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子痫前期胎盘中印记差异甲基化区域特征分析

Characteristics of imprinted differentially methylated regions in preeclampsia placenta

    摘要
  • 摘要:
    目的 探讨胎盘中印记差异甲基化区域（imprinted differentially methylated regions，iDMRs）的特征及其与子痫前期（preeclampsia，PE）的相关性。
    方法  选择2021年9月至2023年9月上海市普陀区妇婴保健院和上海交通大学医学院附属国际和平妇幼保健院的健康孕妇43例（对照组）和PE孕妇33例（PE组）。采用BisCap靶向重亚硫酸盐测序（BisCap-seq），检测76例孕妇胎盘和5例对照组孕妇外周血样本中62个iDMRs的3 362个CpG位点的甲基化水平，计算各位点甲基化水平和邻近位点间甲基化连锁不平衡（methylation linkage disequilibrium，MLD）程度。基于MLD构建印记甲基化单倍型区块（imprinted methylation haplotype blocks，iMHBs），比较健康胎盘、PE胎盘以及外周血样本中各CpG位点、各iMHBs的甲基化水平和可变性差异。
    结果  在iDMRs中的CpG岛上，CpG位点为中等甲基化水平，邻近位点间呈现高度MLD（甲基化水平0.35～0.65，位点间D’＞ 0.8）。构建185个iMHBs，其中60个胎盘特异iMHBs和38个体细胞iMHBs的甲基化水平在胎盘与孕妇外周血间的差异有统计学意义（P校正＜0.05）；27个iMHBs在不同胎盘中呈现高度甲基化可变性。与健康胎盘相比，PE胎盘中的iMHBs甲基化无显著改变。在iMHBs结构外鉴定了27个差异甲基化胞嘧啶（differentially methylated cytosines，DMCs），其中19个CpG位点的甲基化水平在PE组和对照组的差异有统计学意义（P校正＜0.05）。通过胎盘特异甲基化单倍型（placenta-specific haplotype，PSH）对孕妇血浆游离DNA的胎盘组分进行定量估算，结果与去卷积方法的估算结果强相关（r＝0.973，P＜0.01）。
    结论  PE胎盘中基因组印记特征明显，其中PSH可作为PE胎盘的潜在标志物，用于定量估算孕妇血浆游离DNA中的胎盘组分。

     

    Abstract:
    Objective To investigate the characteristics of imprinted differentially methylated regions (iDMRs) in placentas and their correlation with preeclampsia (PE).
    Methods A total of 43 healthy pregnant women (control group) and 33 pregnant women with PE (PE group) at Shanghai Putuo Maternity and Infant Hospital and International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University School of Medicine from September 2021 to September 2023 were selected. A total of 3 362 CpG sites in 62 iDMRs were analyzed in 76 placenta and 5 maternal blood samples using BisCap targeted bisulfite resequencing (BisCap-seq) assays. The CpG sites in the CpG islands of the iDMRs were assessed for their methylation levels and methylation linkage disequilibrium (MLD). Imprinted methylation haplotype blocks (iMHBs) were constructed based on MLD. The methylation levels and variablility of CpG sites and iMHBs were compared among the healthy placenta, PE placenta and blood samples.
    Results The CpG sites in the CpG islands of the iDMRs exhibited intermediate methylation, with adjacent sites displaying high MLD (methylation levels: 0.35-0.65, D’ ＞ 0.8). A total of 185 iMHBs were constructed using these coupled CpG sites, 60 placenta-specific iMHBs and 38 somatic iMHBs were found to be differentially methylated in the placenta compared with maternal blood (Padj＜0.05). Twenty-seven iMHBs were identified with differentially variable methylation patterns in the placenta. The iMHBs methylation was unchanged in the PE placentas compared to the healthy placentas. Twenty-seven differentially methylated cytosines (DMCs) were identified outside the iMHBs structure, among which the methylation levels of 19 CpG sites showed statistically significant differences between the PE group and the control group (Padj＜0.05). The quantitative results of placental compositions of maternal plasma cell-free DNA (cfDNA) using placenta-specific haplotype (PSH) were highly correlated with those estimated by a deconvolution methodology (r＝0.973, P＜0.01).
    Conclusions The genomic imprinting features in the PE placentas were obvious, and PSH could be a potential marker of the placenta to quantify the placental compositions of maternal plasma cfDNA.

     

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