25-hydroxyvitamin D response to antenatal cholecalciferol supplementation is associated with common vitamin D related genetic variants: findings from the MAVIDOS trial
Objectives: Single nucleotide polymorphisms (SNP) in genes related to vitamin D metabolism have been associated with 25-hydroxyvitamin D (25(OH)D) status, but these relationships have not been examined in pregnancy or following antenatal vitamin D supplementation. We assessed whether SNPs in DHCR7 (7-dehydrocholesterol reductase), CYP2R1 (25-hydroxylase), CYP24A1 (24-hydroxylase) and GC (Vitamin D binding protein) were associated with the response to antenatal vitamin D supplementation. Methods: MAVIDOS is a randomised double-blind placebo-controlled trial of 1000IU/day cholecalciferol from 14 weeks gestation until delivery in women with a baseline 25(OH)D of 25–100 nmol/l. Anthropometry, serum 25(OH)D (Diasorin Liaison), health and diet were assessed at 14 and 34 weeks gestation. Genotyping of rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1) and rs2282679 (GC) was undertaken by LGC Genomics (Hoddeston, UK) using KASP™ competitive allele-specific PCR. Multiple linear regression was performed using an additive model with the homozygous minor allele as the reference group (beta represents the change in outcome per additional major allele), adjusting for a number of previously identified determinants of 25(OH)D. Results: 712 women (367 placebo, 345 cholecalciferol) were included (95.8% White ethnicity). Only rs12785878 (DHCR7) was associated with baseline 25(OH)D (β=4.1 nmol/l (95% CI 2.2, 6.1), PCYP2R1) (β=−4.1 nmol/l (95%CI −7.1, −1.2), P=0.006) and rs2282679 (GC) (β=4.4 nmol/l (95%CI 1.2, 7.6), P=0.007) were associated with achieved 25(OH)D after supplementation, but rs12785878 and rs6013897 were not. Conclusion: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the cholesterol/vitamin D biosynthesis pathway in the skin appears to modify baseline 25(OH)D, whereas the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1 and GC, which may alter 25-hydroxylase activity and vitamin D binding protein synthesis. Women with more risk alleles may require higher supplement doses to achieve vitamin D repletion in pregnancy. Disclosure: The authors declared no competing interests.