Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium
Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium
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DOI：
10.2337/dc19-0524
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发表时间：
2020-01-01
期刊：
影响因子：
16.2
通讯作者：
Breton, Carrie V.
中科院分区：
文献类型：
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作者：
Howe, Caitlin G.;Cox, Bianca;Breton, Carrie V.
目的妊娠期糖尿病（GDM）与子代的不良结局有关。越来越多的证据表明，表观基因组可能发挥了作用，但大多数以前的研究都是小规模的，并调整了一些协变量。目前的研究荟萃分析了妊娠和儿童表观遗传学（PACE）联盟中母体GDM和脐带血DNA甲基化之间的关联。研究设计和方法7个妊娠队列（3，677对母亲-新生儿[317例GDM]）使用Infinium HumanMethylation 450 BeadChip阵列获得的DNA甲基化数据，提供了表观基因组关联研究的结果。GDM和DNA甲基化之间的关联使用稳健的线性回归进行了检查，并对潜在的混杂因素进行了调整。使用METAL进行固定效应荟萃分析。差异甲基化区域（DMR）通过采用两种区域方法（comb-p和DMRcate）获得的结果的交集进行鉴定。结果comb-p法和DMRcate法鉴定出2例DMR。与对照组相比，在子宫内暴露于GDM的新生儿中，这两个区域的甲基化程度都较低。一份DMR（chr 1：248100345-248100614）位于OR 2L 13启动子，另一个（chr 10：135341870-135342620）位于CYP 2 E1基因体。基于错误发现率调整的P值阈值0.05，个体CpG分析未显示任何差异甲基化位点。结论：母亲GDM与两个区域内较低的脐带血甲基化水平相关，包括OR 2L 13的启动子（与自闭症谱系障碍相关的基因）和CYP 2 E1的基因体（在1型和2型糖尿病中上调）。未来的研究需要了解这些关联是否是因果关系和可能的健康后果。
OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.