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Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X receptor-alpha (RXRA) is an essential cofactor in the action of 1,25-dihydroxyvitamin D (1,25[OH]2 -vitamin D), and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women's Survey). Relationships between maternal plasma 25-hydroxyvitamin D (25[OH]-vitamin D) concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, a higher percent methylation at four of six RXRA CpG sites measured was correlated with lower offspring bone mineral content (BMC) corrected for body size (β = -2.1 to -3.4 g/SD, p = 0.002 to 0.047). In a second independent cohort (n = 64), similar negative associations at two of these CpG sites, but positive associations at the two remaining sites, were observed; however, none of the relationships in this replication cohort achieved statistical significance. The maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β = -3.3 SD/unit, p = 0.03). Thus, perinatal epigenetic marking at the RXRA promoter region in umbilical cord was inversely associated with offspring size-corrected BMC in childhood. The potential mechanistic and functional significance of this finding remains a subject for further investigation.

Original publication

DOI

10.1002/jbmr.2056

Type

Conference paper

Publication Date

03/2014

Volume

29

Pages

600 - 607

Addresses

Medical Research Council (MRC) Lifecourse Epidemiology Unit, University of Southampton, UK; National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust, Southampton General Hospital, Southampton, UK.

Keywords

Humans, Vitamin D, Retinoid X Receptor alpha, Electrophoretic Mobility Shift Assay, Prospective Studies, DNA Methylation, CpG Islands, Bone Density, Adult, Child, Child, Preschool, Female, Male, Promoter Regions, Genetic