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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 |

REPOSITORIES: biostudies-literature

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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. INTRODUCTION:Breech presentation is associated with altered joint shape and hip dysplasias, but effects on bone mineral content (BMC), area (BA) and density (BMD) are unknown. METHODS:In 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. RESULTS:Neonates 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. CONCLUSIONS:These 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).

Project description:AimTo investigate the associations between indices of bone health in childhood and corresponding parental measures.MethodsThe Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (β-coefficients (95%CI) unit/unit for each bone measure).ResultsData were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (β = 0.26 g·cm-2/g·cm-2 (0.21,0.32)) and father-child aBMD (β = 0.16 g·cm-2/g·cm-2 (0.11,0.21)), P-difference in β = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (β = 0.33 mm2/mm2 (0.17,0.48)), but little evidence of a father-offspring association (β = -0.06 mm2/mm2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (β = 0.48 mg·cm-3/mg·cm-3 (0.15,0.82)) than mothers (β = 0.27 mg·cm-3/mg·cm-3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height.ConclusionsWhilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects.SummaryIn an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships.

Project description:BackgroundRates of childhood obesity are increasing globally, with poor dietary quality an important contributory factor. Evaluation of longitudinal diet quality across early life could identify timepoints and subgroups for nutritional interventions as part of effective public health strategies.ObjectiveThis research aimed to: (1) define latent classes of mother-offspring diet quality trajectories from pre-pregnancy to child age 8-9 years, (2) identify early life factors associated with these trajectories, and (3) describe the association between the trajectories and childhood adiposity outcomes.DesignDietary data from 2963 UK Southampton Women's Survey mother-offspring dyads were analysed using group-based trajectory modelling of a diet quality index (DQI). Maternal diet was assessed pre-pregnancy and at 11- and 34-weeks' gestation, and offspring diet at ages 6 and 12 months, 3, 6-7- and 8-9-years using interviewer-administered food frequency questionnaires. At each timepoint, a standardised DQI was derived using principal component analysis. Adiposity age 8-9 years was assessed using dual-energy X-ray absorptiometry (DXA) and BMI z-scores.ResultsA five-trajectory group model was identified as optimal. The diet quality trajectories were characterised as stable, horizontal lines and were categorised as poor (n = 142), poor-medium (n = 667), medium (n = 1146), medium-better (n = 818) and best (n = 163). A poorer dietary trajectory was associated with higher maternal pre-pregnancy BMI, smoking, multiparity, lower maternal age and lower educational attainment. Using linear regression adjusted for confounders, a 1-category decrease in the dietary trajectory was associated with higher DXA percentage body fat (0.08 SD (95% confidence interval 0.01, 0.15) and BMI z-score (0.08 SD (0.00, 0.16) in the 1216 children followed up at age 8-9 years.ConclusionMother-offspring dietary trajectories are stable across early life, with poorer diet quality associated with maternal socio-demographic and other factors and childhood adiposity. The preconception period may be an important window to promote positive maternal dietary changes in order to improve childhood outcomes.

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

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