Polymorphisms of the peroxisome proliferator-activated receptor γ (PPARγ) gene are associated with osteoporosis

Stimulation of PPAR gamma turns mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the PPAR gamma gene on BMD and fracture risk in two Danish cohorts and found opposing effects of certain SNPs and haplotypes in the two cohorts probably owing to environmental factors. Introduction Stimulation of PPAR gamma causes development of mesenchymal stem cells to adipocytes instead of osteoblasts leading to decreased osteoblast number and BMD. The aim of this study was to examine the effect of PPARG polymorphisms on BMD and fracture risk in two Danish cohorts: AROS, a case-control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for 10 years. On the basis of linkage disequilibrium between SNPs throughout the gene and previous studies we chose 10 polymorphisms for investigation. Methods In AROS, individuals heterozygous for the polymorphisms rs12497191, rs4135263, and rs1151999 had an increased risk of vertebral fractures (OR = 1.48-1.76, p = 0.005-0.04) compared with individuals homozygous for the common allele. In DOPS, individuals heterozygous for rs1151999 had an increased BMD at the hip sites (p a parts per thousand currency signaEuro parts per thousand 0.02). An interaction between rs1151999 and diet was found on BMD in both cohorts. Results For the polymorphism rs1152003 there was an interaction with body weight on BMD at all sites in both cohorts (p a parts per thousand currency signaEuro parts per thousand 0.07). Stratified analyses revealed that in the high weight group in AROS individuals homozygous for the variant allele had a decreased BMD (p a parts per thousand currency signaEuro parts per thousand 0.02), whereas the same pattern was found in the low weight group in DOPS (p a parts per thousand currency signaEuro parts per thousand 0.03). A number of haplotype associations were found as well, the direction of which was opposite in the two cohorts. Conclusion Our study suggests an association SNPs in PPARG and haplotypes thereof and BMD and fracture risk. The effect however appears to be modifiable by environmental factors.