Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus

Background Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays an important role in insulin signaling. Mutations in the IRS-1 gene are associated in some popul ations with obesity and Type 2 diabetes. Methods To determine whether variation in the IRS-1 gene contributes to gen etic susceptibility to insulin resistance and Type 2 diabetes in Mexican Am ericans, the entire coding region of the IRS-1 gene was screened for variat ion in 31 unrelated subjects with Type 2 diabetes using single-stranded con formational polymorphism analysis (SSCP) and dideoxy sequence analysis. Var iants encoding amino acid substitutions were genotyped in 27 unrelated nond iabetic Mexican Americans and in all family members of subjects containing these variants, and association analyses were performed. To trace the ances tral origins of the variants, Iberian Caucasians and Pima Indians were also genotyped. Results Eight single base changes were found: four silent polymorphisms and four missense mutations (Ala94Thr, Ala512Pro, Ser892Gly and Gly971Arg). Al lele frequencies were 0.009, 0.017, 0.017 and 0.043, respectively. There we re no significant associations of any of these variants with diabetes, gluc ose or insulin levels during an oral glucose tolerance test, or with body m ass index (BMI) in Mexican American families except for a modest associatio n between the Ala94Thr variant and decreased BMI (30.4 kg/m(2) vs 24.0 kg/m (2); p=0.035). None of these four missense mutations were detected in Pima Indians. In Iberian Caucasians, neither Ala94Thr nor Ser892Gly were detecte d, and Ala512Pro was detected in only 0/60 diabetic patients and 1/60 nondi abetic controls. Gly971Arg was relatively more common in Iberian Caucasians with 12/58 diabetic patients and 7/60 nondiabetic controls being heterozyg ous for this variant (p = 0.21 for comparison between diabetic and nondiabe tic subjects). Conclusions Ala94Thr, Ala512Pro and Ser892Gly mutation are rare in the popu lations studied. Gly971Arg, is more common in Mexican Americans and Caucasi ans, but is not a major contributor to genetic susceptibility to Type 2 dia betes. Copyright (C) 2000 John Wiley & Sons, Ltd.