The insulin receptor substrate-1 Gly972Arg polymorphism is not associated with Type 2 diabetes mellitus in two population-based studies

Aims The insulin receptor substrate-1 (IRS-1) gene is among the most frequently studied candidate genes for Type 2 diabetes, but findings have been inconsistent. This may have been due to generally small study sizes, or to interaction with body fatness as suggested by studies of insulin sensitivity. The aim of this study was to test the hypothesis that the IRS-1 Gly972Arg variant increases risk of Type 2 diabetes. Methods We conducted two large population-based studies including a total of 725 cases and 742 control subjects, who were Caucasian Dutch men and women aged 40-70 years. We calculated odds ratios adjusted for body mass index, study centre, sex and age. Results Carriers of the Arg allele did not have a higher prevalence of newly detected (OR 0.49, 95% CI 0.24-1.01) or treated (OR 0.71, 0.37-1.35) Type 2 diabetes in the first study, or a higher prevalence of glucose intolerance (OR 1.07, 0.71-1.59) in the second study. The summary odds ratio was 0.86 (0.62-1.17) for carrying the Arg allele as compared with the Gly/Gly genotype. Associations did not differ appreciably by degree of obesity. Also, the Arg variant was not associated with detrimental values for body mass index, waist circumference, plasma HDL-and total cholesterol or hypertension. Conclusions Our findings indicate that the IRS-1 Gly972Arg variant does not substantially increase risk of common Type 2 diabetes, or Type 2 diabetes in obese persons.