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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 [? represents the change in 25(OH)D per additional common allele]. Results:Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [? = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (? = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (? = 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.

SUBMITTER: Moon RJ

PROVIDER: S-EPMC5546866 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Moon Rebecca J RJ Harvey Nicholas C NC Cooper Cyrus C D'Angelo Stefania S Curtis Elizabeth M EM Crozier Sarah R SR Barton Sheila J SJ Robinson Sian M SM Godfrey Keith M KM Graham Nikki J NJ Holloway John W JW Bishop Nicholas J NJ Kennedy Stephen S Papageorghiou Aris T AT Schoenmakers Inez I Fraser Robert R Gandhi Saurabh V SV Prentice Ann A Inskip Hazel M HM Javaid M Kassim MK

The Journal of clinical endocrinology and metabolism 20170801 8

<h4>Context</h4>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.<h4>Objective</h4>To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation.<h4>Design</h4>Within-randomization group analysis of the Maternal Vit ...[more]

PMID: 28575224

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Project description:BackgroundVariability in the 25-hydroxyvitamin D [25(OH)D] response to prenatal and postpartum vitamin D supplementation is an important consideration for establishing vitamin D deficiency prevention regimens.ObjectivesWe aimed to examine interindividual variation in maternal and infant 25(OH)D following maternal vitamin D supplementation.MethodsIn a randomized trial of maternal vitamin D supplementation (Maternal Vitamin D for Infant Growth Trial), healthy pregnant women (n = 1300) received a prenatal cholecalciferol (vitamin D-3) dose of 0, 4200, 16,800, or 28,000 IU/wk from 17 to 24 wk of gestation followed by placebo to 6 mo postpartum. A fifth group received 28,000 IU cholecalciferol/wk both prenatally and postpartum. In a subset of participants, associations of 25(OH)D with hypothesized explanatory factors were estimated in women at delivery (n = 655) and 6 mo postpartum (n = 566), and in their infants at birth (n = 502) and 6 mo of age (n = 215). Base models included initial 25(OH)D and supplemental vitamin D dose. Multivariable models were extended to include other individual characteristics and specimen-related factors. The model coefficient of determination (R2) was used to express the percentage of total variance explained.ResultsSupplemental vitamin D intake and initial 25(OH)D accounted for the majority of variance in maternal 25(OH)D at delivery and postpartum (R2 = 70% and 79%, respectively). Additional characteristics, including BMI, contributed negligibly to remaining variance (<5% increase in R2). Variance in neonatal 25(OH)D was explained mostly by maternal delivery 25(OH)D and prenatal vitamin D intake (R2 = 82%). Variance in 25(OH)D in later infancy could only partly be explained by numerous biological, sociodemographic, and laboratory-related characteristics, including feeding practices (R2 = 43%).ConclusionsPresupplementation 25(OH)D and vitamin D supplemental dose are the major determinants of the response to maternal prenatal vitamin D intake. Vitamin D dosing regimens to prevent maternal and infant vitamin D deficiency should take into consideration the mean 25(OH)D concentration of the target population.

Project description:Vitamin D deficiency represents a major healthcare problem. Vitamin D status is influenced by genetic and environmental determinants. Several observational studies have evaluated the association of single-nucleotide polymorphisms (SNPs) in vitamin D-related genes and vitamin D levels. Nevertheless, little is known about the role of these SNPs in the response to vitamin D supplementation. We conducted an interventional study to define the association between SNPs in vitamin D-related genes and the response to vitamin D supplementation in 100 self-reported healthy women of Arab ancestry for the majority. A total of 100 healthy female subjects received a weekly oral dose of 50,000 IU vitamin D for 12 weeks. Serum vitamin D concentration and metabolic profiles were measured at baseline and 12 weeks post-vitamin D supplementation. The genotypes of 37 SNPs selected from previously reported vitamin D-related genes have been assessed by Fluidigm genotyping assay. Rs731236 (VDR gene) and rs7116978 (CYP2R1 gene) showed a significant association with vitamin D status. The rs731236 GG genotype and the rs7116978 CC genotype were associated with a "vitamin D sufficiency" state. Rs731236 GG and rs7116978 CC genotypes showed a higher response to vitamin D supplementation. Transcription factor binding site prediction analysis showed altered binding sites for transcription factors according to the different rs7116978 alleles. Interestingly, the 37 SNPs previously established to play a role in vitamin D-related pathways explained very little of the response to vitamin D supplementation in our cohort, suggesting the existence of alternative loci whose number and effect size need to be investigated in future studies. In this paper, we present novel data on vitamin D-related SNPs and response to vitamin D supplementation demonstrating the feasibility of applying functional genomic approaches in interventional studies to assess individual-level responses to vitamin D supplementation.

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

Publications

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

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