Wu Jinghao, Mei Yunyun, Li XinYu, Yu Wen-Kai, Zhou Zi Han, Yang Yinghao, Niu Pengpeng, Wang Yunchao, Shi Chang-He, Zhu Hanghang, He Wenjun, Gao Yuan, Xu Yuming, Li Yusheng
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China.
Stroke Vasc Neurol. 2025 Apr 29;10(2):e003076. doi: 10.1136/svn-2023-003076.
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.
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 , 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.
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(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.
This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.
脑动脉瘤是危及生命的脑血管疾病。目前，尚无预防疾病进展的有效治疗方法。孟德尔随机化（MR）被广泛用于重新利用已获许可的药物并确定新的治疗靶点。因此，本研究旨在探究预防脑动脉瘤形成和破裂的有效药物靶点，并分析其潜在机制。
我们进行了一项综合研究，整合了两样本MR分析、共定位分析和基于汇总数据的孟德尔随机化（SMR），以评估血液和脑可药物化的顺式表达定量性状基因座（顺式-eQTL）对颅内动脉瘤（IA）、未破裂颅内动脉瘤（UIA）和IA破裂所致蛛网膜下腔出血（SAH）的因果效应。可药物化基因来自Chris Finan的研究，顺式-eQTL来自eQTLGen和PsychENCODE联盟。结果使用蛋白质组学和转录组学数据进行验证。单基因功能分析探究潜在机制，最终构建药物-基因调控网络。
通过MR分析，我们在血液中确定了四个潜在药物靶点，包括脯氨酰羧肽酶（PRCP）、蛋白酶体20S亚基α4（PSMA4）、LTBP4和用于SAH的GPR160。此外，在进行多重检验校正后（逆方差加权P<8.28e-6），确定了两个针对IA的潜在药物靶点（PSMA4和SLC22A4）以及一个针对UIA的潜在药物靶点（KL）。共定位和SMR分析的有力证据证实了PSMA4和PRCP与研究结果的相关性。PRCP循环蛋白升高与较低的SAH风险相关。疾病队列中PRCP基因表达显著下调。
本研究支持血液中PRCP基因表达升高与IA破裂风险降低存在因果关联。相反，血液中PSMA4表达增加与IA破裂和形成风险增加存在因果关系。
