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

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $84,000

## Abstract

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 t...

## Key facts

- **NIH application ID:** 10424668
- **Project number:** 1R03HL162756-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kathryn Johnson Gray
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $84,000
- **Award type:** 1
- **Project period:** 2022-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424668

## Citation

> US National Institutes of Health, RePORTER application 10424668, Clinical and functional follow-up of maternal and fetal preeclampsia genetic risk loci (1R03HL162756-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10424668. Licensed CC0.

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