BTN3A2 is a key target for the development or prevention of new drugs for knee osteoarthritis:a randomization study based on drug targeting

Wei Bingqi; Sun Jiahui; Chen Liu; Li Yijing; Wan Hejia; Qi Yifan; Wang Shangzeng

doi:10.12307/2026.703

Abstract：BACKGROUND:Knee osteoarthritis has a high prevalence in China,and current therapeutic drugs are often associated with side effects and adverse reactions. OBJECTIVE:To explore the causal relationship between druggable genes and knee osteoarthritis using the Mendelian randomization approach,thereby providing a reference framework for the development of new drugs for knee osteoarthritis. METHODS:This study utilized data from 2 941 druggable genes in the FinnGen database and knee osteoarthritis-related data from the Genome-Wide Association Study(GWAS)Catalog database.Drug target mendelian randomization analysis,false discovery rate correction,and co-localization analysis were conducted to identify potential drug targets for knee osteoarthritis.The final results were validated using the eQTLGen Consortium database to enhance the reliability of the identified drug targets. RESULTS AND CONCLUSION:A total of 2 941 druggable genes were analyzed using Mendelian randomization and 21 potential drug targets were identified.Following false discovery rate correction and sensitivity analyses,two drug targets were retained:Dipeptidase 1(DPEP1)and Butyrophilin Subfamily 3 Member A2(BTN3A2).Further co-localization analysis identified BTN3A2 as the sole key drug target.Validation using the eQTLGen Consortium database,which includes 2 525 drug-target genes,further confirmed the significant causal relationship between BTN3A2 and knee osteoarthritis.To conclude,BTN3A2 is identified as a key therapeutic target for the development of novel drugs or preventive interventions for knee osteoarthritis.This study primarily relied on international genetic databases to identify potential drug targets,providing a reference framework for drug development tailored to the Chinese population.The findings contribute to the establishment of a robust,effective,clearly defined,and low-side-effect framework for the prevention and treatment of knee osteoarthritis in Chinese patients.