A functional polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affects height and lipid metabolism in a French population.
OBJECTIVE
The peroxisome proliferator-activated receptor-gamma (PPARgamma) plays a role in adipocyte differentiation and insulin sensitization. It has been shown that genetic variation in the PPARgamma gene alters body weight control, lipid and insulin homeostasis, and the susceptibility to type 2 diabetes. Four PPARgamma isoforms are generated by alternative splicing and promoter usage. PPARgamma3 is only expressed in adipose tissue, colon, and macrophages and therefore seems to be a good candidate gene for metabolic and cardiovascular-associated diseases. In the present study, we looked for genetic variation in the PPARgamma3 promoter.


RESULTS
The proximal PPARgamma3 promoter was sequenced in 20 individuals. We detected a C/G polymorphism at position -681 from exon A2. Interestingly, it was located in a signal transducer and activator of transcription 5B (STAT5B) binding consensus site. In a French population (n=836), the -681G allele was associated with increased height and plasma low-density lipoprotein cholesterol concentrations. In vitro, we showed that the -681G allele completely abolished the binding of STAT5B to the cognate promoter element as well as the transactivation of the PPARgamma3 promoter by the growth hormone/STAT5B pathway.


CONCLUSIONS
Our results suggest that PPARgamma3 may regulate the control of height and lipid homeostasis via the STAT5B pathway.
Meirhaeghe
Aline
A
Service d'Epidémiologie et de Santé Publique, INSERM U.508, Institut Pasteur de Lille, France.
Fajas
Lluis
L
Gouilleux
Fabrice
F
Cottel
Dominique
D
Helbecque
Nicole
N
Auwerx
Johan
J
Amouyel
Philippe
P
D000328:Adult; D001827:Body Height / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008894:Milk Proteins; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D015534:Trans-Activators; D014157:Transcription Factors