Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy
Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy
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DOI：
10.2337/db19-0798
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发表时间：
2020-03-01
期刊：
影响因子：
7.7
通讯作者：
Bouchard, Luigi
中科院分区：
文献类型：
--
作者：
Hivert, Marie-France;Cardenas, Andres;Bouchard, Luigi
胎盘参与了妊娠期母体胰岛素敏感性的变化，但其机制尚不清楚。我们研究了母体胰岛素敏感性和胎盘基因组DNA甲基化标记之间的关系。我们分析了Gen 3G队列中430对母子的数据。所有妇女在妊娠26周时进行75克口服葡萄糖耐量试验，我们使用葡萄糖和胰岛素测量来估计胰岛素敏感性（Matsuda指数）。在分娩时，我们从胎盘（胎儿侧）收集样品并使用Illumina EPIC阵列测量DNA甲基化。使用线性回归模型量化720，077个胞嘧啶-鸟嘌呤二核苷酸（CpG）的相关性，并调整母亲年龄，妊娠，吸烟，BMI，儿童性别和分娩时胎龄，我们确定了188个CpG位点，其中胎盘DNA甲基化与Matsuda指数相关（P < 6.94 x 10（-8））。在注释到这188个CpG的基因中，我们发现了miRNA靶点、组蛋白修饰和包括H19/MIR 675位点（父系印记）在内的亲本DNA甲基化的富集。我们确定了12个已知的胎盘印迹基因，包括KCNQ 1。孟德尔随机化分析揭示了胎盘DNA甲基化可能会影响母体胰岛素敏感性的5个位点，包括母体印记基因DLGAP 2。我们的研究结果表明，胎盘DNA甲基化是从根本上联系到怀孕的母亲胰岛素敏感性的调节。
The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at similar to 26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P < 6.94 x 10(-8)). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1. Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.