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. 2025 May;82(5):839-848.
doi: 10.1161/HYPERTENSIONAHA.124.23400. Epub 2024 Dec 26.

Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels

Jasmine A Mack  1   2 , Ulla Sovio  1   3 , Felix R Day  4 , Francesca Gaccioli  1   3 , Emma Cook  1 , Nadua Bayzid  5 , Marius Cotic  5 , Nathan J Dunton  5 , Gaganjit Madhan  5 , Alison A Motsinger-Reif  2 , John R B Perry  4   6 , D Stephen Charnock-Jones  1   3 , Gordon C S Smith  1   3
Affiliations

Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels

Jasmine A Mack et al. Hypertension. 2025 May.

Abstract

Background: Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA).

Methods: We studied a prospective cohort of nulliparous women (3968 mother-child pairs). We related maternal and fetal genotype to the adjusted sFLT1 Z score and sFLT1:placental growth factor (PlGF) ratio Z score at each wkGA and the change in the Z score between 28 and 36 wkGA (Δ36-28). We studied genetic variants from a previous fetal genome-wide association study of preeclampsia and an externally defined polygenic score from a maternal genome-wide association study of preeclampsia.

Results: Four variants from the fetal preeclampsia genome-wide association study were positively associated with sFLT1 and sFLT1:PlGF Z score at 36 wkGA, and FLT1 enhancer single-nucleotide polymorphisms were associated with increased Δ36-28 of sFLT1. The associations were specific for the fetal genome or stronger for the fetal than the maternal genome. An increased risk of preeclampsia based on the maternal polygenic score for preeclampsia was associated with lower levels of sFLT1 and sFLT1:PlGF ratio in the first trimester and a greater Δ36-28 for sFLT1.

Conclusions: The current data are consistent with a causal association between sFLT1 released by the placenta in late pregnancy and the pathophysiology of preeclampsia. The data are also consistent with maternal components to the protective effect of high sFLT1 in the first trimester and the rise in third-trimester sFLT1 levels and preeclampsia.

Keywords: PlGF protein; biomarkers; polygenic risk score; polymorphism, single nucleotide; preeclampsia; sFLT-1 protein.

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Conflict of interest statement

G.C.S. Smith and D.S. Charnock-Jones received research support from Roche Diagnostics, Illumina, and Pfizer (fetal growth, restriction and preeclampsia, preterm birth, and infection). G.C.S. Smith has been a paid consultant to GSK (preterm birth) and a member of a Data Monitoring Committee for GSK trials of respiratory syncytial virus (RSV) vaccination in pregnancy. G.C.S. Smith is currently a member of the Data Monitoring Committee for Moderna trials of RSV vaccination in pregnancy. Current or recent government or charity grant support: MRC, the National Institute for Health and Care Research, and Wellcome Trust and Wellcome Leap. The other authors report no conflicts.

Figures

None
Graphical abstract
Figure 1
Figure 1. Overview of study workflow.
PE = preeclampsia; PGS = polygenic score; wkGA = weeks of gestational age
Figure 2
Figure 2
Forest Plots of summary statistics from sFLT1 z-score and multi-ethnic fetal genotype association study across gestation for the Pregnancy Outcome Prediction study (POPs) participants without preeclampsia. Four genetic variants near the FLT1 gene previously found to be associated with preeclampsia (SNP_Effect Allele): A) rs12050029_G; B) rs4769612_C; C) rs4769613_C; D) rs7318880_T;. SD = Standard Deviation; CI = Confidence Interval; 36-28 Delta refers to the change in standard deviation of sFLT1 between 28 and 36 weeks’ gestation.
Figure 3
Figure 3
Cis-pQTL regional plot of fetal enhancer SNPs in relation to the FLT1 gene, for association analysis of the sFLT1 Δ36-28. LD = linkage disequilibrium
Figure 4
Figure 4
Maternal genetic score validation for sFLT1 levels and sFLT1:PlGF ratio across gestation, applying a preeclampsia polygenic score (PGS) based on meta-analyses conducted in Honigberg et al,. The intervals reflect the mean effect per SD of the maternal PGS with 95% confidence upper and lower bounds for: A) sFLT1 and B) sFLT1:PlGF ratio.
Figure 5
Figure 5
Forest Plots of summary statistics for rs4349809 across gestation for the Pregnancy Outcome Prediction study (POPs) participants without preeclampsia. A) fetal and B) maternal multi-ethnic association study. SD = Standard Deviation; CI = Confidence Interval
See this image and copyright information in PMC

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