Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

Abstract

Aims/hypothesis. Several case-control studies have examined the association between the Gly972Arg variant in the IRS-1 gene and Type 2 diabetes, but most had limited power and results could therefore be conflicting. Methods. We systematically reviewed the literature by means of a meta-analysis and investigated sources of heterogeneity in results of different studies.Results. The summary risk ratio, based on 3408 cases and 5419 control cases from 27 studies, was 1.25 (95% CI 1.05-1.48). The results, however, differed according to the type of study, method of verifying non-diabetic status of the control subjects, and age of the case subjects. Population-based studies reported lower odds ratios than hospital-based studies (OR 0.98, 95% CI 0.74-1.30 vs OR 1.43, 95% CI 1.17-1.74). Also, the diagnostic test to exclude diabetes amongst control subjects interacted with the association between the IRS-1 Gly972Arg variant and Type 2 diabetes (p=0.03). Finally, the odds ratio reduced with increasing age (p=0.03). Conclusion/interpretation. Overall, carriers of the 972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers. The odds ratios are generally higher in hospital-based studies, including relatively young, symptomatic, cases. [Diabetologia (2003) 46:990-995]

Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

“…Previous studies of genetic risk factors for the development of Type 2 diabetes with complex polygenic inheritance have shown that the effect of a single genetic variant, measured as relative risk, is likely to be in the range of 1.25 to 1.5 [22,23,24,25]. In the present case-control study we have a high statistical power (>95%) to detect a relative risk of 1.25, and thus it seems unlikely that variation of the INS-VNTR as estimated by genotyping the −23 HphI SNP represents a major risk factor in the pathogenesis of Type 2 diabetes among Danish Caucasians.…”

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

“…Having been unable to reproduce the specific association of G972R with type 2 diabetes suggested by Jellema et al [6], we wondered whether other nearby variants (in LD with G972R in some samples but not in others) might account for the association signal noted by other groups. Our study design was well powered to detect associations with similar allele frequencies and putative GRR as proposed for G972R; in addition, its ability to capture common variants in the region was reasonably comprehensive.…”

“…Indeed, the common missense variant glycine → arginine at codon 972 (G972R) [5] was associated with type 2 diabetes in a meta-analysis of 27 studies comprising 8,827 subjects, although the statistical significance of this result was modest [6]. To test the reproducibility of this association, we recently attempted to replicate the same genetic model in large samples totalling 9,000 white individuals.…”

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

“…Previous epidemiological studies found that the IRS-1 G972R variant is associated with insulin resistance [25,28,56], body fat distribution [27], type II diabetes [28], hyperlipidemia, and coronary artery disease [29][30][31]. Other studies, however, have not confirmed these findings [50,[57][58][59][60][61][62][63].…”

“…IRS-1 has an essential mediating role in apoptosis, cell differentiation, and cell transformation through its activity in these pathways [23,24]. A common variant in the IRS-1 gene results in an amino acid change at codon 972 (G972R) that has been associated with impaired insulin signaling [25], obesity [26], body fat distribution [27], type II diabetes [28], hyperlipidemia, and coronary artery disease [29][30][31]. In vitro assays suggest the missense variant changes the ability of the molecule to bind the p85 subunit of PI3-kinase, but does not alter IRS-1 protein expression levels [32].…”