Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes

Abstract

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.

S-Klotho level and physiological markers of cardiometabolic risk in healthy adult men

“…Participants' age range in this study (30-45 years) will allow to verify if the relationship between s-Klotho and cardiometabolic risk markers levels can also be detected in younger but not too young individuals. The age of onset of age-related cardiometabolic diseases decreases in western countries [40,41], increasing in thirties [42,43]. The onset of these disorders may occur even 9-12 years before its clinical diagnosis [44].…”

Genetic association analysis of LARS2 with type 2 diabetes

“…We also included a set of trios originating from the Botnia region of Finland. This sample, FL2, consisted of 211 probands (multiple diabetic sibs) and 370 parents [ 17 , 18 ]. All study samples are summarised in Table 1 .…”

Impact of Insulin Receptor Substrate-1 Genotypes on Platelet Reactivity and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

“…This is because alleles at 2 different markers have different frequencies and thus not the same as in the case of an absolute LD. Because in the association analysis of marker rs1896832 only a proportion of A alleles has a different effect compared with the other G alleles (those in linkage with the C allele of marker rs956115), a larger sample of individuals as reported by others would be required to detect a significant effect of allele A (51). An independent validation would also allow a better estimation of allelic frequencies of the IRS-1 gene, which in our study showed some differences, likely attributable to the sample size, in patients with and without DM.…”