卒中关联基因驱动不同族裔与卒中亚型的药物重定位研究

doi:10.3969/j.issn.1673-5765.2025.06.004

摘要/Abstract

摘要： 目的针对卒中关联基因在药物转化方面的挑战，以及不同族裔和不同卒中亚型的遗传异质性，在完善卒中关联基因功能注释的基础上，通过靶向这些基因的药物重定位分析，探究可能适用于卒中治疗的跨适应证药物类别。
方法计算机检索GWAS Catalog数据库中的卒中关联单核苷酸变异（single nucleotide variant，SNV），同时获取SNV所涉及的文献，设定检索时间范围为建库日期至2025年4月27日。检索PubMed数据库中卒中相关的队列研究、病例对照研究和meta分析等文献，从文献中获取卒中关联SNV，设定检索时间范围为2018年3月1日—2025年4月27日。通过合并与筛选获得最终纳入分析的SNV和文献，根据SNV和基因的映射关系，明确所纳入的卒中关联基因集合。采用GREP软件（版本号：1.0.0）以卒中关联基因为靶点进行药物重定位分析。
结果通过GWAS Catalog数据库检索，获得卒中关联SNV 1661个，涉及文献49篇；通过PubMed数据库检索，获得文献77篇。筛选后最终纳入卒中关联SNV 835个，涉及文献38篇，SNV所在基因338个，总样本量为11 714 626例。药物重定位分析显示，对于非洲裔、东亚裔、欧洲裔和跨族裔，卒中关联基因富集最显著的药物类别分别是抗肿瘤药物（OR 25.75，P=1.51×10^-2）、其他呼吸系统药物（OR 84.08，P=1.71×10^-2）、其他血液系统用药（OR 36.15，P=2.70×10^-4）、其他消化道和代谢药物（OR 12.67，P=3.09×10^-3）；而西班牙裔和南亚裔的卒中关联基因未发现显著富集的药物类别。对于缺血性卒中、心源性栓塞型卒中和小血管卒中，卒中关联基因富集最显著的药物类别分别是其他血液系统用药（OR 31.31，P=4.00×10^-4）、其他血液系统用药（OR 41.10，P=3.12×10^-2）和外用抗寄生虫药（OR 50.35，P=2.68×10^-2）；而卒中和大动脉卒中的关联基因未发现显著富集的药物类别。此外，还发现卒中关联基因在便秘药物、抗血栓药物、β受体阻滞剂、妇科用抗感染药物及抗菌消毒剂等药物类别中富集。
结论靶向不同族裔和不同卒中亚型关联基因所富集的药物类别存在差异，且在抗肿瘤药物、其他呼吸系统药物、其他消化道和代谢药物、妇科用抗感染药物及抗菌消毒剂、外用抗寄生虫药等非卒中传统治疗领域的药物类别上呈现富集。

文章导读： 本文关注卒中关联基因面临的临床转化难题，通过药物重定位分析，剖析了靶向卒中关联基因所富集的药物类别，初步发现其在不同族裔、不同卒中亚型间存在差异，提示部分药物存在用于卒中治疗的潜能。

关键词: 卒中关联基因; 族裔; 卒中亚型; 药物重定位

Abstract: Objective Given the challenges of drug transformation for stroke-associated genes and the genetic heterogeneity across different ethnic groups and stroke subtypes, this study aims to perform drug repositioning analysis targeting these genes based on improved functional annotation of stroke-associated genes, to identify potential cross-indication drug candidates for stroke treatment.
Methods This paper systematically searched the GWAS Catalog database to identify stroke-associated single nucleotide variants (SNVs) along with their corresponding literature. The search time range was set from the establishment of the database to April 27, 2025. Concurrently, PubMed was searched for stroke-associated cohort studies, case-control studies, and meta-analyses published between March 1, 2018 and April 27, 2025. Additional stroke-associated SNVs were extracted from these publications. After merging and filtering these records, the final set of included SNVs and literature was obtained. Based on the mapping relationships between SNVs and genes, the set of stroke-associated genes was subsequently defined. Drug repositioning analysis targeting these genes was performed using the GREP software (version 1.0.0).
Results A total of 1661 stroke-associated SNVs were retrieved from the GWAS Catalog database across 49 publications, while 77 publications were identified from PubMed. After screening, ‌835 stroke-associated SNVs‌ spanning ‌338 genes‌ were ultimately included from ‌38 publications‌, with pooled samples totaling ‌11 714 626 subjects‌. The drug repositioning analysis revealed that the most significantly enriched drug classes for stroke-associated genes were as follows. For Africans, East Asians, Europeans, and cross-ethnic groups, the most significantly enriched drug classes were anti-neoplastic agents (OR 25.75, P=1.51×10^-2), other respiratory system products (OR 84.08, P=1.71×10^-2), other hematological agents (OR 36.15, P=2.70×10^-4), and other alimentary tract and metabolism products (OR 12.67, P=3.09×10^-3), respectively. In contrast, no significantly enriched drug classes were identified for stroke-associated genes in Hispanics and South Asians. For ischemic stroke, cardioembolic stroke, and small vessel stroke, the most significantly enriched drug classes were other hematological agents (OR 31.31, P=4.00×10^-4), other hematological agents (OR 41.10, P=3.12×10^-2), and ectoparasiticides (OR 50.35, P=2.68×10^-2), respectively. No significantly enriched drug classes were identified for any stroke or large artery stroke-associated genes. Additionally, it was found that stroke-associated genes were also enriched in drug classes such as drugs for constipation, antithrombotic agents, β-blockers, and gynecological anti-infectives and antiseptics.
Conclusions The enriched drug classes for genes associated with different ethnic groups and stroke subtypes demonstrate marked variability. Specifically, significant enrichment is identified in several drug classes that are not conventionally implicated in stroke therapy, including anti-neoplastic agents, other respiratory system products, other alimentary tract and metabolism products, gynecological anti-infectives and antiseptics, and ectoparasiticides.

Key words: Stroke-associated gene; Ethnic group; Stroke subtype; Drug repositioning

中图分类号:

张杰, 勾岚, 李兰欣, 许喆, 石延枫, 姜明慧, 李昊, 程丝. 卒中关联基因驱动不同族裔与卒中亚型的药物重定位研究[J]. 中国卒中杂志, 2025, 20(6): 686-698.

ZHANG Jie, GOU Lan, LI Lanxin, XU Zhe, SHI Yanfeng, JIANG Minghui, LI Hao, CHENG Si. Research on Drug Repositioning across Different Ethnic Groups and Stroke Subtypes Driven by Stroke-Associated Genes[J]. Chinese Journal of Stroke, 2025, 20(6): 686-698.

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