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Diabetes 53:3319-3322, 2004
© 2004 by the American Diabetes Association, Inc.

Association Studies of Insulin Receptor Substrate 1 Gene (IRS1) Variants in Type 2 Diabetes Samples Enriched for Family History and Early Age of Onset

Eleftheria Zeggini1,2, James Parkinson3, Stephanie Halford3, Katharine R. Owen4, Timothy M. Frayling4, Mark Walker5, Graham A. Hitman6, Jonathan C. Levy1, Mike J. Sampson7, Edith J.M. Feskens8, Andrew T. Hattersley4, and Mark I. McCarthy1,2,3

1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
2 Wellcome Trust Centre for Human Genetics, Oxford, U.K
3 Imperial College Faculty of Medicine, London, U.K
4 Centre for Molecular Genetics, Peninsular Medical School, Exeter, U.K
5 School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K
6 Centre of Diabetes and Metabolic Medicine, Bart’s and The London, Queen Mary’s School of Medicine and Dentistry, London, U.K
7 Department of Diabetes and Endocrinology, Norfolk and Norwich University Hospital NHS Trust, Norwich, U.K
8 Center of Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands

The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86–1.44, P = 0.44].) An updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02–1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect.

Address correspondence and reprint requests to Mark McCarthy, Robert Turner Chair of Diabetes, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital Site, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: mark.mccarthy{at}drl.ox.ac.uk


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Copyright © 2004 by the American Diabetes Association.