Brief Genetics Report The Gly3Arg IRS-1 Variant Is Associated With Type 1 Diabetes in Continental Italy

The Arg insulin receptor substrate-1 (IRS-1) variant has been hypothesized to play a role in pancreatic -cell stimulus-coupled insulin secretion and survival. We analyzed the relations between type 1 diabetes and the Arg IRS-1 variant. The frequency of the IRS-1 Arg variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. In the former group, frequency of the IRS-1 Arg variant was significantly increased in the patients (P 0.0008), conferring an OR of 2.5. Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). Arg IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. Arg IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wildtype IRS-1 (0.49 0.058, n 34, and 0.76 0.066, n 134, respectively [means SE]; P 0.051). Our findings suggest a role for Arg IRS-1 in conferring risk for the development of type 1 diabetes. Diabetes 52:887–890, 2003