IRS1 gene variants, dysglycaemic metabolic changes and type-2 diabetes risk

N Yiannakouris,J.A Cooper,S Shah,F Drenos,H.A Ireland,J.W Stephens,K.-W Li,R Elkeles,I.F Godsland,M Kivimaki,A.D Hingorani,M Kumari,P.J Talmud,S.E Humphries

doi:10.1016/j.numecd.2011.05.009

Abstract

Background and aimsA recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk. Methods and resultsWe genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80–1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69–0.96, p = 0.015). ConclusionsWe confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.

Highlights

Genome-wide association studies (GWAS) have identified multiple loci at which common variants modestly but reproducibly influence risk of type-2 diabetes (T2D) [1e6]
Using data from 4752 Caucasians participating in the Whitehall-II study who had been genotyped for 33 insulin receptor substrate-1 gene (IRS1) Single nucleotide polymorphism (SNP) using the HumanCVD BeadChip [14,15] and with follow-up direct genotyping of IRS1 SNPs in the other study cohorts, we explored the potential association with the risk of T2D of SNPs within and flanking IRS1
Using a variable selection model including all riskassociated IRS1 variants, age, gender and body mass index (BMI) considered for entry, we identified that rs6725556 (OR per minor G-allele: 0.50, 95%confidence intervals (CI): 0.33e0.78, p Z 0.002) and SNP rs2943641 near IRS1 (OR per minor T-allele: 0.82, 95%CI: 0.69e0.99, p Z 0.04) were the only variants that were independently associated with T2D risk in WHII, along with age (p < 0.001) and BMI (p < 0.001)

Summary

Introduction

Genome-wide association studies (GWAS) have identified multiple loci at which common variants modestly but reproducibly influence risk of type-2 diabetes (T2D) [1e6]. Rung and colleagues [13] identified rs2943641C > T, located 500 kb downstream of the insulin receptor substrate-1 gene (IRS1), as a T2D risk locus, with the major C-allele being associated with 19% increased risk of T2D. A recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk.

Objectives

Methods

Results

Conclusion