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

摘要 先兆子痫（PE）是妊娠20周后新发高血压和蛋白尿的发展，是一种高血压疾病， 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 PE的特征是由弥漫性母体内皮细胞功能障碍引起的，由内皮细胞的不平衡介导。 母体血液中循环的抗血管生成因子（即，sFlt1、PlGF）。有PE病史的女性 心血管疾病的终生风险增加。PE的潜在病因仍然知之甚少; 因此，预测和治疗选择仍然有限。最近，第一个母亲和胎儿的基因组- 已经发表了先兆子痫的广泛关联研究（GWAS）。这些研究表明，在 母体基因组，易患高血压的遗传风险位点赋予先兆子痫最大的风险。在 胎儿基因组，FLT 1基因附近的遗传风险位点，其编码胎盘来源的抗血管生成 因子sFlt 1，赋予最大的风险。在这个R 03项目中，我们建议利用这些新的见解， 建立一套新的关键资源和技能，用于临床和功能随访， 先兆子痫遗传风险基因座。类似的方法将扩展到受资助的BCC-PREG TOPM 项目（MPI：Gray/Casas）在未来的工作中对新发现的母体和胎儿遗传风险位点进行随访。这 R 03项目建立在母K 08项目的基础上，该项目专注于利用遗传学和其他组学，以及 滋养层细胞和内皮细胞的功能随访，以了解 先兆子痫的临床特征的发展。具体来说，为了了解胎儿的风险， 在FLT 1附近的先兆子痫基因座中，我们将利用已建立的多平行报告基因测定（MPRA）来鉴定 FLT 1附近的致病遗传变异增加了先兆子痫的风险。用这种方法识别的胎儿变异 将评估来自BCC-PREG TOPM的胎儿先兆子痫病例-对照样本中的复制 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局的影响，我们将测试这些已确定的母体 使用妊娠遗传学研究母体合并症和分娩时母体和胎儿并发症的风险位点 数据集已经在我们的实验室用于正在进行的项目（英国生物银行，马萨诸塞州总布里格姆生物银行）和 新的TOPMed BCC-PREG队列。我们预计这项工作将大大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。此外，在缐 根据父K 08的目标，该项目将为我未来的R 01应用程序生成关键数据，并继续 加强我的培训;两者都是实现我发展独立的长期目标所必需的。 转化研究计划，整合临床，人口统计学和分子数据，以了解 不良妊娠结局的潜在机制。

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.