Epigenetic biomarkers of preeclampsia risk among mothers with chronic hypertension

先兆子痫（preE），定义为高血压发作伴蛋白尿和/或其他 妊娠20周后的器官并发症，是一种常见的妊娠并发症， 全世界2-8%的孕妇。这种情况在母亲中更为常见， 妊娠期慢性轻度高血压（影响>25%）。重要的是，preE赋予了 母体和胎儿发病风险显著增加，包括心血管疾病 并发症，早产，低出生体重，甚至死亡。此外，最近的研究 证明前E病史与心血管疾病风险增加相关， 母亲晚年的疾病。前E期的病理生理学还不完全清楚 但胎盘形成异常、血管功能障碍和氧化应激被认为是导致 导致临床症状发作的母体内皮功能障碍。迄今为止唯一的 明确诊断是通过血压和尿蛋白测量在第二或 妊娠晚期然而，病理学怀疑开始于前三个月和更早 识别可以实现更好的治疗和结果。表观基因组被认为是 这是支持怀孕所必需的基因表达变化的重要驱动因素。许多 胎盘组织的表观基因组研究已经鉴定出差异甲基化区域（DMR， 表观遗传修饰的类型）与preE相关的基因和途径， 潜在的疾病一些研究已经发现了母体表观基因组的变化， 在怀孕早期可以识别的血液。总的来说，需要进行更多的研究， 确定母体血细胞中的甲基化位点是否有助于了解preE风险。这 这项研究将利用慢性高血压与妊娠（CHN）研究的丰富资源 旨在确定妊娠期抗高血压治疗的有效性和安全性。 我们的辅助研究将采用巢式病例对照设计（650例病例和650例对照）， 使用现有数据和血液样本发现preE的CpG和DMR。数据的日期及时间为 在Magee产科母婴生物库数据库的参与者中复制 （N~650）。将进一步检测PreE CpG和DMR（通过复制验证）， 与产妇心血管结局的相关性， 使用来自国家心肺和血液中心的现有甲基化数据的观察性队列 研究所的精准医学Transomics（TOPMed）计划。拟议研究 旨在更好地了解preE的病理生理学，并确定潜在的新生物标志物， 有助于早期发现，管理和治疗这种严重的妊娠状况。

Preeclampsia (preE), defined as the onset of hypertension paired with proteinuria and/or other organ complication after 20 weeks of gestation, is a common pregnancy complication affecting 2-8% of pregnancies worldwide. The condition is even more common among mothers with chronic mild hypertension at pregnancy onset (affecting >25%). Importantly, preE confers a significantly increased risk of maternal and fetal morbidity including cardiovascular complications, preterm delivery, low birth weight and even death. Furthermore, recent studies demonstrate that a history of a preE is associated with an increased risk of cardiovascular disease for the mother later in life. The pathophysiology of preE is not completely understood but abnormal placentation, vascular dysfunction and oxidative stress is thought to cause maternal endothelial dysfunction resulting in the onset of clinical symptoms. To date the only definitive diagnosis is through blood pressure and urine protein measurement in the second or third trimester. However, the pathology is suspected to start in the first trimester and earlier identification can allow for better treatment and outcomes. The epigenome is recognized as an important driver of the gene expression changes necessary to support pregnancy. Numerous epigenomic studies of placental tissue have identified differentially methylated regions (DMRs, a type of epigenetic modification) associated with preE in genes and pathways suspected to underlie disease. A handful of studies have identified changes in the maternal epigenome from blood which could be identifiable earlier in pregnancy. Overall, additional research is needed to determine if methylation sites in maternal blood cells are useful to understand preE risk. This study will leverage the rich resource of the Chronic Hypertension And Pregnancy (CHAP) study designed to determine the efficacy and safety of antihypertensive treatment during pregnancy. Our ancillary study will use a nested case-control design (650 cases and 650 controls) to discover CpGs and DMRs for preE using existing data and blood samples. Findings will be replicated among participants from the Magee Obstetric Maternal & Infant Biobank database (N~650). PreE CpGs and DMRs (validated through replication) will be further tested for association with maternal cardiovascular outcomes in CHAP as well as in parous women from observational cohorts with existing metylation data from the National Heart Lung and Blood Institute’s Transomics for Precision Medicine (TOPMed) Program. The proposed research seeks to better understand the pathophysiology of preE and identify potential new biomarkers to facilitate early detection, management, and treatment of this serious pregnancy condition.