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. 2014 Mar;29(3):600-7.
doi: 10.1002/jbmr.2056.

Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth

Nicholas C Harvey  1 , Allan Sheppard, Keith M Godfrey, Cameron McLean, Emma Garratt, Georgia Ntani, Lucy Davies, Robert Murray, Hazel M Inskip, Peter D Gluckman, Mark A Hanson, Karen A Lillycrop, Cyrus Cooper
Affiliations

Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth

Nicholas C Harvey et al. J Bone Miner Res. 2014 Mar.

Abstract

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.

Keywords: DXA; EPIGENETIC; METHYLATION; RXRA; UMBILICAL CORD; VITAMIN D.

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Figures

Figure 1
Figure 1
Location of RXRA CpG sites and transcription start site. (DMR: Differentially methylated region).
Figure 2
Figure 2
Percent methylation at five umbilical cord RXRA promoter sites and offspring percent and size corrected BMC (g) at 4 years old. [RXRA CpG3: chr9:136355569+; RXRA CpG4/5 (chr9:136355593,600+); RXRA CpG6: chr9:136355688+; RXRA CpG7 (chr9:136355836+); RXRA CpG8 (chr9:136355885+)].
Figure 3
Figure 3
Maternal free 25(OH)-vitamin D index, and % methylation at RXRA CpG4/5 (chr9:136355593,600+).
See this image and copyright information in PMC

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