GLUT4 Gene Polymorphisms and Their Association with Type 2 Diabetes in South Indians Dhanasekaran Bodhini, Ph.D., 1,2 Venkatesan Radha, Ph.D., 1,2 Saurabh Ghosh, Ph.D., 3 Partha P. Majumder, Ph.D., 3 M.R. Satyanarayana Rao, Ph.D., 4 and Viswanathan Mohan, M.D., FRCP, Ph.D., D.Sc., FNASc 1,2 Abstract Background and Objectives: The GLUT4 gene, which encodes glucose transporter 4, is a candidate gene for type 2 diabetes mellitus (T2DM). The aim of this study was to screen the GLUT4 gene for polymorphisms and to study association of such polymorphisms with T2DM in an Asian Indian population in southern India. Methods: The GLUT4 gene was sequenced in 25 normal glucose tolerance (NGT) and 25 T2DM subjects, and the variants found were then genotyped by polymerase chain reaction–restriction fragment length polymorphism in a pilot study population of 552 NGT and 643 T2DM subjects, randomly selected from the Chennai Urban Rural Epidemiology Study. Two of the variants (rs5435 and the novel variant), which showed significantly higher minor allele frequency in T2DM compared with NGT individuals in the pilot study population, were then retested with an additional 465 NGT and 363 T2DM subjects, giving a final sample size of 1,017 NGT and 1,006 T2DM subjects. Results: Sequencing of the GLUT4 gene revealed three known polymorphisms (rs5418, rs5421, and rs5435) and one novel T/G variant in the 3¢ untranslated region (UTR) at nucleotide position 6787483. The rs5418 and rs5421 polymorphisms did not show any association with diabetes. The rs5435 [Asn130Asn(C/T)] polymor- phism was found to be associated with diabetes, with the odds ratio for the CT + TT genotype being 1.26 (95% confidence interval, 1.00–1.57; P = 0.043) when the CC genotype was taken as reference. The frequency of the TG genotype of the novel 3¢UTR T/G variant was significantly higher in diabetes subjects (1%) compared with NGT subjects (0.2%) (P = 0.021). There was a significant difference in the proportion of the ACGT haplotype of the rs5418(A/G), rs5435(C/T), rs5421(C/G), and the T/G3¢UTR variant between the NGT (7.5%) and diabetes (5%) groups (P = 0.003). Conclusion: The rs5435 (C/T) polymorphism of the GLUT4 gene is associated with type 2 diabetes in this south Indian population. Introduction T ype 2 diabetes mellitus (T2DM) is characterized at least in part by decreased insulin-stimulated glucose uptake in tissues such as muscle and adipose tissue. Defects in whole- body insulin-mediated glucose uptake in T2DM patients have been tracked to impairments in insulin signaling and trans- location of the glucose transporter, GLUT4. 1–3 The GLUT4 gene [also known as the SLC2A4 (solute carrier family 2, member 4) gene] encoding the GLUT4 protein is therefore a strong candidate gene for T2DM. The GLUT4 gene has not been thoroughly investigated in Asian Indians, who have an increased susceptibility to dia- betes, and currently there are over 50 million people with diabetes in India. 4 It has been shown that plasma insulin levels, a surrogate marker of insulin resistance, were higher in Asian Indians compared with Europeans, 5 and glucose clamp studies confirmed that Asian Indians have a greater degree of insulin resistance. 6 Subsequently, several studies have con- firmed these findings. 7–9 These studies suggest that there could be a genetic predisposition to insulin resistance and diabetes in Asian Indians. 1 Madras Diabetes Research Foundation, ICMR Advanced Centre for Genomics of Type 2 Diabetes, Chennai, India. 2 Dr. Mohan’s Diabetes Specialities Centre, World Health Organization Collaborating Centre for Non Communicable Diseases Prevention and Control, Chennai, India. 3 Human Genetics Unit, Indian Statistical Institute, Kolkata, India. 4 Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India. DIABETES TECHNOLOGY & THERAPEUTICS Volume 13, Number 9, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2010.0219 913