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J Bone Miner Res. 2017 Oct;32(10):2030-2040. doi: 10.1002/jbmr.3153. Epub 2017 May 22.

Perinatal DNA Methylation at CDKN2A Is Associated With Offspring Bone Mass: Findings From the Southampton Women's Survey.

Author information

1
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
2
Institute of Developmental Sciences, University of Southampton, Southampton, UK.
3
NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
4
Singapore Institute for Clinical Sciences (SICS), A*STAR, Brenner Centre for Molecular Medicine, Singapore.
5
Centre for Biological Sciences, University of Southampton, Southampton, UK.
6
NIHR Oxford Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.

Abstract

Poor intrauterine and childhood growth has been linked with the risk of osteoporosis in later life, a relationship that may in part be mediated through altered epigenetic regulation of genes. We previously identified a region within the promoter of the long non-coding RNA ANRIL encoded by the CDKN2A locus, at which differential DNA methylation at birth showed correlations with offspring adiposity. Given the common lineage of adipocytes and osteoblasts, we investigated the relationship between perinatal CDKN2A methylation and bone mass at ages 4 and 6 years. Using sodium bisulfite pyrosequencing, we measured the methylation status of the 9 CpGs within this region in umbilical cord samples from discovery (n = 332) and replication (n = 337) cohorts of children from the Southampton Women's Survey, whose bone mass was assessed by dual-energy X-ray absorptiomietry (DXA; Hologic Discovery). Inverse associations were found between perinatal CDKN2A methylation and whole-body minus head bone area (BA), bone mineral content (BMC), and areal bone mineral density (BMD). This was confirmed in replication and combined data sets (all p < 0.01), with each 10% increase in methylation being associated with a decrease in BMC of 4 to 9 g at age 4 years (p ≤ 0.001). Relationships were similar with 6-year bone mass. Functional investigation of the differentially methylated region in the SaOS-2 osteosarcoma cell line showed that transcription factors bound to the identified CpGs in a methylation-specific manner and that CpG mutagenesis modulated ANRIL expression. In conclusion, perinatal methylation at CDKN2A is associated with childhood bone development and has significance for cell function.

KEYWORDS:

CDKN2A; DEVELOPMENT; DXA; EPIDEMIOLOGY; EPIGENETICS; OSTEOPOROSIS

PMID:
28419547
PMCID:
PMC5528139
DOI:
10.1002/jbmr.3153
[Indexed for MEDLINE]
Free PMC Article

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