Evaluation of the microsomal glutathione S-transferase 3 (MGST3) locus on 1q23 as a Type 2 diabetes susceptibility gene in Pima Indians
Elevation of plasma glucose concentration may induce generation of oxygen-free radicals, which can play an important role in the progression of diabetes and/or development of its complications. Various glutathione transferases utilize the availability of reduced glutathione for the cellular defense against oxygen-free radicals. One such enzyme is microsomal glutathione S-transferase 3 encoded by MGST3, which maps to chromosome 1q23, a region linked to Type 2 diabetes mellitus (T2DM) in Pima Indians, Caucasian, and Chinese populations. We investigated the MGST3 gene as a potential susceptibility gene for T2DM by screening this locus for single nucleotide polymorphisms (SNPs) in diabetic and non-diabetic Pima Indians. We also measured the skeletal muscle MGST3 mRNA level by Real-Time (RT) PCR and its relationship with insulin action in non-diabetic individuals. We identified 25 diallelic variants, most of which, based on their genotypic concordance, could be divided into three distinct linkage disequilibrium (LD) groups. We genotyped unique representative SNPs in selected diabetic and non-diabetic Pima Indians and found no evidence for association with T2DM. Furthermore, inter-individual variation of skeletal muscle MGST3 mRNA was not correlated with differences in insulin action in non-diabetic subjects. We conclude that alterations of MGST3 are unlikely to contribute to T2DM or differences in insulin sensitivity in the Pima Indians.
KeywordsSkeletal Muscle Biopsy Translation Stop Codon Gila River Indian Community Microsomal Glutathione Representative SNPs
We thank the members of the Gila River Indian Community for their continued participation in the ongoing longitudinal studies of Type 2 diabetes. We also thank Dr. Richard Pratley, Mike Millner and Carol Massengil for clinical studies and patient care, and Vicky Ossowski and Shawnell Damon for variant detection and validation.
- Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820Google Scholar
- Hansen LL, Ikeda Y, Olsen GS, Busch AK, Mosthaf L (1999) Insulin signaling is inhibited by micromolar concentrations of H2O2. J Biol Chem 274:2078–25084Google Scholar
- Hanson RL, Ehm MG, Pettitt DJ, Prochazka M, Thompson DB, Timberlake D, Foroud T, Kobes S, Baier L, Burns DK, Almasy L, Blangero J, Garvey WT, Benneett PH, Knowler WC (1998) An autosomal genomic scan for loci linked to Type 2 diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 63:1130–1138PubMedGoogle Scholar
- Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, Knowler WC, Bennett PH, Bogardus C (1993) Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 329:1988–1992PubMedGoogle Scholar
- Knowler WC, Pettitt DJ, Saad MF, Bennett PH (1990) Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diab Metab Rev 6:1–27Google Scholar
- St. Jean P, Mitchell B, Hsueh WC, Burn D, Gelder-Ehm M, Wagner MJ, Bell C, Aburomia R, Nanthakumar E, Shuldiner AR (1999) Type 2 diabetes in the Old Order Amish. Diabetes 48(Suppl.1):A196Google Scholar
- Vionnet N, Hani EL, Dupont S, Gallina S, Francke S, Dotte S, DeMatos F, Durand E, Lepretre F, Lecoeur C, Gallina P, Zekiri L, Dina C, Froguel P (2000) Genome wide search for Type 2 diabetes susceptibility genes in French Whites: Evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a Type 2-diabetes locus on chromosome 1q21–24. Am J Hum Genet 67:1470–1480PubMedGoogle Scholar
- Wang L, Wang X, Adamo ML (2000) Two putative GATA motifs in the proximal exon 1 promoter of the rat insulin-like growth factor I gene regulate basal promoter activity. Endocrinol 141:1118–1126Google Scholar
- Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, O'Rahilly S, Frayling TM, Bell JI, Lathrop, GM, Bennett A, Dhillon R, Fletcher C, Groves CJ, Jones E, Prestwich P, Simecek N, Rao PV, Wishart M, Foxon R, Howell S, Smedley D, Cardon LR, Menzel S, McCarthy MI (2001) A genome wide scan for loci predisposing to Type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet 69:553–69PubMedGoogle Scholar
- Xiang K, Wang Y, Zheng T, Shen K, Jia W, Li J, Lin X, Wu S, Wu S, Zhang G, Wang S, Lu H (2002) Genome wide scan search for Type 2 diabetes susceptibility loci in Chinese. Diabetes. 51 (Suppl.2):A262Google Scholar
- Xu W, Murphy LJ (2000) Cloning of the mouse Pax4 gene promoter and identification of a pancreatic beta cell specific enhancer. Mol Cell Endocrinol 170:79–89Google Scholar