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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：
10604382
负责人：
RICHA SAXENA
金额：
$ 70.48万
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/10604382
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 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 Onset of illness Outcome Study Pathway interactions Patients Phenotype Placenta Plasma Pre-Eclampsia Predisposition Pregnancy Pregnancy Trimesters Premature Birth Prevention approach 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 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 risk factor genetic variant genome sequencing genome wide association study improved insight interest lifetime risk maternal morbidity metabolomics molecular phenotype molecular subtypes mortality multi-ethnic multidisciplinary multiple omics neonatal morbidity novel particle 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.

先兆子痫（PE）是妊娠20周后新发高血压和蛋白尿的一种疾病