ORIGINAL ARTICLE Evidence that an HMGA1 Gene Variant Associates with Type 2 Diabetes, Body Mass Index, and High-Density Lipoprotein Cholesterol in a Hispanic-American Population Clive R. Pullinger, PhD, 1 Ira D. Goldfine, MD, 2 Sinan Tanyolac ¸, MD, 3 Irina Movsesyan, BS, 1 Mark Faynboym, 4 Vincent Durlach, MD, 5 Eusebio Chiefari, MD, 6 Daniela P. Foti, MD, PhD, 6 Philip H. Frost, MD, 1 Mary J. Malloy, MD, 1 Antonio Brunetti, MD, PhD, 6 and John P. Kane MD, PhD 1 Abstract Background: High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans. Methods: This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI). Results: In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09–1.90, P = 0.011). The variant was also associated with BMI (positively, P = 0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P = 0.047). Conclusions: As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency. Introduction I t is estimated that 25.8 million Americans are affected by diabetes mellitus with 1.9 million over age 20 newly being diagnosed in 2010. 1,2 Type 2 diabetes mellitus (T2DM) is increasing in prevalence, and Hispanic Americans are at an especially high risk. 1 The hallmark of T2DM is insulin resistance, which is also a component of the metabolic syn- drome, the latter also rapidly increasing in prevalence. 3 We and others have recently shown that the high-mobility group AT-hook 1 (HMGA1) gene is associated with insulin resis- tance and metabolic syndrome. 4–9 This gene codes for the HMGA1 protein, a member of a family of non-histone chromatin binding factors that attach to AT-rich regions of DNA and recruit transcription factors, resulting in upregu- lation of the insulin receptor gene (INSR) expression. 10 We have shown that a specific polymorphism in the HMGA1 gene, IVS5-13insC (c.136-14_136-13insC; rs146052672), is as- sociated with markedly decreased levels of protein and mRNA for both HMGA1 and INSR in circulating human monocytes and lymphoblasts. 6 This IVS5-13insC variant was shown to associate with the presence of metabolic syndrome 5 1 Cardiovascular Research Institute and Department of Physiological Nursing, University of California, San Francisco, California. 2 Diabetes Center, and Department of Medicine, University of California, San Francisco, California. 3 Department of Internal Medicine, School of Medicine, Istanbul Bilim University, Istanbul, Turkey. 4 City College, San Francisco, California. 5 Pole Thoracique et Cardio-Vasculaire, Ho ˆ pital Robert Debre ´, Reims, France. 6 Department of Health Sciences, University ‘‘Magna Græcia’’ of Catanzaro, Catanzaro, Italy. METABOLIC SYNDROME AND RELATED DISORDERS Volume X, Number X, 2013 Ó Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/met.2013.0086 1