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

摘要 子痫前期(PE)是妊娠20周后出现的新发高血压和蛋白尿，是一种 由胎盘介导的严重妊娠特有疾病，影响所有妊娠的5%。临床部 PE的特征是由弥漫性母体内皮细胞功能障碍引起的，由 母血中循环中的抗血管生成因子(即sFlt1、PlGF)。有过PE经历的女性有 增加了心血管疾病的终生风险。PE的潜在病因仍知之甚少； 因此，预测性和治疗性选择仍然有限。最近，第一个母婴基因组-- 先兆子痫的广谱关联研究(GWAS)已经发表。这些研究表明，在 孕妇基因组，易患高血压的遗传风险基因座，是先兆子痫的最大风险。在……里面 胎儿基因组，FLT1基因附近的遗传危险基因，编码胎盘衍生的抗血管生成 因子sFlt1，带来最大的风险。在这个R03项目中，我们建议利用这些新的见解 为子痫前期的临床和功能随访建立一套新的关键资源和技能 子痫前期遗传风险基因座。随后，类似的方法将扩展到由BCC-PREG TOPMed资助的 项目(MPI：GRAY/CAAS)在今后的工作中，对新确定的孕产妇和胎儿遗传风险基因座采取后续行动。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 对滋养层细胞和内皮细胞的功能跟踪，以了解在 先兆子痫临床特征的演变。具体地说，要了解胎儿的风险 我们将利用建立的多重平行报告试验(MPRA)来确定 Flt1附近增加先兆子痫风险的因果遗传变异。用这种方法确定的胎儿变异 将在BCC-PREG TOPMed的胎儿先兆子痫病例对照样本中进行复制评估 全基因组测序数据与先兆子痫的关系。了解母婴传播的影响 PE相关遗传变异对临床结局的影响，我们将测试这些已建立的母体之间的关联 妊娠基因与母体合并症和分娩时母婴并发症的危险基因 已经在我们实验室中用于正在进行的项目的数据集(英国生物库、麻省理工学院生物库)和 新的TOPMed BCC-PREG队列。我们期待这项工作能极大地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，在这条线上 在父K08的目标下，该项目将为我未来的R01应用程序生成关键数据并继续 加强我的培训；两者对于实现我发展独立生活的长期目标是必不可少的 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.