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

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.

Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions

“…Moreover, within the Gc2 polymorphic region (rs4588), individuals in an Iranian population with an AA genotype within this polymorphic region showed a greater increase in 25(OH)D levels following vitamin D supplementation than those with the GG genotype did (47). Similar results were found with a different polymorphism at rs2282679 in Caucasian women (48). Rs2282679, an intronic polymorphism in the DBP gene that does not alter DBP structure, was previously shown in GWAS studies to be associated with lower 25(OH)D and DBP levels in several different populations (49)(50)(51).…”

“…DBP is comprised of 3 structurally similar domains. The first domain is the binding site for the vitamin D metabolites (aa [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. Fatty acid binding utilizes a single high affinity site for both palmitic acid and arachidonic acid, but only arachidonic acid competes with 25(OH)D for binding (16,17).…”

Early‐life dietary and epigenetic influences on childhood musculoskeletal health: Update on the UK component of the ALPHABET project

“…The results of this trial suggest that such a supplementary approach leads to improved offspring bone mineral content (of around 0.5 SD) compared with placebo, for neonates born in the winter months, when background 25(OH)D concentrations are lowest (although not in the population overall) . Subsequent work has identified interactions with both environmental and genetic factors in the achieved 25 (OH)D in response to treatment (Moon et al , 2017; mechanistic investigations using placental samples have identified novel relationships between vitamin D and placental nutrient transport (Cleal et al 2015). These candidate-focused studies contrast with findings from a recent investigation using the Illumina Human Methylation 450 BeadChip, an array covering methylation marks at over 450 000 CpG sites across the genome.…”

“…Subsequent work has identified interactions with both environmental and genetic factors in the achieved 25(OH)D in response to treatment (Moon et al . , ); mechanistic investigations using placental samples have identified novel relationships between vitamin D and placental nutrient transport (Cleal et al . ).…”

Maternal and Foetal Health Implications of Vitamin D Status during Pregnancy

“…This dose is sufficient for the general population who adequately expose themselves to the sun, but it is too low to treat situations of vitamin D deficiency, especially in mothers and newborns with genetic variation in genes involved in vitamin D metabolism [22], or with a goal to achieve vitamin D levels higher than 30 ng/mL. In fact, some health organizations suggest that at least 400 IU/day is used as a supplement, and the total intake should be in the range of 1,000-2,000 IU/day from dietary sources (e.g., oily fish) and supplements [23].…”