Epigenetic biomarkers of preeclampsia risk among mothers with chronic hypertension

先兆子痫(Pree)，定义为高血压发作并伴有蛋白尿和/或其他 妊娠20周后的脏器并发症，是影响妊娠的常见并发症 世界范围内2-8%的怀孕。这种情况在患有以下疾病的母亲中更为常见 妊娠初期慢性轻度高血压(影响-gt；25%)。重要的是，普瑞授予了一个 显著增加孕产妇和胎儿发病率，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Pree病史与心血管疾病风险增加相关 母亲晚年的疾病。Pree的病理生理机制尚不完全清楚。 但异常胎盘、血管功能障碍和氧化应激被认为是导致 母血内皮细胞功能障碍导致临床症状的出现。到目前为止唯一的 确诊是通过测量血压和尿蛋白在第二或第二或 怀孕第三个月。然而，病理被怀疑始于妊娠的前三个月和更早。 身份识别可以提供更好的治疗和结果。表观基因组被认为是一种 支持怀孕所必需的基因表达变化的重要驱动因素。数不胜数 对胎盘组织的表观基因组学研究已经确定了差异甲基化区域(DMRS，a 表观遗传修饰类型)与Pree相关的可疑基因和途径 潜伏的疾病。一些研究已经确定了母体表观基因组的变化 可以在怀孕早期辨认出来的血液。总体而言，需要进行更多的研究来 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 研究将利用慢性高血压和妊娠(CHAP)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。 我们的辅助研究将使用嵌套式病例对照设计(650例病例和650例对照)来 使用现有数据和血样发现Pree的CPGS和DMRS。调查结果将是 在Magee产科母婴生物库数据库的参与者中复制 (n~650)。Pree CPG和DMRS(通过复制验证)将进一步测试 CHAP与产妇心血管结局的关系 使用国家心肺和血液中现有甲基化数据的观察队列 研究所的精准医学转基因计划(TOPMed)。拟议的研究 旨在更好地了解Pree的病理生理机制，并确定潜在的新生物标志物 促进这一严重妊娠状况的早期发现、管理和治疗。

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.