Molecular Bioscience and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI 96822 USA.
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813 USA.
Clin Epigenetics. 2015 Mar 13;7(1):21. doi: 10.1186/s13148-015-0052-x. eCollection 2015.
Preeclampsia is one of the leading causes of fetal and maternal morbidity and mortality worldwide. Preterm babies of mothers with early onset preeclampsia (EOPE) are at higher risks for various diseases later on in life, including cardiovascular diseases. We hypothesized that genome-wide epigenetic alterations occur in cord blood DNAs in association with EOPE and conducted a case control study to compare the genome-scale methylome differences in cord blood DNAs between 12 EOPE-associated and 8 normal births.
Bioinformatics analysis of methylation data from the Infinium HumanMethylation450 BeadChip shows a genome-scale hypomethylation pattern in EOPE, with 51,486 hypomethylated CpG sites and 12,563 hypermethylated sites (adjusted P <0.05). A similar trend also exists in the proximal promoters (TSS200) associated with protein-coding genes. Using summary statistics on the CpG sites in TSS200 regions, promoters of 643 and 389 genes are hypomethylated and hypermethylated, respectively. Promoter-based differential methylation (DM) analysis reveals that genes in the farnesoid X receptor and liver X receptor (FXR/LXR) pathway are enriched, indicating dysfunction of lipid metabolism in cord blood cells. Additional biological functional alterations involve inflammation, cell growth, and hematological system development. A two-way ANOVA analysis among coupled cord blood and amniotic membrane samples shows that a group of genes involved in inflammation, lipid metabolism, and proliferation are persistently differentially methylated in both tissues, including IL12B, FAS, PIK31, and IGF1.
These findings provide, for the first time, evidence of prominent genome-scale DNA methylation modifications in cord blood DNAs associated with EOPE. They may suggest a connection between inflammation and lipid dysregulation in EOPE-associated newborns and a higher risk of cardiovascular diseases later in adulthood.
子痫前期是全球导致胎儿和产妇发病率和死亡率的主要原因之一。患有早发型子痫前期（EOPE）的母亲所生的早产儿在以后的生活中更容易患上各种疾病，包括心血管疾病。我们假设与 EOPE 相关的脐带血 DNA 中存在全基因组表观遗传改变，并进行了病例对照研究，以比较 12 例 EOPE 相关病例和 8 例正常分娩的脐带血 DNA 中全基因组甲基组差异。
对来自 Infinium HumanMethylation450 BeadChip 的甲基化数据进行生物信息学分析表明，EOPE 存在全基因组低甲基化模式，有 51486 个低甲基化 CpG 位点和 12563 个高甲基化位点（调整后的 P < 0.05）。在与蛋白质编码基因相关的近端启动子（TSS200）中也存在类似的趋势。使用 TSS200 区域 CpG 位点的汇总统计数据，分别有 643 个和 389 个基因的启动子呈低甲基化和高甲基化。基于启动子的差异甲基化（DM）分析表明，法尼醇 X 受体和肝 X 受体（FXR/LXR）通路的基因富集，表明脐带血细胞中脂质代谢功能障碍。其他生物学功能改变涉及炎症、细胞生长和血液系统发育。在脐带血和羊膜膜样本的双向方差分析中，有一组涉及炎症、脂质代谢和增殖的基因在两种组织中均持续表现出差异甲基化，包括 IL12B、FAS、PIK31 和 IGF1。
这些发现首次提供了与 EOPE 相关的脐带血 DNA 中存在显著全基因组 DNA 甲基化修饰的证据。它们可能表明 EOPE 相关新生儿中炎症和脂质失调之间存在联系，并且成年后患心血管疾病的风险更高。
