Study of a new PPARgamma2 promoter polymorphism and haplotype analysis in a French population.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma 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 PPARgamma. The P3 -681C>G, P2 -689C>T, and Pro12Ala polymorphisms and related haplotypes were associated with higher body weight and plasma LDL-cholesterol concentrations.
Meirhaeghe
Aline
A
INSERM, U508, Institut Pasteur de Lille, 1 rue du Pr. Calmette, BP 245, Lille Cedex F-59019, France. Aline.Meirhaeghe-Hurez@pasteur-lille.fr
Tanck
Michael W T
MW
Fajas
Lluis
L
Janot
Caroline
C
Helbecque
Nicole
N
Cottel
Dominique
D
Auwerx
Johan
J
Amouyel
Philippe
P
Dallongeville
Jean
J
D000328:Adult; D000483:Alleles; D000818:Animals; D001835:Body Weight / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D008078:Cholesterol, LDL / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005602:France; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D047495:PPAR gamma; D015534:Trans-Activators; D014157:Transcription Factors