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The combinations of polymorphisms in vitamin D receptor, osteoprotegerin and tumour necrosis factor superfamily member 11 genes are associated with bone mineral density
Mencej Bedrač, Simona ...
{alpha},25-dihydroxyvitamin D3 upregulates tumour necrosis factor superfamily member 11 (TNFSF11) that codes for the receptor activator of nuclear factor {kappa}B ligand (RANKL), and downregulates ...osteoprotegerin (OPG) expression. We have analyzed the individual effects of polymorphisms in the vitamin D receptor gene (VDR), OPG and TNFSF11, and searched for interactions between them. Six hundred and forty one subjects were evaluated: 239 osteoporotic and 228 non-osteoporotic post-menopausal, 57 pre-menopausal women and 117 elderly men. The subjects were genotyped for BsmI, FokI and Cdx2 in VDR, K3N in OPG and -290C>T, -643C>T and -693G>C in TNFSF11 gene. Bone mineral density (BMD) and biochemical markers were measured. In the osteoporotic women, femoral neckBMD (BMD-fn) showed associations with BsmI(VDR) and Cdx2(VDR) (P=0.015 and0.047 respectively), and lumbar spine BMD (BMD-ls) with K3N(OPG) and -290C>T(TNFSF11) (P=0.021 and 0.017). No association with BMD was found in thenon-osteoporotic women. In the pre-menopausal women, the Cdx2(VDR) polymorphism was associated with BMD-fn and total hip BMD (P=0.011 and 0.011).In elderly men, FokI(VDR) was associated with BMD-fn and BMD-ls (P=0.040 and 0.036). Interestingly, the -290C>T(TNFSF11)-K3N(OPG) combination was associated with BMD-th (P=0.041) in the osteoporotic women. In the non-osteoporotic women, the combination K3N(OPG)-Cdx2(VDR) was associated withBMD-ls, BMD-th and BMD-fn (P=0.032, 0.049 and 0.022), and the combination -290C>T(TNFSF11)-K3N(OPG) with BMD-fn (P=0.029). For the first time, the presence of gene-gene interactions between VDR, OPG and TNFSF11 genes was studied. Our results strongly suggest further confirmation of their combined influence on larger cohorts.
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