Response to antenatal cholecalciferol supplementation is associated with common vitamin D related genetic variants.

Context: Single nucleotide polymorphisms (SNP) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation. Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1 and GC are associated with the response to gestational cholecalciferol supplementation. Design: Within-randomization-group analysis of the MAVIDOS trial of antenatal cholecalciferol supplementation. Setting: Hospital antenatal clinics. Participants: 682 women of White ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1) and rs2282679 (GC) were genotyped. Interventions: 1000 IU/day cholecalciferol from 14 weeks gestation until delivery. Main Outcome Measure: 25(OH)D at randomisation and 34 weeks gestation were measured in a single batch (Diasorin Liaison). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model (beta represents the change in 25(OH)D per additional common allele). Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β=3.1nmol/l (95% CI 1.0, 5.2), p<0.004]. In contrast, rs10741657 (CYP2R1) [β=-5.2nmol/l (95%CI -8.2, -2.2), p=0.001] and rs2282679 (GC) [β=4.2nmol/l (95%CI 0.9, 7.5), p=0.01] were associated with achieved 25(OH)D status following supplementation, while rs12785878 and rs6013897 (CYP24A1) were not. Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity.