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Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial.

Curtis, EM; Krstic, N; Cook, E; D'Angelo, S; Crozier, SR; Moon, RJ; Murray, R; Garratt, E; Costello, P; Cleal, J; et al. Curtis, EM; Krstic, N; Cook, E; D'Angelo, S; Crozier, SR; Moon, RJ; Murray, R; Garratt, E; Costello, P; Cleal, J; Ashley, B; Bishop, NJ; Kennedy, S; Papageorghiou, AT; Schoenmakers, I; Fraser, R; Gandhi, SV; Prentice, A; Javaid, MK; Inskip, HM; Godfrey, KM; Bell, CG; Lillycrop, KA; Cooper, C; Harvey, NC; MAVIDOS Trial Group (2019) Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial. J Bone Miner Res, 34 (2). pp. 231-240. ISSN 1523-4681 https://doi.org/10.1002/jbmr.3603
SGUL Authors: Papageorghiou, Aris

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Abstract

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at -80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was -1.98% (95% CI, -3.65 to -0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Item Type: Article
Additional Information: © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: EPIDEMIOLOGY, EPIGENETIC, METHYLATION, OSTEOPOROSIS, RXRA, VITAMIN D, MAVIDOS Trial Group, EPIGENETIC, METHYLATION, RXRA, VITAMIN D, OSTEOPOROSIS, EPIDEMIOLOGY, 11 Medical And Health Sciences, 06 Biological Sciences, 09 Engineering, Anatomy & Morphology
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Clinical Education (INMECE )
Journal or Publication Title: J Bone Miner Res
ISSN: 1523-4681
Language: eng
Dates:
DateEvent
14 February 2019Published
18 January 2019Published Online
6 October 2018Accepted
Projects:
Project IDFunderFunder ID
17702Versus ArthritisUNSPECIFIED
MC_UP_A620_1015Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_U147585827Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_U105960371Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
21231Versus ArthritisUNSPECIFIED
UNSPECIFIEDArthritis Research UKhttp://dx.doi.org/10.13039/501100000341
MC_UU_12011/2Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_U147585819Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UP_A620_1014Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
69629Horizon 2020UNSPECIFIED
MC_UU_12011/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
201268/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
G0601019Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_12011/4Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0400491Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_U147585824Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/J000094/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
4050502589Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
289346Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
613977Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
BB/P028179/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
PubMed ID: 30321476
Web of Science ID: WOS:000458653600004
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111358
Publisher's version: https://doi.org/10.1002/jbmr.3603

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