Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China; Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, PR China.
Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Diabetes Res Clin Pract. 2018 Aug;142:10-18. doi: 10.1016/j.diabres.2018.03.016. Epub 2018 Mar 26.
Offspring exposed to gestational diabetes mellitus (GDM) are at a high risk for metabolic diseases. The mechanisms behind the association between offspring exposed to GDM in utero and an increased risk of health consequences later in life remain unclear. The aim of this study was to clarify the changes in methylation levels in the foetuses of women with GDM and to explore the possible mechanisms linking maternal GDM with a high risk of metabolic diseases in offspring later in life.
A genome-wide comparative methylome analysis on the umbilical cord blood of infants born to 30 women with GDM and 33 women with normal pregnancy was performed using Infinium HumanMethylation 450 BeadChip assays. A quantitative methylation analysis of 18 CpG dinucleotides was verified in the validation umbilical cord blood samples from 102 newborns exposed to GDM and 103 newborns who experienced normal pregnancy by MassARRAY EpiTYPER.
A total of 4485 differentially methylated sites (DMSs), including 2150 hypermethylated sites and 2335 hypomethylated sites, with a mean β-value difference of >0.05, were identified by the 450k array. Good agreement was observed between the massarray validation data and the 450k array data (R > 0.99; P < 0.0001). Thirty-seven CpGs (representing 20 genes) with a β-value difference of > 0.15 between the GDM and healthy groups were identified and showed potential as clinical biomarkers for GDM. "hsa04940: Type I diabetes mellitus" was the most significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, with a P-value = 3.20E-07 and 1.36E-02 in the hypermethylated and hypomethylated genepathway enrichment analyses, respectively. In the Gene Ontology (GO) pathway analyses, immune MHC (major histocompatibility complex)-related pathways and neuron development-related pathways were significantly enriched.
Our results suggest that GDM has epigenetic effects on genes that are preferentially involved in the Type I diabetes mellitus pathway, immune MHC-related pathways and neuron development-related pathways, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.
暴露于妊娠糖尿病（GDM）的后代患代谢疾病的风险较高。宫内暴露于 GDM 的后代与晚年健康后果风险增加之间的关联的机制尚不清楚。本研究旨在阐明 GDM 孕妇胎儿中甲基化水平的变化，并探讨将 GDM 与后代晚年患代谢疾病的高风险联系起来的可能机制。
使用 Infinium HumanMethylation 450 BeadChip 检测对 30 名 GDM 孕妇和 33 名正常妊娠孕妇的脐带血进行全基因组比较甲基组分析。通过 MassARRAY EpiTYPER 在 102 名暴露于 GDM 的新生儿和 103 名经历正常妊娠的新生儿的验证脐带血样本中对 18 个 CpG 二核苷酸进行定量甲基化分析。
450k 阵列共鉴定出 4485 个差异甲基化位点（DMS），包括 2150 个高甲基化位点和 2335 个低甲基化位点，平均β值差异>0.05。Massarray 验证数据与 450k 阵列数据之间存在良好的一致性（R>0.99；P<0.0001）。在 GDM 和健康组之间β值差异>0.15 的 37 个 CpG（代表 20 个基因）被鉴定为 GDM 的潜在临床生物标志物。“hsa04940：I 型糖尿病”是京都基因与基因组百科全书（KEGG）途径中最显著的途径，在高甲基化和低甲基化基因途径富集分析中，分别具有 P 值=3.20E-07 和 1.36E-02。在基因本体论（GO）途径分析中，免疫 MHC（主要组织相容性复合体）相关途径和神经元发育相关途径显著富集。
我们的研究结果表明，GDM 对优先参与 I 型糖尿病途径、免疫 MHC 相关途径和神经元发育相关途径的基因具有表观遗传效应，对胎儿生长发育有影响，并提供了支持性证据表明 DNA 甲基化参与了胎儿代谢编程。
