PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis

作者：Jinghao Wu, Yunyun Mei, Xinyu Li, Wen-Kai Yu, Zi Han Zhou, Yinghao Yang, Peng‐Peng Niu, Yunchao Wang, Changhe Shi, Hanghang Zhu, Wenjun He, Yuan Gao, Yuming Xu, Yusheng Li · 发表于：Stroke and Vascular Neurology · 年份：2024 · DOI：10.1136/svn-2023-003076 · 被引用次数：10 · 研究领域：Intracranial Aneurysms: Treatment and Complications、Glioma Diagnosis and Treatment、Axon Guidance and Neuronal Signaling

Background Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms. Methods We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al , cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network. Results Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(in...