; mean age 57.8 years) with measures of coronary artery or abdominal aortic calcium, internal and common carotid intima-media thickness, and ankle-brachial index (ABI). We tested 1) four SNPs previously shown to be associated with IR (rs2972146, rs2943650), T2D (rs2943641) or CAD (rs2943634) and 2) any SNP at 2q36.3-IRS1, for association with subclinical atherosclerosis traits, adjusting for atherosclerosis risk factors. We set type 1 error rate for test 1) as 0.05/5 traits = P < 0.01, and for test 2) as 0.05 divided by the effective number of independent tests, divided by 5 for the number of traits analyzed.

Results: We found no association between the four known SNPs and subclinical atherosclerosis, but identified one SNP (rs10167219, r(2) with rs2943634 = 0.07) at 2q36.3 that was significantly associated with ABI (corrected P = 0.009). However, rs10167219 was not associated with ABI (P = 0.70) in 35,404 participants in a published ABI association study.

Conclusion: Common variants at the 2q36.3-IRS1 locus were not associated with subclinical atherosclerosis traits in this study which was adequately powered to find associations with moderate effect size. Although IR and T2D may be mechanistically linked to CAD via subclinical atherosclerosis, an alternate mechanism for the IR-T2D-CAD associations at 2q36.3-IRS1 must be postulated.

Fig. 1

A regional association plot for four SNPs known to be associated with insulin resistance (rs2972146, rs2943641, rs2943650), type 2 diabetes (rs2943641) or CAD (rs2943634, at the center of the plot), and a SNP (rs10167219) at 2q36.3 associated with ABI (corrected P value of rs10167219 = 0.0045). Linkage disequilibrium (LD) is shown in relation to rs10167219; four SNPs (rs10498199, rs950503, rs11675231, rs964818) in high LD with rs10167219 are displayed in red; the four known SNPs (rs2943634, rs2943641, rs2972146, rs2943650) in relatively low LD with rs10167219 are displayed in white. The LD map is from HapMap 2, B36, CEU population. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)