Exploration of potential therapeutic target genes for preeclampsia through genetic analysis

Abstract

Preeclampsia (PE) is a prevalent and severe pregnancy-related complication, for which effective intervention targets remain limited, posing significant risks to maternal and fetal health. This study aimed to identify potential therapeutic target genes through genetic analyses. Specifically, we utilized cis-expression quantitative trait loci (cis-eQTL) of druggable genes derived from blood samples obtained from the eQTLGen consortium as exposure data. Subsequently, Mendelian randomization (MR) analysis was conducted to explore causal associations between these druggable genes and PE. Functional enrichment analysis, Summary-data-based MR (SMR), and colocalization analysis were employed to validate the identified genes. MR results revealed 17 druggable genes significantly associated with PE after multiple testing correction (FDR < 0.05). Functional enrichment analysis indicated that these genes are involved in key biological processes such as leukocyte proliferation and activation, immune response regulation, and the metabolism of water-soluble vitamins. Additionally, they were found to participate in several critical signaling pathways, including the complement and coagulation cascades, the renin-angiotensin system, and folate biosynthesis. SMR and colocalization analyses further confirmed the causal relationships between PE and five genes—TESK2, LNPEP, CD320, NELL2, and SF3B3. Moreover, single-cell RNA sequencing data supported the association between the expression levels of TESK2, CD320, and SF3B3 and the development of PE. This study provides preliminary evidence identifying several potential genetic targets that may help reduce the risk of PE from a genomic perspective. These findings offer novel scientific insights and research directions for future drug development and the optimization of therapeutic strategies aimed at managing and preventing PE.