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.
Keywords Common variants - Genetic association - Insulin resistance - IRS1 - Linkage disequilibrium - Single nucleotide polymorphism - SNP - Type 2 diabetes
D. Altshuler and L. Groop jointly supervised this project.