Placental DNA Methylation Adaptation to Maternal Glycemic Response in Pregnancy
Placental DNA Methylation Adaptation to Maternal Glycemic Response in Pregnancy
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DOI：
10.2337/db18-0123
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发表时间：
2018-08-01
期刊：
影响因子：
7.7
通讯作者：
Hivert, Marie-France
中科院分区：
文献类型：
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作者：
Cardenas, Andres;Gagne-Ouellet, Valerie;Hivert, Marie-France
妊娠期母体高血糖与胎儿过度生长及不良围产期和发育结局相关。胎盘表观遗传适应不良可能是这些关联的基础。我们对448对母婴进行了一项表观基因组关联研究（> 850，000个CpG位点），研究对象为妊娠24-30周口服葡萄糖激发后2小时的足月胎盘和产前母体血糖反应。母体产后2小时负荷与磷酸二酯酶4 B基因（PDE 4 B）内4个CpG位点的较低DNA甲基化（错误发现率[FDR] q < 0.05）密切相关。此外，在TNFRSF 1B、LDLR和BLM基因中，相对于母体葡萄糖反应，其他三个单独的CpG位点被差异甲基化（FDR q < 0.05）。胎盘组织中DNA甲基化与PDE 4 B（r = 0.31，P < 0.01）、TNFRSF 1B（r = 20.24，P = 0.013）和LDLR（r = 0.32，P < 0.001）三个独立位点的基因表达相关。在一个独立的重复队列（N = 65-108个样本）中，结果在方向上一致，但在PDE 4 B和TNFRSF 1B中检测的CpG位点之间没有显著重复。我们的研究提供的证据表明，孕妇在怀孕期间的血糖反应与胎盘DNA甲基化的关键炎症基因的表达水平部分表观遗传控制。
Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-h post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-h glycemia postload was strongly associated with lower DNA methylation of four CpG sites (false discovery rate [FDR] q < 0.05) within the phosphodiesterase 4B gene (PDE4B). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the TNFRSF1B, LDLR, and BLM genes (FDR q < 0.05). DNA methylation correlated with expression of its respective genes in placental tissue at three out of four independent identified loci: PDE4B (r = 0.31, P < 0.01), TNFRSF1B (r = 20.24, P = 0.013), and LDLR (r = 0.32, P < 0.001). In an independent replication cohort (N = 65-108 samples), results were consistent in direction but not significantly replicated among tested CpG sites in PDE4B and TNFRSF1B. Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control.