组织蛋白酶与骨密度的因果关系:双向孟德尔随机化分析  

Causal association between cathepsins and bone mineral density:two-way Mendelian randomization analyses

作　　者：姜楠 符浩楠 郝宇涵 陈祉霖 朱芷晴 徐峰 于栋 Jiang Nan;Fu Haonan;Hao Yuhan;Chen Zhilin;Zhu Zhiqing;Xu Feng;Yu Dong(The Third Clinical School of Beijing University of Chinese Medicine,Beijing 100029,China;College of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China;Anhui University of Chinese Medicine,Hefei 230031,Anhui Province,China;The Third Clinical Hospital of Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]北京中医药大学第三临床医学院,北京市100029 [2]北京中医药大学中医学院,北京市100029 [3]安徽中医药大学,安徽省合肥市230031 [4]北京中医药大学第三附属医院,北京市100029

出　　处：《中国组织工程研究》2025年第12期2623-2630,共8页Chinese Journal of Tissue Engineering Research

基　　金：北京市教育科学规划课题项目(CDDB21167),课题名称:以建立中医基层临床实践基地为导向开展中医临床本科教育全科方向的改革探索研究,项目负责人:徐峰。

摘　　要：背景:既往研究表明,中老年人体内组织蛋白酶K水平可通过影响骨密度来干预骨质疏松的发生和发展,但组织蛋白酶家族与其他人群骨密度之间是否存在因果关系仍未知。目的:探讨组织蛋白酶与骨密度的因果关系。方法:从IEU Open GWAS数据库提取与8种组织蛋白酶相关的遗传位点作为工具变量,以5个年龄段人群的骨密度作为结局。通过双向孟德尔随机化分析,评估组织蛋白酶与骨密度的因果关系。使用Cochran’s Q检验评估遗传工具变量的异质性,使用MR-Egger截距检验评估多效性,使用留一法评估作为工具变量的单核苷酸多态性对暴露和结局因果关系影响的敏感性。结果与结论:①正向孟德尔随机化的逆方差加权法结果显示,组织蛋白酶H与>45岁且≤60岁人群的骨密度呈负相关[OR(95%CI)=0.965(0.94-0.99),P=0.04],组织蛋白酶Z与>30岁且≤45岁人群的骨密度呈负相关[OR(95%CI)=1.06(1.00-1.11),P=0.03];②敏感性分析结果显示因果关系稳定,MR-Egger截距分析未检测到潜在的水平多效性;③反向孟德尔随机化结果显示,骨密度对组织蛋白酶无显著反向作用;④上述结果证实,组织蛋白酶对部分年龄段人群骨密度会造成影响,可能会增加骨质疏松症的发病风险,应给予更多关注。BACKGROUND:Previous studies have indicated that cathepsin K can intervene with the occurrence and development of osteoporosis by regulating bone mineral density in middle-aged and older adults.However,whether there is a causal relationship between the cathepsin family and bone mineral density in other populations remains unknown.OBJECTIVE:To investigate the causal relationship between cathepsin and bone mineral density.METHODS:Genetic loci associated with eight cathepins were extracted from the IEU Open GWAS database as instrumental variables,and bone mineral density values in five age groups acted as an outcome.The causal relationship between cathepin and bone mineral density was assessed by two-way Mendelian randomization analysis.Heterogeneity of the genetic instrumental variables was assessed using Cochran’s Q test,pleiotropy was assessed using the MR-Egger intercept test,and the sensitivity of single nucleotide polymorphisms used as instrumental variables to the causal effect of exposure and outcome was assessed using the leave-one-out method.RESULTS AND CONCLUSION:The results of the inverse variance weighting method with positive Mendelian randomization showed that cathepin H was negatively associated with bone mineral density in people aged 45-60 years[odds ratio(95%confidence interval)=0.965(0.94-0.99),P=0.04];cathepin Z was negatively associated with bone mineral density in people aged 30-45 year[odds ratio(95%confidence interval)=1.06(1.00-1.11),P=0.03].The results of sensitivity analysis showed a stable causal relationship,and MR-Egger intercept analysis did not detect potential horizontal pleiotropy.The inverse Mendelian randomization results showed that bone mineral density had no significant inverse effect on cathepin.The above results confirm that cathepin can affect bone mineral density in some age groups,which may increase the risk of osteoporosis and should be given more attention.

关 键 词：骨密度 组织蛋白酶 孟德尔随机化 因果关联 不同年龄段 

分 类 号：R459.9[医药卫生—治疗学] R336[医药卫生—临床医学] R363.25