Wang Huihui, Shen Meihong, She Guangtong, Wang Huiyan, Zhou Wenbo
Department of Obstetrics and Gynecology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China.
Medical Research Center, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China.
J Hum Hypertens. 2025 Jul 25. doi: 10.1038/s41371-025-01054-0.
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.
子痫前期（PE）是一种常见且严重的妊娠相关并发症，其有效的干预靶点仍然有限，对母婴健康构成重大风险。本研究旨在通过基因分析确定潜在的治疗靶点基因。具体而言，我们利用从eQTLGen联盟获得的血液样本中可成药基因的顺式表达定量性状位点（cis-eQTL）作为暴露数据。随后，进行孟德尔随机化（MR）分析，以探索这些可成药基因与PE之间的因果关联。采用功能富集分析、基于汇总数据的MR（SMR）和共定位分析来验证所鉴定的基因。MR结果显示，经过多重检验校正后（FDR < 0.05），有17个可成药基因与PE显著相关。功能富集分析表明，这些基因参与关键的生物学过程，如白细胞增殖和激活、免疫反应调节以及水溶性维生素的代谢。此外，还发现它们参与了几个关键的信号通路，包括补体和凝血级联反应、肾素-血管紧张素系统以及叶酸生物合成。SMR和共定位分析进一步证实了PE与五个基因（TESK2、LNPEP、CD320、NELL2和SF3B3）之间的因果关系。此外，单细胞RNA测序数据支持TESK2、CD320和SF3B3的表达水平与PE发生之间的关联。本研究提供了初步证据，从基因组角度确定了几个可能有助于降低PE风险的潜在遗传靶点。这些发现为未来药物开发以及旨在管理和预防PE的治疗策略优化提供了新的科学见解和研究方向。
