Epigenetic biomarkers of preeclampsia risk among mothers with chronic hypertension

慢性高血压母亲先兆子痫风险的表观遗传生物标志物

• 批准号: 10542416
• 负责人: Bertha Hidalgo
• 金额: $ 67.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542416
• 关键词: Abnormal placentation; Adverse effects; Affect; Age; Alabama; Ancillary Study; Antihypertensive Agents; Biological Assay; Biological Markers; Blood; Blood Banks; Blood Cells; Blood Pressure; Blood Volume; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Cessation of life; Chemicals; Chronic; Chronic Kidney Failure; Circulation; Clinical; Clinical Trials; Complication; Cytosine; DNA Methylation; DNA Modification Process; Dangerousness; Data; Databases; Detection; Diabetes Mellitus; Diagnosis; Dinucleoside Phosphates; Discipline of obstetrics; Disease; Disease Marker; Disease Outcome; Early Diagnosis; Early identification; End stage renal failure; Epigenetic Process; Fetal Growth; First Pregnancy Trimester; Future; Gene Expression; Gene Expression Regulation; Genes; Guanine; Heritability; Hypertension; Infant; Inflammation; Inflammatory; Labetalol; Life; Low Birth Weight Infant; Maternal Health; Maternal Mortality; Measurement; Methylation; Modification; Molecular; Monitor; Morbidity - disease rate; Mothers; Myocardial Infarction; National Heart, Lung, and Blood Institute; Organ; Outcome; Oxidative Stress; Participant; Pathology; Pathway interactions; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Proteins; Proteinuria; Randomized; Recording of previous events; Renal function; Reporting; Research; Research Design; Resources; Risk; Risk Factors; Safety; Sampling; Second Pregnancy Trimester; Site; Specimen; Stroke; Symptoms; Testing; Third Pregnancy Trimester; Tissues; Transcriptional Regulation; Universities; Urine; Uterus; Vascular Diseases; Whole Blood; Woman; Women' s Health; adverse maternal outcomes; adverse outcome; biobank; cardiovascular disorder epidemiology; cardiovascular disorder risk; case control; cell bank; clinical diagnostics; clinical research site; cohort; design; early screening; efficacy evaluation; endothelial dysfunction; epigenetic marker; epigenetic regulation; epigenome; epigenomics; fetal; genomic biomarker; hypertensive; improved; inorganic phosphate; maternal risk; methylation pattern; mortality; novel; parous; pathophysiology of preeclampsia; precision medicine; pregnancy hypertension; prepregnancy; prevent; programs; pyrosequencing; release factor; symptom treatment; treatment and outcome

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.

预防症（PREE），定义为与蛋白尿和/或其他的高血压发作 妊娠20周后器官并发症是一种常见的妊娠并发症 全球2-8％的怀孕。这种情况在母亲中更为普遍 妊娠发作时慢性轻度高血压（影响> 25％）。重要的是，Pree承认 孕产妇和胎儿发病率（包括心血管）的风险显着增加 并发症，早产，低出生体重甚至死亡。此外，最近的研究 证明预科的病史与心血管的风险增加有关 母亲的疾病以后生命。尚未完全了解PREE的病理生理学 但是，认为异常位置，血管功能障碍和氧化应激被认为会导致 母体内皮功能障碍导致临床症状发作。迄今唯一 确定的诊断是通过血压和尿液蛋白质测量 三个月。但是，怀疑该病理是在头三个月开始的 识别可以提供更好的治疗和结果。表观基因组被认为是 基因表达的重要驱动力是支持怀孕所必需的。很多的 斑点组织的表观基因组研究已经鉴定出不同的甲基化区域（DMR，A 与基因和途径相关的表观遗传修饰的类型） 基础疾病。少数研究已经确定了孕产妇表观基因组的变化 血液可以在怀孕期间早期识别。总体而言，需要其他研究来 确定孕产妇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 旨在确定怀孕期间降压治疗的效率和安全性。 我们的辅助研究将使用嵌套的病例对照设计（650例和650个对照） 使用现有数据和血液样本发现CPG和DMR进行PREE。发现将是 在Magee产科产妇和婴儿生物银行数据库中复制 （n〜650）。 PREE CPG和DMR（通过复制验证）将进一步测试 与CHAP的母亲心血管结局以及来自Parous的妇女相关联 与国家心脏肺和血液中现有的基因化数据的观察人群 研究所的精密医学跨性别（TOPMED）计划。拟议的研究 试图更好地了解PREE的病理生理学，并确定潜在的新生物标志物 促进这种严重怀孕状况的早期发现，管理和治疗。