Clinical and functional follow-up of maternal and fetal preeclampsia genetic risk loci

母婴子痫前期遗传风险位点的临床和功能随访

基本信息

批准号：
10660975
负责人：
Kathryn Johnson Gray
金额：
$ 8.4万
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：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10660975
关键词：
Affect Angiogenesis Inhibitors Angiogenic Factor Biological Biological Assay Blood Boston Cardiac health Cardiometabolic Disease Cardiovascular Diseases Cell Line Clinical Clinical Skills Colombia Complex DNA Data Data Set Development Diffuse Disease Endothelial Cells Etiology FLT1 gene Fetal Growth Retardation Functional disorder Funding Future Genes Genetic Genetic Risk Genetic Transcription Genetic Variation Genome Goals Heritability Hypertension In Vitro Individual Investigation Maternal Mortality Mediating Medical Metabolic Diseases Molecular National Heart, Lung, and Blood Institute Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Outcome Study PGF gene Parents Pathway interactions Phase Phenotype Placenta Pre-Eclampsia Pregnancy Premature Birth Prevention strategy Proteins Proteinuria Public Health Publishing Reporter Resources Risk Risk Factors Role SH2B gene Sampling Schizophrenia Testing Therapeutic Tissues Training Trans-Omics for Precision Medicine United States Variant Woman Work adverse pregnancy outcome biobank blood pressure elevation cardiovascular disorder risk case control cell type clinical development cohort fetal follow-up genetic information genetic risk factor genetic variant genome sequencing genome wide association study genomic locus improved induced pluripotent stem cell insight lifetime risk maternal comorbidity maternal hypertension maternal morbidity maternal risk mortality neonatal morbidity novel strategies novel therapeutics pathophysiology of preeclampsia risk variant severe maternal morbidity stillbirth tool translational research program trophoblast urinary whole genome

项目摘要

ABSTRACT 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. The clinical features of PE are caused by diffuse maternal endothelial cell dysfunction, mediated by an imbalance of circulating anti-angiogenic factors in the maternal blood (i.e., sFlt1, PlGF). Women with prior PE have an increased lifetime risk of cardiovascular disease. The underlying etiology of PE remains poorly understood; consequently, predictive and therapeutic options remain limited. Recently, the first maternal and fetal genome- wide association studies (GWAS) of preeclampsia have been published. These studies revealed that in the maternal genome, genetic risk loci that predispose to hypertension confer the greatest risk for preeclampsia. In the fetal genome, genetic risk loci near the FLT1 gene, which encodes for the placentally-derived anti-angiogenic factor sFlt1, confer the greatest risk. Here in this R03 project we propose to capitalize on these new insights into preeclampsia to establish a new set of key resources and skills for clinical and functional follow-up of preeclampsia genetic risk loci. Similar approaches will then be extended to the funded BCC-PREG TOPMed project (MPI: Gray/Casas) in future work for follow-up of newly identified maternal and fetal genetic risk loci. This R03 project builds on the parent K08 project that is focused on utilizing genetics and other omics, as well as functional follow-up in trophoblasts and endothelial cells, to understand biologic pathways altered prior to the development of clinical features of preeclampsia. Specifically, to understand risk conferred by the fetal preeclampsia locus near FLT1, we will utilize an established multiple parallel reporter assay (MPRA) to identify the causal genetic variants near FLT1 that increase preeclampsia risk. Fetal variants identified with this approach will be assessed for replication in the fetal preeclampsia case-control samples from the BCC-PREG TOPMed whole genome sequencing data for their association with preeclampsia. To understand the influence of maternal PE-associated genetic variants on clinical outcomes, we will test the association of these established maternal risk loci with maternal comorbidities and maternal and fetal complications at delivery using pregnancy genetic datasets already in use in our lab for ongoing projects (UK Biobank, Mass General Brigham Biobank) and the new TOPMed BCC-PREG cohort. We anticipate this work significantly advance understanding of preeclampsia pathophysiology and allow for development of novel therapeutic and prevention strategies. Additionally, in line with the goals of the parent K08, this project will generate key data for my future R01 application and continue to enhance my training; both are essential for achieving my long-term goal of developing an independent translational research program that integrates clinical, demographic, and molecular data to understand mechanisms underlying adverse pregnancy outcomes.

抽象的先兆子痫 (PE) 是妊娠 20 周后新发高血压和蛋白尿的一种疾病。由胎盘介导的严重妊娠特异性疾病，影响所有妊娠的 5%。临床上 PE 的特征是由弥漫性母体内皮细胞功能障碍引起，该功能障碍是由母体血液中循环的抗血管生成因子（即 sFlt1、PlGF）。既往患有 PE 的女性有终生患心血管疾病的风险增加。 PE 的根本病因仍然知之甚少；因此，预测和治疗选择仍然有限。最近，第一个母体和胎儿基因组- 先兆子痫的广泛关联研究（GWAS）已发表。这些研究表明，在母体基因组中，易患高血压的遗传风险位点赋予先兆子痫的最大风险。在胎儿基因组，FLT1 基因附近的遗传风险位点，该基因编码胎盘源性抗血管生成因子因素 sFlt1 带来最大的风险。在这个 R03 项目中，我们建议利用这些新见解先兆子痫建立一套新的关键资源和技能，用于子痫前期的临床和功能随访先兆子痫遗传风险位点。类似的方法将扩展到资助的 BCC-PREG TOPMed 项目（MPI：Gray/Casas）在未来工作中对新发现的孕产妇和胎儿遗传风险位点进行后续工作。这 R03 项目建立在父 K08 项目的基础上，该项目专注于利用遗传学和其他组学，以及对滋养层和内皮细胞进行功能随访，以了解在发生之前改变的生物途径先兆子痫临床特征的发展。具体来说，要了解胎儿带来的风险子痫前期基因座靠近 FLT1，我们将利用已建立的多重平行报告基因测定 (MPRA) 来识别 FLT1 附近的致病基因变异会增加先兆子痫的风险。用这种方法鉴定的胎儿变异将评估 BCC-PREG TOPMed 的胎儿先兆子痫病例对照样本中的复制情况全基因组测序数据与先兆子痫的关联。了解母亲的影响 PE 相关的遗传变异对临床结果的影响，我们将测试这些已确定的母体之间的关联利用妊娠遗传学确定孕产妇合并症以及分娩时母婴并发症的风险位点数据集已在我们的实验室中用于正在进行的项目（英国生物银行、麻省总医院布里格姆生物银行）以及新的 TOPMed BCC-PREG 队列。我们预计这项工作将显着促进对先兆子痫的理解病理生理学并允许开发新的治疗和预防策略。另外，在行秉承母体 K08 的目标，该项目将为我未来的 R01 应用生成关键数据并继续加强我的训练；两者对于实现我发展独立的长期目标都是至关重要的。整合临床、人口统计和分子数据来理解的转化研究计划不良妊娠结局的潜在机制。