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

Peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ 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 Pro12Ala (exon B) polymorphisms were performed. Carriers of the G-T-Ala haplotype (corresponding to the P3 −681C > G, P2 −689C > T and Pro12Ala 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 PPARγ. The P3 −681C > G, P2 −689C > T, and Pro12Ala polymorphisms and related haplotypes were associated with higher body weight and plasma LDL-cholesterol concentrations.