Role of the Vitamin D Receptor (VDR) in the Pathogenesis of Osteoporosis: A Genetic, Epigenetic and Molecular Pilot Study.

The vitamin D receptor (VDR) regulates bone development and calcium homeostasis, suggesting a central role in musculoskeletal diseases such as osteoporosis (OP). Several studies have examined the contribution of polymorphisms and epigenetic signatures in bone metabolism and OP risk, with sometimes inconclusive results. Our study aimed to explore the association between genetic variability, expression and the methylation pattern of with the risk of OP in a cohort of Caucasian patients. Genomic DNA from 139 OP, 54 osteopenic (Ope) and 73 healthy (CTR) subjects were used for genotyping the rs731236 (), rs2228570 () and rs11568820 () polymorphisms of the gene by an allelic discrimination assay. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of expression levels and pyrosequencing analysis of a promoter CpG island were carried out in a subcohort (25 OP and 25 CTR) of subjects. Data obtained showed a significantly higher OP risk for rs11568820 G/A and A/A genotypes ( = 0.05). qRT-PCR revealed lower gene expression levels in the OP group compared to CTR subjects ( = 0.0009), also associated with both the rs11568820 A/A genotype ( = 0.03) and femoral fragility fractures ( = 0.05). No association was found between the methylation pattern of the region analyzed of the promoter and its expression levels. Our results identify a significative association between rs11568820 polymorphism and OP risk. In addition, the transcriptomic profile suggests a putative interconnection with OP progression, providing a useful tool to stratify OP phenotype and fragility fracture risk.