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

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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.