BACKGROUND The impact of methylation gestational age (GAmAge; a biomarker of fetal maturity) at birth on childhood blood pressure (BP) trajectories is unknown. METHODS This cohort study included 500 boys and 440 girls with data on cord blood DNA methylation and BP at 3 to 15 years of age. Systolic BP (SBP) and diastolic BP percentiles were calculated based on clinical guidelines. Time-series K-means clustering identified 4 distinct SBP and diastolic BP percentile trajectories: high-steady, high-decrease, normal-increase, and normal-steady. GAmAge was estimated using an existing pediatric epigenetic clock. Extrinsic age acceleration was calculated as residuals of associations between GAmAge and chronological gestational age. Intrinsic age acceleration was calculated using the same method adjusting for cord blood cell compositions. RESULTS Extrinsic age acceleration and intrinsic age acceleration were inversely associated with repeated measures of BP percentiles. Significant inverse associations were observed between extrinsic age acceleration and SBP percentiles in boys (β=-2.02; P=0.02) but not in girls (β=-0.49; P=0.58). Both extrinsic age acceleration and intrinsic age acceleration were inversely associated with SBP percentiles in girls born preterm (<37 weeks; βEAA=-2.95; βIAA=-3.00; P<0.05). Compared with the normal-steady SBP trajectory, significant inverse associations were observed between intrinsic age acceleration and high-steady, high-decrease, and normal-increase SBP trajectories in boys (odds ratio, 0.73-0.81; P<0.03), and significant positive associations were observed for high-decrease and normal-increase SBP trajectories in girls (odds ratio, 1.26-1.38; P<0.01). Significant sex differences were observed (Psex-interaction<2×10-16). CONCLUSIONS GAmAge acceleration at birth was inversely associated with child BP, and such association was more pronounced in boys than in girls. Our findings may shed new light on the developmental origins of high BP and sex differences in cardiovascular risk.

中文翻译：

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出生时的表观遗传时钟和儿童血压轨迹：一项前瞻性出生队列研究。


背景 出生时甲基化胎龄（GAmAge；胎儿成熟度的生物标志物）对儿童血压（BP）轨迹的影响尚不清楚。方法 这项队列研究纳入了 500 名男孩和 440 名女孩，提供了 3 至 15 岁时脐带血 DNA 甲基化和血压的数据。根据临床指南计算收缩压 (SBP) 和舒张压百分位数。时间序列 K 均值聚类确定了 4 个不同的收缩压和舒张压百分位轨迹：高稳定、高下降、正常增加和正常稳定。 GAmAge 使用现有的儿科表观遗传时钟进行估算。外在年龄加速计算为 GAmAge 与实际孕龄之间关联的残差。使用调整脐带血细胞成分的相同方法计算内在年龄加速。结果 外在年龄加速和内在年龄加速与血压百分位数的重复测量呈负相关。在男孩中观察到外在年龄加速与 SBP 百分位数之间存在显着的负相关（β=-2.02；P=0.02），但在女孩中则不然（β=-0.49；P=0.58）。外在年龄加速和内在年龄加速均与早产女孩的 SBP 百分位呈负相关（<37 周；βEAA=-2.95；βIAA=-3.00；P<0.05）。与正常稳定 SBP 轨迹相比，男孩的内在年龄加速与高稳定、高下降和正常增加 SBP 轨迹之间观察到显着的负相关（比值比，0.73-0.81；P<0.03），女孩的 SBP 轨迹高度下降和正常上升呈显着正相关（比值比，1.26-1.38；P<0.01）。观察到显着的性别差异（Psex-interaction<2×10-16）。 结论 出生时年龄加速与儿童血压呈负相关，并且这种相关性在男孩中比女孩更明显。我们的研究结果可能为高血压的发育起源和心血管风险的性别差异提供新的线索。