中国卒中杂志2025，Vol.20Issue(6)：686-698,13.DOI:10.3969/j.issn.1673-5765.2025.06.004
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
Research on Drug Repositioning across Different Ethnic Groups and Stroke Subtypes Driven by Stroke-Associated Genes
摘要
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.关键词
卒中关联基因/族裔/卒中亚型/药物重定位Key words
Stroke-associated gene/Ethnic group/Stroke subtype/Drug repositioning分类
医药卫生引用本文复制引用
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):686-698,13.基金项目
国家自然科学基金(82471304)国家重点研发计划(2022YFE0209600)首都医科大学优秀青年人才项目B类(B2417) （82471304）
