title: Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth.
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.
authors.affiliation: 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.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Harvey
authors.forename: Allan
authors.initials: A
authors.lastname: Sheppard
authors.forename: Keith M
authors.initials: KM
authors.lastname: Godfrey
authors.forename: Cameron
authors.initials: C
authors.lastname: McLean
authors.forename: Emma
authors.initials: E
authors.lastname: Garratt
authors.forename: Georgia
authors.initials: G
authors.lastname: Ntani
authors.forename: Lucy
authors.initials: L
authors.lastname: Davies
authors.forename: Robert
authors.initials: R
authors.lastname: Murray
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Inskip
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hanson
authors.forename: Karen A
authors.initials: KA
authors.lastname: Lillycrop
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
mesh_terms: D000328:Adult; D015519:Bone Density; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D047490:Retinoid X Receptor alpha; D014807:Vitamin D; C104450:25-hydroxyvitamin D
keywords: DXA; EPIGENETIC; METHYLATION; RXRA; UMBILICAL CORD; VITAMIN D
references.citation: Biosci Biotechnol Biochem. 2011;75(2):208-13
references.pmid: 21307571
references.citation: J Clin Endocrinol Metab. 2009 Mar;94(3):765-71
references.pmid: 19116232
references.citation: Am J Physiol Renal Physiol. 2004 Feb;286(2):F363-9
references.pmid: 14583431
references.citation: J Clin Invest. 2008 Jun;118(6):2316-24
references.pmid: 18464933
references.citation: N Engl J Med. 2008 Jul 3;359(1):61-73
references.pmid: 18596274
references.citation: Pediatr Res. 1997 Apr;41(4 Pt 1):590-6
references.pmid: 9098865
references.citation: J Clin Endocrinol Metab. 1999 Sep;84(9):3058-63
references.pmid: 10487665
references.citation: Br J Nutr. 2008 Aug;100(2):278-82
references.pmid: 18186951
references.citation: Calcif Tissue Int. 2012 Feb;90(2):120-7
references.pmid: 22159788
references.citation: Diabetes. 2011 May;60(5):1528-34
references.pmid: 21471513
references.citation: Osteoporos Int. 2001;12(8):623-9
references.pmid: 11580075
references.citation: J Clin Endocrinol Metab. 2002 May;87(5):2001-7
references.pmid: 11994332
references.citation: Nucleic Acids Res. 2011 Nov 1;39(20):8689-702
references.pmid: 21785139
references.citation: J Clin Endocrinol Metab. 2008 May;93(5):1676-81
references.pmid: 18285416
references.citation: Nat Genet. 2012 Apr 15;44(5):491-501
references.pmid: 22504420
references.citation: Nat Genet. 2009 Nov;41(11):1199-206
references.pmid: 19801982
references.citation: Osteoporos Int. 2011 Jan;22(1):69-73
references.pmid: 20379699
references.citation: Br J Nutr. 2007 Jun;97(6):1064-73
references.pmid: 17433129
references.citation: J Nutr. 2009 Jun;139(6):1054-60
references.pmid: 19339705
references.citation: J Dev Orig Health Dis. 2010 Feb;1(1):35-41
references.pmid: 23750315
references.citation: Gene. 2006 May 10;372:118-27
references.pmid: 16517099
references.citation: Lancet. 2006 Jan 7;367(9504):36-43
references.pmid: 16399151
references.citation: FASEB J. 2010 Sep;24(9):3135-44
references.pmid: 20385621
references.citation: J Biol Regul Homeost Agents. 2003 Jan-Mar;17(1):29-45
references.pmid: 12757020
references.citation: J Bone Miner Res. 2001 Sep;16(9):1694-703
references.pmid: 11547840