The National Institute of Diabetes & Digestive & Kidney Diseases

The Pima Indians of Arizona have the highest reported prevalence of type 2 diabetes mellitus (T2DM) of any population in the world. They are also a very obese population. Studies have shown that both T2DM and obesity are heritable diseases. The goal of my lab is to identify and characterize susceptibility genes for T2DM and obesity among this Native American population. Two approaches are being pursued: 1) Positional cloning in chromosomal regions identified through linkage studies and 2) Candidate gene analysis.

Positional Cloning in Chromosomal Regions Identified through Linkage Studies- Results from the linkage study in Pima Indians indicated a locus linked to both obesity and T2DM on chromosome 11q23-24, and a second locus linked to T2DM alone on chromosome 1q21-24. During the past several years, more than 1000 SNPs across these regions of linkage on chromosomes 1 and 11 have been genotyped in more than 1300 Pima Indian DNA samples for linkage disequlibrium mapping.

Candidate Gene Analysis- Type 2 diabetes and obesity are polygenic disorders, making it unlikely that the genes on chromosomes 1 and 11 are the sole susceptiblity genes. Therefore we are also investigating phyioslogic candidate genes that do not map to chromosomes 1q and 11q. Candidate genes are selected based on a known physiologic role in glucose and/or lipid metabolism, as well as genes that are associated with T2DM or obesity in other populations or animal models.

1. Kovacs P, Stumvoll M, Bogardus C, Hanson RL, Baier LJ A functional Tyr1306Cys variant in LARG is associated with increased insulin action in vivo. Diabetes (55): 1497-503, 2006. [Full Text/Abstract]

2. Hanson RL, Looker HC, Ma L, Muller YL, Baier LJ, Knowler WC Design and analysis of genetic association studies to finely map a locus identified by linkage analysis: sample size and power calculations. Ann Hum Genet (70): 332-49, 2006. [Full Text/Abstract]

3. Korner A, Ma L, Franks PW, Kiess W, Baier LJ, Stumvoll M, Kovacs P Sex-specific effect of the Val1483Ile polymorphism in the fatty acid synthase gene (FAS) on body mass index and lipid profile in Caucasian children. Int J Obes (Lond) , 2006. [Full Text/Abstract]

4. Kovacs P, Ma L, Hanson RL, Franks P, Stumvoll M, Bogardus C, Baier LJ Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians. Diabetologia (48): 2292-5, 2005. [Full Text/Abstract]

5. Nair S, Lee YH, Rousseau E, Cam M, Tataranni PA, Baier LJ, Bogardus C, Permana PA Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with non-obese Pima Indians. Diabetologia (48): 1784-8, 2005. [Full Text/Abstract]

6. Muller YL, Infante AM, Hanson RL, Love-Gregory L, Knowler W, Bogardus C, Baier LJ Variants in hepatocyte nuclear factor 4alpha are modestly associated with type 2 diabetes in Pima Indians. Diabetes (54): 3035-9, 2005. [Full Text/Abstract]

7. Ma L, Tataranni PA, Hanson RL, Infante AM, Kobes S, Bogardus C, Baier LJ Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men. Diabetes (54): 1598-602, 2005. [Full Text/Abstract]

8. Kovacs P, Harper I, Hanson RL, Infante AM, Bogardus C, Tataranni PA, Baier LJ A novel missense substitution (Val1483Ile) in the fatty acid synthase gene (FAS) is associated with percentage of body fat and substrate oxidation rates in nondiabetic Pima Indians. Diabetes (53): 1915-9, 2004. [Full Text/Abstract]

9. Baier LJ, Hanson RL Genetic studies of the etiology of type 2 diabetes in Pima Indians: hunting for pieces to a complicated puzzle. Diabetes (53): 1181-6, 2004. [Full Text/Abstract]

10. Ma L, Tataranni PA, Bogardus C, Baier LJ Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians. Diabetes (53): 2696-9, 2004. [Full Text/Abstract]

11. Muller YL, Bogardus C, Beamer BA, Shuldiner AR, Baier LJ A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. Diabetes (52): 1864-71, 2003. [Full Text/Abstract]

12. Muller YL, Bogardus C, Pedersen O, Baier L A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor gamma coactivator-1 is associated with altered lipid oxidation and early insulin secretion in Pima Indians. Diabetes (52): 895-8, 2003. [Full Text/Abstract]

13. Kovacs P, Lehn-Stefan A, Stumvoll M, Bogardus C, Baier LJ Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians. Diabetes (52): 1292-5, 2003. [Full Text/Abstract]

14. Kovacs P, Hanson RL, Lee YH, Yang X, Kobes S, Permana PA, Bogardus C, Baier LJ The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians. Diabetes (52): 3005-9, 2003. [Full Text/Abstract]

15. Kovacs P, Yang X, Permana PA, Bogardus C, Baier LJ Polymorphisms in the oxygen-regulated protein 150 gene (ORP150) are associated with insulin resistance in Pima Indians. Diabetes (51): 1618-21, 2002. [Full Text/Abstract]

16. Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen GQ, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest(106): R69-73, 2000. [Full Text/Abstract]