中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (16): 4021-4029.doi: 10.12307/2026.703

• 骨组织构建 bone tissue construction •    下一篇

BTN3A2是膝骨关节炎新型药物研发或防治的关键靶点：药靶随机化分析

魏炳琦1，2，孙佳慧1，2，陈  柳1，2，李宜静1，2，万和伽1，2，祁翼帆1，2，王上增1，2   

  1. 1河南省中医院(河南中医药大学第二附属医院)关节病科，河南省郑州市  450002；2河南中医药大学骨伤学院，河南省郑州市  450002
  • 收稿日期:2025-03-01 接受日期:2025-08-20 出版日期:2026-06-08 发布日期:2025-11-25
  • 通讯作者: 王上增，主任医师，博士生导师，河南省中医院(河南中医药大学第二附属医院)关节病科，河南省郑州市 450002；河南中医药大学骨伤学院，河南省郑州市 450002
  • 作者简介:魏炳琦，男，2002年生，河南省驻马店市人，汉族，河南中医药大学在读硕士，主要从事中医药防治骨关节病与运动损伤研究。
  • 基金资助:
    国家自然科学基金项目(82374490)，项目负责人：王上增；河南省自然科学基金项目(222300420486)，项目负责人：王上增；河南省高校科技创新团队(24IRTSTHN040)，项目负责人：王上增；河南省中医药科学研究专项课题项目(2023ZYZD06，2021ZY2010，2019ZY2035)，项目负责人：王上增；郑州市科技惠民计划项目(2023KJHM0009)，项目负责人：王上增；河南省大学生创新创业训练计划(202410471006)，项目负责人：祁翼帆；河南省重点研发专项(241111311700)，项目负责人：王上增；河南省中青年卫生健康科技创新领军人才(LJRC2024020)，项目负责人：王上增

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

Wei Bingqi1, 2, Sun Jiahui1, 2, Chen Liu1, 2, Li Yijing1, 2, Wan Hejia1, 2, Qi Yifan1, 2, Wang Shangzeng1, 2   

  1. 1Department of Orthopedics, Henan Provincial Hospital of Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, Henan Province, China; 2School of Orthopedics, Henan University of Chinese medicine, Zhengzhou 450002, Henan Province, China 
  • Received:2025-03-01 Accepted:2025-08-20 Online:2026-06-08 Published:2025-11-25
  • Contact: Wang Shangzeng, Chief physician, Doctoral supervisor, Department of Orthopedics, Henan Provincial Hospital of Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, Henan Province, China; School of Orthopedics, Henan University of Chinese medicine, Zhengzhou 450002, Henan Province, China
  • About author:Wei Bingqi, MS candidate, Department of Orthopedics, Henan Provincial Hospital of Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, Henan Province, China; School of Orthopedics, Henan University of Chinese medicine, Zhengzhou 450002, Henan Province, China
  • Supported by:
    National Natural Science Foundation of China, No. 82374490 (to WSZ); Henan Provincial Natural Science Foundation Project, No. 222300420486 (to WSZ); Henan University Science and Technology Innovation Team, No. 24IRTSTHN040 (to WSZ); Henan Province Traditional Chinese Medicine Scientific Research Projects, Nos. 2023ZYZD06,  2021ZY2010, and 2019ZY2035 (all to WSZ); Zhengzhou Science and Technology Benefit People Plan Project, No. 2023KJHM0009 (to WSZ); Henan College Students’ Innovation and Entrepreneurship Training Program, No. 202410471006 (to QYF); Henan Province Key Research and Development Project, No. 241111311700 (to WSZ); Henan Province Middle-aged and Young Leading Talent for Health and Wellness Science and Technology Innovation, No. LJRC2024020 (to WSZ)

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摘要：

文题释义：
孟德尔随机化：是一种利用遗传学原理探究暴露因素与疾病之间因果关系的分析工具。通过将与暴露因素显著相关的遗传变异作为工具变量，可以有效降低混杂因素和逆向因果关系对研究结果的干扰，从而更精确地评估暴露因素对疾病的因果效应。
BTN3A2：是一种属于免疫球蛋白超家族的跨膜蛋白，主要在免疫系统调控中发挥作用，广泛表达于多种组织和细胞类型中，尤其是在免疫相关细胞(如T细胞和单核细胞)中具有重要功能，其可通过调控炎症和组织修复过程影响膝骨关节炎的进展。

摘要
背景：目前国内膝骨关节炎患病率较高，且现有治疗药物存在诸多不良反应。
目的：运用药靶孟德尔随机化分析可成药基因与膝骨关节炎间的因果关系，以便为膝骨关节炎新型治疗药物的研发提供参考依据。
方法：采用FinnGen数据库中2 941种可成药基因和全基因组关联研究(GWAS)Catalog数据库中的膝骨关节炎数据，进行药靶孟德尔随机化、错误发现率校正以及共定位分析，探究膝骨关节炎的潜在药物靶点，并将最终结果在eQTLGen Consortium数据库中进行验证，以增强药物靶点的可靠性。
结果与结论：①2 941种可成药基因经过孟德尔随机化分析后共得到21个潜在的药物靶点，经错误发现率校正、敏感性分析后得到二肽酶1 (DPEP1)和嗜乳脂蛋白亚家族3成员A2(BTN3A2)这2个药物靶点；②进行共定位分析后仅筛选出BTN3A2这一个关键药物靶点；③经eQTLGen Consortium数据库中2 525种药靶验证基因验证后进一步提示BTN3A2与膝骨关节炎间具有显著的因果关系；④提示BTN3A2 可作为膝骨关节炎新型药物研发或防治的关键靶点；此次研究主要采用国际基因数据库进行分析，可为国内膝骨关节炎药物研发提供参考依据，有助于构建一条理论扎实、疗效确切、不良反应小且适用于中国患者的膝骨关节炎防治链。

https://orcid.org/0009-0005-1065-4520(魏炳琦)；https://orcid.org/0000-0003-4159-4848(王上增)

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: BTN3A2, 膝骨关节炎, 成药基因, 孟德尔随机化, 药物靶点, 因果关系, 共定位分析, 基因验证

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.

Key words: BTN3A2, knee osteoarthritis, druggable genes, Mendelian randomization, drug targets, causal relationship, co-location analysis, gene verification

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