Study of a new PPARγ2 promoter polymorphism and haplotype analysis in a French population

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) plays a role in adipocyte differentiation and insulin sensitization. We identified and characterized a new C/T substitution at position -689 (-689C > T) in the P2 promoter of PPAR gamma in a putative GATA binding site. By electrophoretic mobility shift assay, both GATA2 and GATA3 proteins could bind weakly to the wild-type P2 -689 GATA binding site but not to the mutated site. Neither GATA2 nor GATA3 was able to regulate significantly the P2 promoter activity in a reporter-luciferase assay, whatever the allele at position -689 was, suggesting that the -689 putative GATA site was probably not a functional target for GATAs. However, the presence of the -689T allele rendered the P2 promoter less active at the basal state. We genotyped a population of 1155 men and women for the -689C > T polymorphism and looked for possible associations with anthropometric and lipid variables. The carriers of the -689T allele had elevated body weight and LDL-cholesterol concentrations compared with the homozygous for the common allele. Haplotype analyses including the -681C > G (P3 promoter), -689C > T (P2 promoter), and Prol2Ala (exon B) polymorphisms were performed. Carriers of the G-T-Ala haplotype (corresponding to the P3 -681C > G, P2 -689C > T and Prol2AIa polymorphisms in this order) had elevated LDL-cholesterol concentrations and body weight compared with C-C-Pro individuals. In conclusion, we identified a new polymorphism in the P2 promoter of PPAR gamma. The P3 -681C > G, P2 -689C > T, and Prol2A1a polymorphisms and related haplotypes were associated with higher body weight and plasma LDL-cholesterol concentrations. (C) 2005 Elsevier Inc. All rights reserved.