Brief Genetics Report 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 Zeggini, 1,2 James Parkinson, 3 Stephanie Halford, 3 Katharine R. Owen, 4 Timothy M. Frayling, 4 Mark Walker, 5 Graham A. Hitman, 6 Jonathan C. Levy, 1 Mike J. Sampson, 7 Edith J.M. Feskens, 8 Andrew T. Hattersley, 4 and Mark I. McCarthy 1,2,3 The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contribu- tory role in type 2 diabetes susceptibility. Indeed, func- tional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies sug- gested 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 con- trol subjects matched by ethnicity. There was no evi- dence 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. Diabetes 53:3319 –3322, 2004 A bnormalities in both insulin secretion and ac- tion contribute to the development of type 2 diabetes (1). In the search for genetic variants underlying the familial aggregation of defective insulin action that contributes to type 2 diabetes suscep- tibility (2), there has been an understandable focus on proximal components of the insulin signaling pathway, since functional variation in these molecules could readily explain the widespread disruption of postreceptor signal- ing that characterizes this condition. Insulin receptor substrate (IRS)-1 plays a key role in proximal insulin signaling and has been extensively stud- ied in this respect. While many sequence variants within the IRS1 gene have been identified, the main focus has been on two relatively infrequent nonsynonymous vari- ants, P512A (sometimes called P513A, rs1801276) and G971R (G972R, rs1801278), following an initial study that suggested that the combined prevalence of these variants was increased in type 2 diabetes (3). More than 25 studies, featuring diverse sizes and study designs and using sam- ples recruited from many populations, have subsequently pursued these associations (4). Most attention has been concentrated on the G971R variant, which is more com- mon than P512A (albeit with a minor allele frequency around 5%), and has stronger evidence supporting direct consequences on gene product function (5–7). Individual studies have reached apparently conflicting conclusions (4), although this diversity may be partly explained by questions of study design (notably small sample size) and differences in sample ascertainment and potential ethnic heterogeneity. Combined analysis can help to address such confound- ing factors and provide more robust estimates of effect size: a recent meta-analysis of 27 association studies that had been published prior to 2000 (a total of 3,408 case and 5,419 control subjects) indicated that carriage of the 971R allele conferred a significant increase in disease risk (summary risk ratio 1.25 [95% CI 1.05–1.48]) (4). Interest- ingly, this association was entirely attributable to studies in which cases had been recruited from hospital-based clinics rather than population cohorts. This may reflect the likelihood that selective ascertainment results in samples From the 1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.; the 2 Wellcome Trust Centre for Human Genetics, Oxford, U.K.; the 3 Imperial College Faculty of Medicine, London, U.K.; the 4 Centre for Molecular Genetics, Peninsular Medical School, Exeter, U.K.; the 5 School of Clinical Medical Sciences, University of Newcastle, Newcastle, U.K.; the 6 Centre of Diabetes and Metabolic Medicine, Bart’s and The London, Queen Mary’s School of Medicine and Dentistry, London, U.K.; the 7 Department of Diabetes and Endocrinology, Norfolk and Norwich University Hospital NHS Trust, Norwich, U.K.; and the 8 Center of Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands. 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, Head- ington, Oxford OX3 7LJ, U.K. E-mail: mark.mccarthy@drl.ox.ac.uk. Received for publication 9 July 2004 and accepted in revised form 24 August 2004. E.Z. and J.P. contributed equally to this study. ECACC, European Collection of Cell Cultures; IRS, insulin receptor sub- strate; LD, linkage disequilibrium; SNP, single nucleotide polymorphism. © 2004 by the American Diabetes Association. DIABETES, VOL. 53, DECEMBER 2004 3319 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/53/12/3319/377718/zdb01204003319.pdf by guest on 04 November 2022