A gene is considered a candidate gene for type 2 diabetes in Pimas if 1) it is associated with a diabetic phenotype in another population or 2) it has a physiologically relevant function and is positioned in a chromosomal region that is linked to diabetes. Candidate genes which have been analyzed to date include those genes which are associated with Mody in other populations. We identified several polymorphisms in the HNFla, HNFlb, and HNF3b genes, but none were associated with early onset diabetes in Pimas. One polymorphism in HNFlb, however, predicts a non-conservative amino acid substitution within the DNA binding region of the protein. Therefore the substitution in HNF1b was investigated for functional variability. We have cloned the two polymorphic forms of HNF1b into expression vectors. In addition, we have cloned the rat albumin promoter, which is regulated by HNF1b, into a luciferase reporter plasmid. Each of the vectors containing HNF1b were co- transfected with the luciferase reporter plasmid into Cos 7 cells. We have found that the uncommon amino acid variant upregulates transcription from the rat albumin promoter.We have also analyzed a polymorphism in a candidate gene which is thought to be responsible for the diabetic locus NIDDM1 in Mexican Americans. We have genotyped this polymophism in 1300 Pima Indians and have found an association with insulin resistance and nutrient partitioning in non-diabetic Pimas. We have also genotyped a second polymorphism near a related gene on chromosome 15 which is thought to interact with the NIDDM1 locus in Mexican Americans. We did not find any significant associations with the polymorphism on chromosome 15 in Pimas. - Human Subjects

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK069071-03
Application #
6289867
Study Section
Special Emphasis Panel (PECR)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Traurig, Michael; Mack, Janel; Hanson, Robert L et al. (2009) Common variation in SIM1 is reproducibly associated with BMI in Pima Indians. Diabetes 58:1682-9
Rong, Rong; Hanson, Robert L; Ortiz, Daniel et al. (2009) Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes 58:478-88
Korner, A; Ma, L; Franks, P W et al. (2007) 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) 31:353-8
Traurig, M; Hanson, R L; Kobes, S et al. (2007) Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians. Diabetologia 50:985-9
Guo, Tingwei; Hanson, Robert L; Traurig, Michael et al. (2007) TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3,501 individuals. Diabetes 56:3082-8
Traurig, Michael T; Permana, Paska A; Nair, Saraswathy et al. (2006) Differential expression of matrix metalloproteinase 3 (MMP3) in preadipocytes/stromal vascular cells from nonobese nondiabetic versus obese nondiabetic Pima Indians. Diabetes 55:3160-5
Guo, Yan; Traurig, Michael; Ma, Lijun et al. (2006) CHRM3 gene variation is associated with decreased acute insulin secretion and increased risk for early-onset type 2 diabetes in Pima Indians. Diabetes 55:3625-9
Muller, Yunhua Li; Infante, Aniello M; Hanson, Robert L et al. (2005) Variants in hepatocyte nuclear factor 4alpha are modestly associated with type 2 diabetes in Pima Indians. Diabetes 54:3035-9
Kovacs, P; Ma, L; Hanson, R L et al. (2005) Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians. Diabetologia 48:2292-5
Ma, Lijun; Tataranni, P Antonio; Hanson, Robert L et al. (2005) Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men. Diabetes 54:1598-602

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