BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
Hum Mol Genet. 2018 Jan 1;27(1):135-146. doi: 10.1093/hmg/ddx391.
Placental health is a key component to a successful pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analysed them separately. This study aims to utilize DNAm profiling to better understand the underlying placental variation associated with PE and IUGR. Placental samples from a discovery (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To account for gestational age (GA) effects, EOPE samples were compared with pre-term births of varying etiologies (GA <37 weeks). LOPE and IUGR were compared with term controls (GA >37 weeks). While 1703 sites were differentially methylated (DM) (FDR < 0.05, Δβ > 0.1) in EOPE, few changes were associated with LOPE (N = 5), or IUGR (N = 0). Of the 1703 EOPE sites, 599 validated in the second cohort. Using these 599 sites, both cohorts clustered into three distinct groups. Interestingly, LOPE samples diagnosed between 34 and 36 weeks with co-occurring IUGR clustered with the EOPE. DNAm profiling may provide an independent tool to refine clinical/pathological diagnoses into subgroups with more uniform pathology. Despite large changes observed in EOPE, there were challenges in reproducing genome-wide DNAm hits that are discussed.
胎盘健康是成功妊娠的关键组成部分。胎盘功能不全（PI），即胎儿营养供应不足，与子痫前期（PE）、母体高血压疾病以及胎儿宫内生长受限（IUGR）有关，即病理性胎儿生长不良。早发型子痫前期（EOPE）比晚发型子痫前期（LOPE）更常见胎盘功能不全。然而，这些疾病之间的关系尚不清楚。虽然在 PE 和 IUGR 中已经发现了 DNA 甲基化（DNAm）改变，但这些实体可能会重叠，而且很少有研究单独对其进行分析。本研究旨在利用 DNAm 谱分析来更好地了解与 PE 和 IUGR 相关的潜在胎盘变异。使用 Illumina HumanMethylation450 阵列对来自发现队列（43 个对照、22 个 EOPE、18 个 LOPE、11 个 IUGR）和验证队列（15 个对照、22 个 EOPE、11 个 LOPE）的胎盘样本进行评估。为了考虑胎龄（GA）的影响，将 EOPE 样本与不同病因（GA<37 周）的早产进行了比较。将 LOPE 和 IUGR 与足月对照组（GA>37 周）进行了比较。在 EOPE 中，有 1703 个位点存在差异甲基化（DM）（FDR<0.05，Δβ>0.1），而在 LOPE（N=5）或 IUGR（N=0）中，很少有变化与这些差异相关。在 1703 个 EOPE 位点中，有 599 个在第二个队列中得到验证。使用这 599 个位点，两个队列都聚类成三个不同的组。有趣的是，在 34 至 36 周之间被诊断为 LOPE 并伴有 IUGR 的样本与 EOPE 聚类在一起。DNAm 谱分析可能提供一种独立的工具，将临床/病理诊断细化为具有更均匀病理的亚组。尽管在 EOPE 中观察到了很大的变化，但在复制全基因组 DNAm 命中方面存在一些挑战，这些挑战将在讨论中进行探讨。
