Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D–Related Genetic Variants

Rebecca J Moon,Stephen Kennedy,Stefania D’Angelo,Cyrus Cooper,Robert Fraser,Elizabeth M Curtis,Ann Prentice,Inez Schoenmakers,Hazel Inskip ,John W Holloway ,Siân Robinson ,Nicholas Bishop ,Nikki Graham ,Seema Gandhi ,Aris T Papageorghiou ,Nicholas C Harvey ,Sheila J Barton ,Sarah Crozier ,Keith M Godfrey ,M K Javaid

doi:10.1210/jc.2017-00682

Abstract

Context:Single-nucleotide polymorphisms (SNPs) 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 Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation.Setting:Hospital antenatal clinics.Participants:In total, 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/d cholecalciferol from 14 weeks of gestation until delivery.Main Outcome Measure:25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele].Results:Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (β = −5.2 nmol/L; 95% CI, −8.2 to −2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas 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.

Highlights

Context: Single-nucleotide polymorphisms (SNPs) 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
The response to antenatal cholecalciferol supplementation was associated with single-nucleotide polymorphisms (SNPs) in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity. (J Clin Endocrinol Metab 102: 2941–2949, 2017)
Antenatal vitamin D supplementation is recommended for all pregnant women in many national guidelines [1,2,3] as severe maternal vitamin D deficiency can result in symptomatic neonatal hypocalcemia [4]

Summary

Methods

The Maternal Vitamin D Osteoporosis Study The Maternal Vitamin D Osteoporosis Study is a multicenter, double-blind, randomized, placebo-controlled trial of vitamin D supplementation in pregnancy. The Maternal Vitamin D Osteoporosis Study was registered prospectively (ISRCTN:82927713; EUDRACT:2007-001716-23); full approval from UK Medicines and Healthcare Products Regulatory Agency was granted, and written, informed consent was obtained from all participants. Women attending one of three UK hospitals [University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton, UK (latitude 50.9° North); Oxford University Hospitals NHS Foundation Trust, Oxford, UK (latitude 51.8° North); Sheffield Hospitals NHS Trust (University of Sheffield), Sheffield, UK (latitude 53.4° North)] for early pregnancy ultrasound screening (11 to 14 weeks of gestation) between 6 October 2008 and 11 February 2014 were invited to participate in the study. A screening blood sample was obtained and analyzed on the local NHS platform [all three laboratories (Southampton, Oxford, and Sheffield) participate in the Vitamin D External Quality Assessment Scheme (http://www.deqas.org/)].

Results

Discussion

Conclusion