vitamin D receptor genetic variants

Vitamin D insufficiency has been implicated in many musculoskeletal and extra skeletal diseases, which has led to substantial interest in the determinants of vitamin D status.
This paper by Wang et al Our findings establish a role for common genetic variants in regulation of circulating 25-hydroxyvitamin D concentrations. The presence of harmful alleles at the three confirmed loci more than doubled the risk of vitamin D insufficiency. These findings improve – our understanding of vitamin D homoeostasis and could assist identification of a subgroup of the white population who are at risk of vitamin D insufficiency.
DHCR7/NADSYNl is a novel locus for association with vitamin D status, DHCR7 encodes the enzyme 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, thereby removing the substrate from the synthetic pathway of vitamin D, a precursor of 25-hydroxyvitamin DJ. Rare mutations in DHCR7lead to Smith-Lernli-Opitz syndrome, which is characterised by reduced activity of 7-DHC reductase, accumulation of 7-DHC, low cholesterol, and many congenital abnormalities.” Mutations in DHCR7 might also confer a competitive advantage to heterozygous carriers, because high concentrations of 7-DHC could provide protection against rickets and osteomalacia from hypovitaminosis D.The finding that common variants at DHCR7 are strongly associated with circulating 25-hydroxyvitamin D concentrations suggests that this enzyme could have a larger role in regulation of vitamin D status than has previously been recognised.
The gene at the second locus, CYP2Rl, encodes a hepatic microsomal enzyme. CYP2Rl could be the enzyme underlying 25-hydroxylation of vitamin D in the liver, but this suggestion is uncertain because many other enzymes with 25-hydroxylase activity in vitro have been described These finding that common variants at the CYP2Rl locus are associated with circulating 25-hydroxyvitamin D concentrations is the strongest evidence so far that CYP2R1 is the enzyme underlying the crucial first step in vitamin D metabolism.
The third gene, GC, encodes vitamin D binding protein, which is a 52-59 kDA protein synthesised in the liver that binds and transports vitamin D and its metabolites (including25-hydroxyvitarninDand1,25-dihydroxyvitamin D).
Wang et al 2010 Common genetic determinants of vitamin D insufficiency : a genome – wide association study. Lancet vol 376 pp 180-88

Martin Eastwood
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