Integrative omics of preeclampsia in TOPMED and maternal cardiovascular health

TOPMED 中子痫前期的综合组学和孕产妇心血管健康

基本信息

批准号：
10418036
负责人：
RICHA SAXENA
金额：
$ 69.93万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2022-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418036
关键词：
Address Affect Age of Onset Award Biological Blood Boston Cardiometabolic Disease Cardiovascular Diseases Clinical Cluster Analysis Cohort Studies Collection Colombia Colombian Data Development Discipline of obstetrics Disease Etiology Exclusion Fetal Diseases Fetal Growth Functional disorder Funding Future Genes Genetic Genetic Risk Genome Genomics Gestational Age Grant Heritability Histopathology Human Genetics Hypertension Individual Laboratory Study Link Maternal Mortality Mediating Metabolic Molecular Molecular Profiling Myocardial Ischemia National Heart, Lung, and Blood Institute Neonatal Mortality Onset of illness Outcome Study Pathway interactions Patients Phenotype Placenta Plasma Pre-Eclampsia Predisposition Pregnancy Pregnancy Trimesters Premature Birth Prevention approach Prevention therapy Proteins Proteinuria Proteomics Public Health Publishing Quantitative Trait Loci Risk Risk Factors Sample Size Sampling Severities Stroke Subgroup Symptoms Testing Therapeutic Therapeutic Intervention Trans-Omics for Precision Medicine Transcript United States National Institutes of Health Variant Woman Women&apos s Health adverse pregnancy outcome antenatal base blood pressure elevation cardiovascular disorder risk cardiovascular health cardiovascular risk factor case control clinical care clinical phenotype cohort disease heterogeneity disorder risk fetal gene discovery genetic profiling genetic risk factor genetic variant genome sequencing genome wide association study improved insight interest lifetime risk maternal morbidity metabolomics molecular phenotype molecular subtypes multi-ethnic multidisciplinary multiple omics neonatal morbidity novel pathophysiology of preeclampsia personalized approach polygenic risk score precision medicine prevent preventive intervention rare variant risk variant severe maternal morbidity transcriptomics urinary whole genome

项目摘要

Preeclampsia (PE), the development of new-onset hypertension and proteinuria after 20 weeks gestation, is a severe pregnancy-specific disorder mediated by the placenta that affects 5% of all pregnancies. Women with prior PE have an 2-4 fold increased lifetime risk of cardiovascular disease, including ischemic heart disease and stroke. The underlying etiology of PE remains poorly understood; consequently, predictive and therapeutic options remain limited. PE has a substantial heritable component estimated at 55-60%, with both maternal and fetal contributions, estimated at 30-35% and 20%, respectively. Progress in understanding PE genetics has lagged other disorders due to: the involvement of two genomes (maternal and fetal), disease heterogeneity, the exclusion of obstetric phenotypes from many large cohort studies, and the lack of PE collections of adequate sample size for power to identify genetic risk loci. Beyond genetics, profiling of PE using other omic strategies has identified transcriptomic, proteomic, and metabolomic alterations that precede disease. However, PE cohorts with multiple omics on the same well-phenotyped individuals are lacking. To address these challenges and advance understanding of PE pathophysiology, we propose to leverage TOPMed data in the “Boston-Colombia Collaborative Adverse Pregnancy Outcome study” which capitalizes on two large, multi-ethnic pregnancy cohorts, LIFECODES (Boston) and GenPE (Colombia). LIFECODES is an ongoing longitudinal pregnancy cohort (2009–present, N >3000 pregnancies, 152 PE cases) with maternal samples from each trimester of pregnancy and delivery samples. GenPE is a Colombian study (2000 – 2012, N = 3260 cases, 4331 controls) created to identify maternal and fetal genetic risk variants. Specifically, for this proposal, we will leverage TOPMed X01 funded whole genome sequencing (WGS) on the entire LIFECODES and GenPE cohorts, as well as in-depth multi-omic profiling (metabolic, circulating microparticle proteomic and transcriptomic) on all antepartum plasma samples in matched PE case-control samples within LIFECODES, expected to be available before the grant start date. We propose three specific aims. First, we will perform gene discovery for preeclampsia using common variant, rare variant, gene based and maternal-fetal interaction analyses. Second, we will leverage longitudinal in-depth multi-omic profiling on all antepartum plasma samples in matched PE case- control samples to identify molecular subtypes of PE and link these to known and novel genetic variants. Third, we will test if polygenic risk scores for PE, supplemented by longitudinal molecular and clinical phenotypes, predict maternal morbidity at delivery and future cardiovascular disease. Taken together, analysis of this multi- omics project of PE in TOPMed, together with replication in independent cohorts, will yield novel insights into the etiology of preeclampsia. As adverse pregnancy outcomes dramatically increase the risk of future cardiometabolic disease in affected women, improved mechanistic understanding of pregnancy-related disorders will enhance strategies for improving women’s health and preventing future cardiovascular disease.

妊娠20周后，新发型高血压和蛋白尿的开发是一个抑制（PE），是一个严重的妊娠特异性疾病是由plapeta介导的，影响了所有妊娠的5％。女人先前的PE具有2-4倍的增加，增加了心血管疾病的终身风险，包括缺血性心脏病和中风。 PE的潜在病因仍然很众所周知。因此，预测和治疗选项仍然有限。 PE的基本成分估计为55-60％，同时胎儿贡献分别为30-35％和20％。理解PE遗传学的进展由于：两个基因组（母体和胎儿），疾病异质性，滞后其他疾病的参与，从许多大型队列研究中排除了产科表型，缺乏足够的PE收集识别遗传风险基因座的功率样本量。除了遗传学之外，还使用其他OMIC策略对PE进行分析已经确定了疾病之前的转录组，蛋白质组学和代谢组改变。但是，PE队列缺乏在相同良好的个人上的多个OMIC。应对这些挑战和提前了解PE病理生理学，我们建议利用“波士顿 - 哥伦比亚”中的最佳数据协作性不良怀孕结果研究”，该研究大写了两个大型多种族怀孕人群，生命系数（波士顿）和Genpe（哥伦比亚）。生命模子是一种持续的纵向怀孕队列（2009年 - 词，n> 3000妊娠，152例PE病例），每个孕早期的孕妇样品怀孕和分娩样品。 Genpe是一项哥伦比亚研究（2000年至2012年，n = 3260例，4331个对照）为识别母体和胎儿遗传风险变异而创建。具体而言，对于此提案，我们将利用顶部的X01还资助了整个生命模型和Genpe队列上的整个基因组测序（WGS）作为所有在所有人上的深度多摩尼克分析（代谢，循环微粒蛋白质组学和转录组）匹配的PE病例对照样品中的抗原性等离子体样品，预计可用在授予开始日期之前。我们提出了三个具体目标。首先，我们将执行基因发现先兆子痫使用常见变体，稀有变体，基因和母体相互作用分析。第二，我们将利用在匹配的PE病例中的所有触角等离子体样品上的纵向深度分析。控制样品以鉴定PE的分子亚型，并将其与已知和新颖的遗传变异联系起来。第三，我们将测试PE的多基因风险评分，以纵向分子和临床表型补充，预测分娩和未来心血管疾病的孕产妇发病率。总而言之，分析了这一多 PE的OMICS Project Topmed以及独立队列中的复制将产生新颖的见解先兆子痫的病因。随着不良怀孕的结果极大地增加了未来的风险受影响女性的心脏代谢疾病，对妊娠有关的机械理解得到了改善疾病将增强改善妇女健康和预防未来心血管疾病的策略。