A functional variant in the peroxisome proliferator--activated receptor [gamma]2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians

Peroxisome proliferator-activated receptor [gamma] (PPAR[gamma])-2 is a member of the nuclear hormone receptor super-family that is expressed predominantly in adipocytes and is thought to have a role in energy homeostasis, adipogenesis, and insulin sensitivity. A functional single nucleotide polymorphism (SNP) that predicts a proline to alanine substitution (Pro12Ala) within the coding region of this gene has previously been associated with obesity and type 2 diabetes in several populations. In this study, we identified several novel SNPs in the promoter region of PPAR[gamma]2 and genotyped them, along with the previously identified Pro12Ala SNP. In 241 nondiabetic Pima subjects, the Pro12Ala was associated with whole-body insulin action (P = 0.05), hepatic insulin action (P = 0.03), and fasting plasma insulin concentrations (P = 0.01). One of the promoter SNPs positioned within a putative E2 box was in high linkage disequilibrium ([absolute value of D'] = 0.98) with the Pro12Ala. This promoter SNP was similarly associated with whole-body insulin action (P = 0.04) and hepatic insulin action (P = 0.05), but not fasting plasma insulin concentrations. Functional studies in transfected 3T3-L1 cells demonstrated that this single base substitution in the putative E2 box significantly altered transcriptional activity front a luciferase reporter construct. These data indicate that this promoter SNP, via its effect on PPAR[gamma]2 expression, may also have functional consequences on PPAR[gamma]2-activated pathways, and perhaps both the promoter SNP and the Pro12Ala contribute to PPAR[gamma]2-related phenotypes.