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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

先兆子痫 (preE)，定义为高血压发作并伴有蛋白尿和/或其他症状妊娠20周后的器官并发症是一种常见的妊娠并发症，影响全球 2-8% 的孕妇患有此病的情况更为常见。妊娠初期慢性轻度高血压（影响>25%）。显着增加母婴发病风险，包括心血管疾病此外，最近的研究还发现，并发症、早产、低出生体重甚至死亡。证明 preE 病史与心血管疾病风险增加相关 preE 的病理生理学尚不完全清楚。但胎盘异常、血管功能障碍和氧化应激被认为是导致迄今为止，母体内皮功能障碍导致临床症状的出现是唯一的。最终诊断是通过第二次或第二次测量血压和尿蛋白来确定的。然而，病理学疑似在妊娠早期或更早开始。表观基因组被认为是一种更好的治疗和结果。支持妊娠所需的基因表达变化的重要驱动因素。胎盘组织的表观基因组研究已经确定了差异甲基化区域（DMR，表观遗传修饰的类型）与疑似基因和途径中的 preE 相关一些研究已经确定了母体表观基因组的变化。总体而言，需要进行更多研究来确定怀孕早期的血液。确定母体血细胞中的甲基化位点是否有助于了解 preE 风险。研究将利用慢性高血压与妊娠 (CHAP) 研究的丰富资源旨在确定妊娠期间抗高血压治疗的有效性和安全性。我们的辅助研究将使用巢式病例对照设计（650 个病例和 650 个对照）来使用现有数据和血液样本发现 preE 的 CpG 和 DMR。在 Magee 产科母婴生物库数据库的参与者中进行复制 (N~650) 将进一步测试 PreE CpG 和 DMR（通过复制验证）。与 CHAP 以及经产妇女的母亲心血管结局相关具有来自国家心肺和血液的现有甲基化数据的观察队列研究所的精准医学转组学 (TOPMed) 计划拟议的研究。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促进这种严重妊娠状况的早期发现、管理和治疗。