Dataset Information

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

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. © 2017 American Society for Bone and Mineral Research.

SUBMITTER: Curtis EM

PROVIDER: S-EPMC5528139 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Curtis Elizabeth M EM Murray Robert R Titcombe Philip P Cook Eloïse E Clarke-Harris Rebecca R Costello Paula P Garratt Emma E Holbrook Joanna D JD Barton Sheila S Inskip Hazel H Godfrey Keith M KM Bell Christopher G CG Cooper Cyrus C Lillycrop Karen A KA Harvey Nicholas C NC

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20170522 10

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 pe ...[more]

PMID: 28419547

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Project description:We compared bone outcomes in children with breech and cephalic presentation at delivery. Neonatal whole-body bone mineral content (BMC) and area were lower in children with breech presentation. At 4 years, no differences in whole-body or spine measures were found, but hip BMC and area were lower after breech presentation.IntroductionBreech presentation is associated with altered joint shape and hip dysplasias, but effects on bone mineral content (BMC), area (BA) and density (BMD) are unknown.MethodsIn the prospective Southampton Women's Survey mother-offspring cohort, whole-body bone outcomes were measured using dual-energy X-ray absorptiometry (DXA) in 1430 offspring, as neonates (mean age 6 days, n = 965, 39 with a breech presentation at birth) and/or at age 4.1 years (n = 999, 39 breech). Hip and spine bone outcomes were also measured at age 4 years.ResultsNeonates with breech presentation had 4.2 g lower whole-body BMC (95% CI -7.4 to - 0.9 g, P = 0.012) and 5.9 cm2 lower BA (- 10.8 to - 1.0 cm2, P = 0.019), but BMD was similar between groups (mean difference - 0.007, - 0.016 to 0.002 g/cm2, P = 0.146) adjusting for sex, maternal smoking, gestational diabetes, mode of delivery, social class, parity, ethnicity, age at scan, birthweight, gestational age and crown-heel length. There were no associations between breech presentation and whole-body outcomes at age 4 years, but, in similarly adjusted models, regional DXA (not available in infants) showed that breech presentation was associated with lower hip BMC (- 0.51, - 0.98 to - 0.04 g, P = 0.034) and BA (- 0.67, - 1.28 to - 0.07 cm2, P = 0.03) but not with BMD (- 0.009, - 0.029 to 0.012 g, P = 0.408), or spine outcomes.ConclusionsThese results suggest that breech presentation is associated with lower neonatal whole-body BMC and BA, which may relate to altered prenatal loading in babies occupying a breech position; these differences did not persist into later childhood. Modest differences in 4-year hip BMC and BA require further investigation.

Project description:Systemic inflammation is associated with reduced bone mineral density and may be influenced by pro-inflammatory diets. We undertook an observational analysis of associations between late pregnancy energy-adjusted dietary inflammatory index (E-DII) scores and offspring bone outcomes in childhood. E-DII scores (higher scores indicating pro-inflammatory diets) were derived from food frequency questionnaires in late pregnancy in two prospective mother-offspring cohorts: the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). The mean (SD) offspring age at dual-energy X-ray absorptiometry (DXA) scanning was 9.2 (0.2) years. Linear regression was used to assess associations between E-DII and bone outcomes, adjusting for offspring sex and age at DXA and maternal age at childbirth, educational level, pre-pregnancy body mass index (BMI), parity, physical activity level, and smoking in pregnancy. Associations were synthesized using fixed-effect meta-analysis. Beta coefficients represent the association per unit E-DII increment. In fully adjusted models (total n = 5910) late pregnancy E-DII was negatively associated with offspring whole body minus head bone area (BA: β = -3.68 [95% confidence interval -6.09, -1.27] cm2 /unit), bone mineral content (BMC: β = -4.16 [95% CI -6.70, -1.62] g/unit), and areal bone mineral density (aBMD: β = -0.0012 [95% CI -0.0020, -0.0004] g.cm-2 /unit), but there was only a weak association with BMC adjusted for BA (β = -0.48 [95% CI -1.11, 0.15] g/unit) at 9 years. Adjustment for child height partly or, for weight, fully attenuated the associations. Higher late pregnancy E-DII scores (representing a more pro-inflammatory diet) are negatively associated with offspring bone measures, supporting the importance of maternal and childhood diet on longitudinal offspring bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Dataset Information

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

Publications

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

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