母体促肾上腺皮质激素释放激素与 LEPDNA 甲基化在出生时和儿童期有关：来自 Viva 计划的全基因组表观遗传学研究。

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva.

机构信息

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China.

出版信息

Int J Obes (Lond). 2019 Jun;43(6):1244-1255. doi: 10.1038/s41366-018-0249-0. Epub 2018 Nov 21.

DOI:10.1038/s41366-018-0249-0

PMID:30464231

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6529291/

Abstract

BACKGROUND

Corticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.

METHODS

We investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.

RESULTS

Maternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).

CONCLUSION

In our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood.

摘要

背景

促肾上腺皮质激素释放激素（CRH）在调节皮质醇分泌中起着核心作用，皮质醇控制着广泛的生物过程。胎儿暴露于皮质醇过多会增加日后患病的风险。DNA 甲基化可能是产前皮质醇暴露与健康影响之间的潜在关联。我们研究了母体 CRH 水平与脐带血中成纤维细胞中表观基因组范围的 DNA 甲基化之间的关联，并评估了这些关联是否持续到儿童中期。

方法

我们调查了参加前瞻性 Viva 项目孕前队列的母婴对。我们使用 HumanMethylation450 Bead Chip 测量了 257 个脐带血样本中的 DNA 甲基化。我们通过调整模型来测试母体 CRH 浓度与脐带血细胞 DNA 甲基化的关联，该模型包括母体入组时的年龄、教育程度、母体种族/民族、母体吸烟状况、孕前体重指数、产次、分娩时的胎龄、儿童性别和脐带血中的细胞类型组成。我们还进一步检查了在儿童中期（n=239，年龄：6.7-10.3 岁）采集的儿童血液细胞中母体 CRH 水平与 DNA 甲基化之间关联的持续性，同时还调整了儿童采血时的年龄。

结果

母体 CRH 水平与脐带血细胞中 96 个个体 CpG 位点的 DNA 甲基化变异性相关（False Discovery Rate<0.05）。在 96 个 CpG 位点中，我们鉴定出 3 个位于 LEP 基因附近的 CpG 位点。区域分析证实了母体 CRH 与 LEP 附近 DNA 甲基化之间的关联。此外，较高的母体 CRH 水平与儿童中期 LEP 启动子区域的血液细胞 DNA 甲基化水平较高相关（P<0.05，β=0.64，SE=0.30）。