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Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes
J C Florez1, M Sjögren, C M Agapakis
1Simches Research Building-CPZN 6820, Diabetes Unit/Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. jcflorez@partners.org
Aims/Hypothesis:
Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal.
Subjects And Methods:
We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects.
Results:
In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits.
Conclusions/Interpretation:
Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
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