Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Front Endocrinol (Lausanne). 2022 May 26;13:875180. doi: 10.3389/fendo.2022.875180. eCollection 2022.
Gestational diabetes mellitus (GDM) "program" an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.
妊娠期糖尿病（GDM）“程序”会增加后代代谢综合征的风险。表观遗传改变是一种可疑的机制。一些全基因组关联研究表明，GDM 与胎盘 DNA 甲基化变化有关。目前尚不清楚哪些基因或途径受到影响，以及胎盘的差异基因甲基化是否与胎儿生长或循环代谢健康生物标志物相关。在一项使用 Infinium MethylationEPIC Beadchip 的全基因组关联研究中，我们试图确定 GDM 中全基因组胎盘差异甲基化基因和富集途径，并评估它们与脐带血中胎儿生长和代谢健康生物标志物的相关性。该研究样本为 30 对在上海出生队列中按婴儿性别和分娩时的孕龄匹配的 GDM 与血糖正常妊娠（对照组）的足月胎盘。脐带血代谢健康生物标志物包括胰岛素、C 肽、胰岛素原、IGF-I、IGF-II、瘦素和脂联素。在调整了母亲年龄、孕前 BMI、产次、分娩方式和胎盘细胞类型异质性后，在 GDM 和对照组之间检测到 256 个差异甲基化位置（DMP，130 个高甲基化和 126 个低甲基化），这与假发现率<0.05 和β值差异>0.05 的多次检验有关。WSCD2 在基于位点和基于区域的分析中均被确定为差异甲基化基因。我们验证了先前全基因组关联研究中报道的 7 个高甲基化（CYP1A2、GFRA1、HDAC4、LIMS2、NAV3、PAX6、UPK1B）和 10 个低甲基化（DPP10、CPLX1、CSMD2、GPR133、NRXN1、PCSK9、PENK、PRDM16、PTPRN2、TNXB）基因。我们没有发现任何富集途径可以解释多次检验。11 个基因（CYP2D7P1、PCDHB15、ERG、SIRPB1、DKK2、RAPGEF5、CACNA2D4、PCSK9、TSNARE1、CADM2、KCNAB2）的 DMP 与出生体重（z 分数）相关，这与多次检验有关。胎盘基因甲基化与脐带血生物标志物之间没有显著相关性。总之，GDM 与一些胎盘基因的 DNA 甲基化变化有关，但这些胎盘基因的甲基化与脐带血中观察到的代谢健康生物标志物（胎儿生长因子、瘦素和脂联素）无关。我们验证了 17 个在 GDM 中差异甲基化的胎盘基因，并确定了 11 个与胎儿生长相关的差异甲基化基因。
