中国药物警戒 ›› 2025, Vol. 22 ›› Issue (3): 241-248.
DOI: 10.19803/j.1672-8629.20240899

• 骨与关节退行性疾病用药安全性研究专栏 • 上一篇    下一篇

基于多组学数据的孟德尔随机化分析鉴定椎间盘退变可成药靶点及中药预测

郭东琪1,2, 王浩3,△, 白欣1, 白建琦1, 苏红梅1, 张静茹1, 郭宵飞1, 赵小琪4, 王敏5, 王源1#, 张平1,*   

  1. 1中国中医科学院望京医院病理科,北京 100102;
    2北京中医药大学研究生院,北京 100029;
    3中国中医科学院望京医院学术发展处,北京 100102;
    4中国中医科学院望京医院超声科,北京 100102;
    5中国中医科学院望京医院人事处,北京 100102
  • 收稿日期:2024-11-25 出版日期:2025-03-15 发布日期:2025-03-17
  • 通讯作者: *张平,女,博士,主任医师·博导,中西医结合防治骨关节退变。E-mail: Pinglele@sina.com;#为共同通信作者。
  • 作者简介:郭东琪,男,在读硕士,中西医结合防治骨关节退变。△为并列第一作者。
  • 基金资助:
    国家自然科学基金资助项目（82174415、82405441）;中国中医科学院创新工程重大攻关项目（C12021A05054）;中国中医科学院望京医院高水平医院建设循证研究重点专项（WJYY-XZKT-2023-25）

Identification of Druggable Targets for Intervertebral Disc Degeneration Based on Multi-Omics Data-Driven Mendelian Randomization and Prediction of Traditional Chinese Medicine Interventions

GUO Dongqi1,2, WANG Hao,BAI Xin1, BAI Jianqi1, SU Hongmei1, ZHANG Jingru1, GUO Xiaofei1, ZHAO Xiaoqi4, WANG Min5, WANG Yuan1#, ZHANG Ping1,*   

  1. 1Department of Pathology, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing 100102, China;
    2Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China;
    3Office of Academic Development, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing 100102, China;
    4Department of Ultrasound, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing 100102, China;
    5Office of Human Resources, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing 100102, China
  • Received:2024-11-25 Online:2025-03-15 Published:2025-03-17

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摘要： 目的 研究治疗椎间盘退变的可成药靶点并评估其安全性,预测调控可成药靶点治疗椎间盘退变的中药。方法 从eQTLGen Consortium获取可成药基因的表达数量性状位点作为暴露,GWAS Catalog数据库获取椎间盘退变的全基因组关联研究数据作为结局进行药物靶点孟德尔随机化（Mendelian Randomization, MR）分析,寻找椎间盘退变潜在的治疗靶点。对椎间盘退变可成药基因进行GO、KEGG富集分析。从FinnGen数据库获取椎间盘退变可成药基因的蛋白数量性状位点,作为暴露进行MR验证上述可成药基因的有效性。通过PheWAS Portal进行全表型组关联研究,评估药物安全性;利用BATMAN-TCM 2.0及ETCM 2.0平台挖掘中药成分,分析用药规律。通过CB-Dock 2平台对靶点及中药成分进行分子对接,寻找潜在的先导化合物。结果 延胡索、巴戟天、艾叶等35味中药中的20个有效成分可通过调控ZP3、RRM2B、CCL4等3个可成药靶点治疗椎间盘退变;基因表达MR提示248个可成药基因与椎间盘退变存在因果关系,富集分析显示上述基因与细胞因子活性、细胞衰老等过程相关,蛋白MR验证其中6个基因为椎间盘退变的可成药靶点;全表型组关联研究未发现上述可成药靶点存在明显不良反应;分子对接显示上述中药成分与可成药靶点的结合活性较好,最佳结合能-10.2 kcal·mol-1。结论 ZP3、RRM2B、CCL4等基因是椎间盘退变的潜在药靶,安全性较好;延胡索、巴戟天、艾叶等中药通过可成药靶点治疗椎间盘退变,其有效成分如黄嘌呤核苷等是新药研发的潜在化合物。

关键词: 椎间盘退变, 孟德尔随机化, 药物靶点, 全表型组关联研究, 安全性, 中药预测

Abstract: Objective To identify druggable targets for the treatment of intervertebral disc degeneration (IDD), evaluate their safety, and to predict the traditional Chinese medicines (TCMs) that can regulate these druggable targets for IDD. Methods Data on expression quantitative trait loci of druggable genes was retrieved from the eQTLGen Consortium as exposures, while data on IDD genome-wide association study was downloaded from the GWAS Catalog to serve as outcomes for Mendelian randomization analysis intended to identify potential IDD therapeutic targets. Enrichment analyses were conducted on druggable genes related to IDD. The data on protein quantitative trait loci of druggable genes related to IDD was retrieved from the FinnGen database to validate the efficacy of these genes. A phenome-wide association study (PheWAS) via the PheWAS Portal was conducted to assess drug safety. The BATMAN-TCM 2.0 and ETCM 2.0 platforms were used to mine TCM components and analyze medication patterns. Potential lead compounds were identified through molecular docking of targets and TCM components on the CB-Dock 2 platform. Results 35 TCMs, including Corydalis yanhusuo W. T. Wang., Morinda officinalis How., and Artemisia argyi Lévl. et Vant., were found to treat IDD by regulating three druggable targets-ZP3, RRM2B, and CCL4, through their 20 active components. Gene expression MR indicated that 248 druggable genes were causally related to IDD, and enrichment analyses showed that these genes were associated with cytokine activities and cellular senescence. Protein MR validated six of these genes as druggable targets for IDD. PheWAS revealed no significant adverse effects associated with the aforementioned druggable targets. Molecular docking results showed good binding activity between the TCM components and the druggable targets, with the best binding energy of -10.2 kcal·mol-1. Conclusion Such genes as ZP3, RRM2B, and CCL4 are potential therapeutic targets for IDD with good safety profiles. TCMs like Morinda officinalis How., Corydalis yanhusuo W. T. Wang., and Artemisia argyi Lévl. et Vant. can treat IDD through these druggable targets, and their active components, such as Xanthosine, are potential compounds for new drug development.

Key words: Intervertebral Disc Degeneration, Mendelian Randomization, Drug Targets, Phenome-Wide Association Study, Safety, Traditional Chinese Medicine Prediction

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