We are performing global exon expression profiling to complement the ongoing positional cloning effort to identify susceptibility genes for diabetes and its predictors, insulin resistance, insulin secertory dysfunction and obesity. To this end, we are examining exon expression profiles in tissue samples from non-diabetic full-blooded Pima Indians using Affymetrix exon arrys that query over 1 million known and predicted exons across the entire genome. We have collected 225 skeletal muscle tissue samples and 250 adipose tissue samples from non-diabetic Pima Indians who have been metabolically phenotyped for body composition and insulin action in vivo using the hyperinsulinemic euglycemic clamp. Follow up data is available on the diabtic status of most of these volunteers, up to 7-10 years later, so will be able to identify a prediabtic exon expression profile in this population. We have completed the exon arrays on all skeletal muscle and adipose tissue samples and are currently analyzing these data and comparing to genotypic data collected on many of the subjects from our genome-wide association study using single nucleotide polymorphisms. Initial analyses ahve identified several trancripts with a bimodal distribuiton apparently due to cis acting DNA elements. One of these transcripts was HLA-DRB1 and levels of this trancript were associated with early insulin secretion indicating an autoimmune regulation of insulin secretion in this population.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2011
Total Cost
$1,224,253
Indirect Cost
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Piaggi, Paolo; Masindova, Ivica; Muller, Yunhua L et al. (2017) A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in GPR158 Associated With Reduced Energy Expenditure in American Indians. Diabetes 66:2284-2295
Traurig, Michael; Hanson, Robert L; Marinelarena, Alejandra et al. (2016) Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression. Diabetes 65:510-9
Muller, Yunhua L; Piaggi, Paolo; Hanson, Robert L et al. (2015) A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians. Hum Mol Genet 24:2985-96
Muller, Yunhua L; Piaggi, Paolo; Hoffman, Duncan et al. (2014) Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure. Diabetologia 57:1382-90
Traurig, Michael T; Orczewska, Julieanna I; Ortiz, Daniel J et al. (2013) Evidence for a role of LPGAT1 in influencing BMI and percent body fat in Native Americans. Obesity (Silver Spring) 21:193-202
Bian, Li; Traurig, Michael; Hanson, Robert L et al. (2013) MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation. Hum Mol Genet :
Traurig, Michael T; Orczewska, Julieanna I; Ortiz, Daniel J et al. (2012) Evidence for a Role of LPGAT1 in Influencing BMI and Percent Body Fat in Native Americans. Obesity (Silver Spring) :
Mason, Clinton C; Hanson, Robert L; Ossowski, Vicky et al. (2011) Bimodal distribution of RNA expression levels in human skeletal muscle tissue. BMC Genomics 12:98
Williams, R C; Muller, Y L; Hanson, R L et al. (2011) HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion. Diabetologia 54:1684-92
Bian, Li; Hanson, Robert L; Ossowski, Victoria et al. (2010) Variants in ASK1 are associated with skeletal muscle ASK1 expression, in vivo insulin resistance, and type 2 diabetes in Pima Indians. Diabetes 59:1276-82