Epigenetic biomarkers of preeclampsia risk among mothers with chronic hypertension

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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.