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| 欧洲人群的多疾病模型研究组织蛋白酶和骨质疏松症关联 |
| The association between cathepsins and various osteoporosis complications in a European population-based multi-disease model: a two-sample and multivariate Mendelian randomization study |
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| DOI：10.3969/j.issn.1006-7108.2025.04.015 |
| 中文关键词: 组织蛋白酶 骨质疏松症 孟德尔随机化 全基因组关联研究 |
| 英文关键词:cathepsin osteoporosis Mendelian randomization genome wide association study |
| 基金项目:2023年国家自然科学基金青年项目（82305264）；2024年度基础与应用基础研究专题（青年博士“启航”项目）（2024A04J4331）；广州市青年科技人才托举项目（QT-2023-022）；2024年度广州中医药大学“揭榜挂帅”博士研究生创新能力提升项目（A3-0317-24-229-006）；广州中医药大学第一附属医院中青年骨干人才培育项目-青优人才（2023QY13）；国家中医药传承创新中心科研项目（2022QN26） |
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| 中文摘要: |
| 目的 随着中国进入老龄化社会，骨质疏松症（osteoporosis, OP）发病率不断升高，给中国社会带来巨大压力。近年来，研究发现组织蛋白酶（Cathepsin，CTS）可能和OP发病以及进展具有密切关系。因此，本研究采用双样本和多变量孟德尔随机化研究方法评估8种CTS与多种OP及并发症之间潜在的因果关系，以期为临床预防、治疗和改善OP提供新思路。方法 从已发表的全基因组关联研究中选择了8种CTS作为暴露，并从全基因组显著性水平(P<510–6)、去除连锁反应(R2=0.001，kb=10 000)和排除与其他混杂因素不存在显著相关性等方面进行筛选，最终得到CTS的单核苷酸多态性将作为工具变量进行后续的分析。同时，选用多种OP及并发症作为结局进行孟德尔随机化分析，以评估暴露与结局的因果关系。采用逆方差加权法作为主要孟德尔随机化分析方法，采用加权中位数法、简单中位数法、加权中值方法和MR-Egger回归计算CTS与OP及并发症之间的因果关联，并用孟德尔随机化多效性残差和异常值等方法检测和校正多效性的存在。结果 ①双样本孟德尔随机化的逆方差加权法结果显示，CTS-D、 CTS-B、CTS-G、CTS-L2 水平分别和不同类型的OP存在相关关系；②多变量孟德尔分析中显示，CTS-D、 CTS-G、CTS-L2 、 CTS-B、CTS-F 水平和不同类型的OP存在相关关系。结论 CTS-D 、 CTS-G、CTS-L2 、CTS-B、 CTS-F水平和OP 存在因果关联，可能会增加OP的发病风险。 |
| 英文摘要: |
| Objective As China enters an aging society, the incidence of OP is increasing, which brings great pressure to Chinese society. Recently, Researchers have found that cathepsins may be closely related to the pathogenesis and progression of OP. Therefore, the research uses two-sample and multivariate Mendelian randomization to evaluate potential relationship between 8 types of CTS and various OP complications to provide a new mind to prevent, to treat, and to relieve symptom of OP in clinical practice. Methods The research chose 8 types of CTS from Genome wide association study, which were published publicly, and extracted single nucleotide polymorphism from these CTS as instrumental variable. Meanwhile, the research required that these instrumental variables were in accord with the following three criteria: having a genome-wide significance level (P<510–6), removing linkage disequilibrium, and having no significant correlation with other confounding factors. Finally, these single nucleotide polymorphism from CTS which were in accord with these criteria might be used as instrumental variables in subsequent analyses. At the same time, the research chose various OP complications as results to evaluate causal relationship between exposure and outcome by two-sample and multivariate Mendelian randomization. The research used inverse variance weighted as the primary method for Mendelian randomization analysis and used weighted median, weighted median estimator, simple median, weighted median estimator and MR-Egger to calculate the causal relationship between CTS and various OP complications. Also, the research used MR-PRESSO including pleiotropy residual sum and outlier to detect and to correct the presence of pleiotropy. Results ①The results of inverse variance weighted by two-sample Mendelian randomization indicated that CTS-D, CTS-B, CTS-G, and CTS-L2 levels were correlated with different types of OP. ②The results of inverse variance weighted by multivariate Mendelian randomization indicated that CTS-D, CTS-G, CTS-L2, CTS-B, and CTS-F levels were correlated with different types of OP. Conclusion CTS-D, CTS-G, CTS-L2, CTS-B, and CTS-F levels have a causal association with OP, which may increase the risk of developing OP. |
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