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Evaluation of the microsomal glutathione S-transferase 3 (MGST3) locus on 1q23 as a Type 2 diabetes susceptibility gene in Pima Indians

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Abstract

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.

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References

  • Aronson D, Rayfield EJ (2002) How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol 1:1–10

    Article  PubMed  Google Scholar 

  • Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9

    CAS  PubMed  Google Scholar 

  • Blair AS, Hajduch E, Litherland GJ, Hundal HS (1999) Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress. J Biol Chem 274:36293–36299

    Article  CAS  PubMed  Google Scholar 

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Google Scholar 

  • Elbein SC, Hoffman MD, Teng K, Leppert MF, Hasstedt SJ (1999) A genome-wide search for Type 2 diabetes susceptibility gene in Utah Caucasians. Diabetes 48:1175–1182.

    PubMed  Google Scholar 

  • Ford-Hutchinson AW (1990) Leukotriene B4 in inflammation. Crit Rev Immunol 10:1–12

    CAS  PubMed  Google Scholar 

  • Hansen LL, Ikeda Y, Olsen GS, Busch AK, Mosthaf L (1999) Insulin signaling is inhibited by micromolar concentrations of H2O2. J Biol Chem 274:2078–25084

    Google 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 63:1130–1138

    PubMed  Google Scholar 

  • Jakobsson PJ, Mancini JA, Riendeau D, Ford-Hutchinson AW (1997) Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities. J Biol Chem 272:22934–22939

    Article  CAS  PubMed  Google 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 329:1988–1992

    CAS  PubMed  Google Scholar 

  • Lu SC (1999) Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 13:1169–1183

    CAS  PubMed  Google Scholar 

  • Knowler WC, Pettitt DJ, Saad MF, Bennett PH (1990) Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diab Metab Rev 6:1–27

    CAS  Google Scholar 

  • Pugh BF, Tjian R (1990) Mechanism of transcriptional activation by SP1: Evidence for coactivators. Cell 61:1187–1197

    CAS  PubMed  Google Scholar 

  • Rudich A, Kozlovsky N, Potashnik R, Bashan N (1997) Oxidant stress reduces insulin responsiveness in 3T3-L1 adipocytes. Am J Physiol 272:E935–940

    CAS  PubMed  Google 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):A196

  • Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155–7174

    PubMed  Google 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 67:1470–1480

    PubMed  Google 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 141:1118–1126

    CAS  Google Scholar 

  • West IC (2000) Radicals and oxidative stress in diabetes. Diabet Med 17:171–180

    Article  CAS  PubMed  Google 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 69:553–69

    PubMed  Google Scholar 

  • Wingender E, Chen X, Hehl R, Karas H, Liebich I, Matys V, Meinhardt T, Prub M, Reuter I, Schacherer F (2000) TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res 28:316–319

    CAS  PubMed  Google Scholar 

  • Wolford JK, Blunt D, Ballecer C, Prochazka M (2000) High-throughput SNP detection by using DNA pooling and denaturing high performance liquid chromatography (DHPLC). Hum Genet 107:483–487

    Article  CAS  PubMed  Google 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):A262

  • Xu W, Murphy LJ (2000) Cloning of the mouse Pax4 gene promoter and identification of a pancreatic beta cell specific enhancer. Mol Cell Endocrinol 170:79–89

    Google Scholar 

  • Young IS, Woodside JV (2001) Antioxidants in health and disease. J Clin Pathol 54:176–186

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 4212 North 16th Street, AZ 85016, Phoenix, USA

    Farook Thameem, Xiaolin Yang, Paska A. Permana, Johanna K. Wolford, Clifton Bogardus & Michal Prochazka

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  1. Farook Thameem
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  2. Xiaolin Yang
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  3. Paska A. Permana
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  4. Johanna K. Wolford
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  5. Clifton Bogardus
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  6. Michal Prochazka
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Correspondence to Farook Thameem.

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Thameem, F., Yang, X., Permana, P.A. et al. Evaluation of the microsomal glutathione S-transferase 3 (MGST3) locus on 1q23 as a Type 2 diabetes susceptibility gene in Pima Indians. Hum Genet 113, 353–358 (2003). https://doi.org/10.1007/s00439-003-0980-y

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  • DOI: https://doi.org/10.1007/s00439-003-0980-y

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