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

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

doi:10.1016/j.numecd.2011.05.009

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

N. Yiannakouris
- Harokopio University of Athens, 17671 Athens, Greece
J.A. Cooper
- Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
S. Shah
- University College London Genetics Institute, Department of Genetics, Environment and Evolution, Gower St, London WC1E 6BT, UK
F. Drenos
- Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
H.A. Ireland
- Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
J.W. Stephens
- Diabetes Research Group, Institute of Life Sciences, School of Medicine, Swansea University, Swansea SA2 8PP, UK
K-W Li
- Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
R. Elkeles
- Endocrinology and Metabolic Medicine, Imperial College London and St Mary’s Hospital, London W2 1NY, UK
I.F. Godsland
- Endocrinology and Metabolic Medicine, Imperial College London and St Mary’s Hospital, London W2 1NY, UK
M. Kivimaki
- Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK
A.D. Hingorani
- Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK
M. Kumari
- Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Street, London WC1E 6BT, UK
P.J. Talmud
- Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
- On behalf of the EARSII Group. (See Supplementary material for full author list).
S.E. Humphries
- Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
- Corresponding author. Tel.: +44 0 207 679 6968; fax: +44 0 207 679 6212.
- On behalf of the EARSII Group. (See Supplementary material for full author list).

Received 11 January 2011; received in revised form 25 May 2011; accepted 31 May 2011. published online 15 September 2011.
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Abstract

Background and aims

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.

Methods and results

We 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).