Association between polymorphic variation in VDR and RXRA and circulating levels of vitamin D metabolites

The vitamin D metabolite 1,25(OH)₂D is the bioactive ligand of the vitamin D receptor (VDR). VDR forms a heterodimer with the retinoid X receptors (RXRs) that when bound to ligand influences the transcriptional control of genes that regulate circulating levels of vitamin D metabolites. Whether genetic variation in VDR or RXRA affects circulating levels of 1,25(OH)₂D or 25(OH)D has not been established. We used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between SNPs in VDR and RXRA and serum levels of 1,25(OH)₂D and 25(OH)D. A total of 42 tagSNPs in VDR and 32 in RXRA were analyzed in a sample of 415 participants. Principal components analyses revealed a gene-level association between RXRA and serum 1,25(OH)₂D concentrations (P=0.01), but not 25(OH)D. No gene-level association was found for VDR with either serum biomarker. At the single-SNP level, a significant positive trend was observed for increasing 1,25(OH)₂D levels with each additional copy of the A allele for RXRA SNP rs9409929 (P-trend=0.003). After a multiple comparisons adjustment, no individual SNP in VDR or RXRA was significantly associated with either outcome. These results demonstrate an association between genetic variation in RXRA and 1,25(OH)₂D serum concentrations.