Baetens Machteld, Van Gaever Bram, Deblaere Stephanie, De Koker Andries, Meuris Leander, Callewaert Nico, Janssens Sandra, Roelens Kristien, Roets Ellen, Van Dorpe Jo, Dehaene Isabelle, Menten Björn
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Department of Pathology, Ghent University, Ghent, Belgium.
Clin Epigenetics. 2024 Dec 18;16(1):182. doi: 10.1186/s13148-024-01798-5.
Aberrant embryo implantation and suboptimal placentation can lead to (severe) complications such as preeclampsia and fetal growth restriction later in pregnancy. Current identification of high-risk pregnancies relies on a combination of risk factors, biomarkers, and ultrasound examinations, a relatively inaccurate approach. Previously, aberrant DNA methylation due to placental hypoxia has been identified as a potential marker of placental insufficiency and, hence, potential (future) pregnancy complications. The goal of the Early Prediction of prEgnancy Complications Testing, or the ExPECT study, is to validate a genome-wide, cell-free DNA (cfDNA) methylation strategy to diagnose preeclampsia accurately. More importantly, the predictive potential of this strategy is also explored to reliably identify high-risk pregnancies early in gestation. Furthermore, a longitudinal study was conducted, including sequential blood samples from pregnant individuals experiencing both uneventful and complicated gestations, to assess the methylation dynamics of cfDNA throughout these pregnancies. A significant strength of this study is its enzymatic digest, which enriches CpG-rich regions across the genome without the need for proprietary reagents or prior selection of regions of interest. This makes it useful for the cost-effective discovery of novel markers.
Investigation of methylation patterns throughout pregnancy showed different methylation trends between unaffected and affected pregnancies. We detected differentially methylated regions (DMRs) in pregnancies complicated with preeclampsia as early as 12 weeks of gestation, with distinct differences in the methylation profile between early and late pregnancy. Two classification models were developed to diagnose and predict preeclampsia, demonstrating promising results on a small set of validation samples.
This study offers valuable insights into methylation changes at specific genomic regions throughout pregnancy, revealing critical differences between normal and complicated pregnancies. The power of noninvasive cfDNA methylation profiling was successfully proven, suggesting the potential to integrate this noninvasive approach into routine prenatal care.
胚胎着床异常和胎盘形成欠佳可导致妊娠后期出现（严重）并发症，如先兆子痫和胎儿生长受限。目前对高危妊娠的识别依赖于风险因素、生物标志物和超声检查的综合运用，这是一种相对不准确的方法。此前，已确定胎盘缺氧导致的异常DNA甲基化是胎盘功能不全的潜在标志物，因此也是潜在（未来）妊娠并发症的标志物。妊娠并发症早期预测检测（Early Prediction of prEgnancy Complications Testing，简称ExPECT研究）的目标是验证一种全基因组无细胞DNA（cfDNA）甲基化策略，以准确诊断先兆子痫。更重要的是，还探索了该策略的预测潜力，以便在妊娠早期可靠地识别高危妊娠。此外，还进行了一项纵向研究，包括收集经历正常和复杂妊娠的孕妇的连续血样，以评估这些妊娠期间cfDNA的甲基化动态变化。这项研究的一个显著优势是其酶消化法，该方法可富集全基因组中富含CpG的区域，无需使用专利试剂或事先选择感兴趣的区域。这使其有助于以具有成本效益的方式发现新的标志物。
对整个孕期甲基化模式的研究表明，未受影响和受影响的妊娠之间存在不同的甲基化趋势。早在妊娠12周时，我们就在并发先兆子痫的妊娠中检测到了差异甲基化区域（DMRs），妊娠早期和晚期的甲基化谱存在明显差异。开发了两种分类模型来诊断和预测先兆子痫，在一小批验证样本上显示出了有前景的结果。
本研究为整个孕期特定基因组区域的甲基化变化提供了有价值的见解，揭示了正常妊娠和复杂妊娠之间的关键差异。无创cfDNA甲基化分析的能力得到了成功证明，表明将这种无创方法整合到常规产前护理中的潜力。
