Functional variants of the HMGA1 gene and type 2 diabetes mellitus

Abstract

Context: High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM). Objective: To examine the association of HMGA1 gene variants with type 2 DM. Design, Settings, and Participants: Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n=3278) and 2 groups of controls (n=3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n=970) were recruited in Northern California clinics between 1994 and 2005 and controls (n=958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n=354) and healthy controls (n=50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls. Main Outcome Measures: The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2DMwere estimated by logistic regression analysis. Results: The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P=.01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P