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. and Humphries, S. E. (2012) IRS1 gene variants, dysglycaemic metabolic changes and type-2 diabetes risk. Nutrition, Metabolism and Cardiovascular Diseases, 22 12: 1024-1030. doi:10.1016/j.numecd.2011.05.009


Author 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.
Title IRS1 gene variants, dysglycaemic metabolic changes and type-2 diabetes risk
Journal name Nutrition, Metabolism and Cardiovascular Diseases   Check publisher's open access policy
ISSN 0939-4753
1590-3729
Publication date 2012
Sub-type Article (original research)
DOI 10.1016/j.numecd.2011.05.009
Open Access Status
Volume 22
Issue 12
Start page 1024
End page 1030
Total pages 7
Place of publication Oxford, United Kingdom
Publisher Elsevier
Language eng
Formatted 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). Conclusions: We confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.
Keyword Genetic variation
GWAS
Hyperinsulinemia
Insulin resistance
IRS1
Type-2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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