摘要
背景:药物相关性骨坏死是一类应用药物后出现的严重不良反应。大量的证据表明,肠道菌群与药物相关性骨坏死有关。然而,肠道菌群对药物相关性骨坏死的因果关系尚不清楚。目的:采用孟德尔随机化方法来评估肠道菌群与药物相关性骨坏死风险之间的潜在因果关系。方法:使用MiBioGen联盟肠道菌群的全基因组关联分析(GWAS)汇总统计数据(n=13266)和芬兰R9数据库中药物相关性骨坏死的GWAS数据(264例药物相关性骨坏死患者和377013例健康对照者)。采用逆方差加权法、MR-Egger回归法、加权中位数法、加权模型法和简单模型法来研究肠道菌群与药物相关性骨坏死之间的因果关系。敏感性分析用于检验孟德尔随机化分析结果是否可靠。反向孟德尔随机化以全部肠道菌群作为结局进行效应分析和敏感性分析。结果与结论:①逆方差加权法结果显示,黏胶球形菌门、黏胶球形菌纲、黑色素杆菌纲、嗜胃杆菌目、红螺菌目、食物谷菌目和双歧杆菌属与药物相关性骨坏死呈直接的正向因果关联;甲烷杆菌纲、芽孢杆菌目、甲烷杆菌目、毛螺菌科、甲烷杆菌科、霍尔德曼氏菌属、毛螺菌属(UCG010)、厌氧杆菌和泰泽氏菌属与药物相关性骨坏死呈直接的负向因果关联。②反向孟德尔随机化结果显示,药物相关性骨坏死与梭菌科、消化链球菌科、链球菌科、梭状芽胞杆属和链球菌属呈直接的负向因果关联,与艾森伯格菌属呈直接的正向因果关联。③双向敏感性分析均未发现存在异质性或水平多效性。④结果证实,肠道菌群作为暴露,药物相关性骨坏死作为结局,7种细菌性状对药物相关性骨坏死呈正相关因果关系,9种细菌性状对药物相关性骨坏死呈负相关因果关系;药物相关性骨坏死作为暴露,肠道菌群作为结局,药物相关性骨坏死与5种细菌性状有负相关因果关系,与1种细菌性状有正相关因果关系。改变肠道菌群的多样性和组成,有望改善药物相关性骨坏死的发病与预后,为骨科疾病的研究提供了思路。
BACKGROUND:Osteonecrosis due to drugs is a serious adverse reaction occurring after the application of such drugs.Increasing evidence suggests that the gut microbiota composition is associated with osteonecrosis due to drugs.However,the causal relationship of the gut microbiota to osteonecrosis due to drugs is still unclear.OBJECTIVE:To evaluate the potential causal relationship between the gut microbiota and the risk of osteonecrosis due to drugs using the Mendelian randomization method.METHODS:A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genomewide association study meta-analysis(n=13266)conducted by the MiBioGen consortium as well as the summary statistics of osteonecrosis due to drugs obtained from the FinnGen consortium R9 release data(264 cases and 377013 controls).Inverse variance weighted,MR-Egger,weighted median,weighted model and simple model were used to examine the causal association between gut microbiota and osteonecrosis due to drugs.Sensitivity analysis was used to test whether the results of the Mendelian randomization analysis were reliable.Reverse Mendelian randomization analysis was performed on all the bacteria as an outcome for effect analysis and sensitivity analysis.RESULTS AND CONCLUSION:Inverse variance weighted estimates suggested that Lentisphaerae(phylum),Lentisphaeria(class),Melainabacteria(class),Gastranaerophilales(order),Rhodospirillales(order),Victivallales(order)and Bifidobacterium(genus)had protective causal effects on osteonecrosis due to drugs.Methanobacteria(class),Bacillales(order),Methanobacteriaceae(family),Lachnospiraceae(family),Methanobacteriales(order),Holdemania(genus),Holdemania(UCG010 group)(genus),Odoribacter(genus)and Tyzzerella3(genus)had negative causal effects on osteonecrosis due to drugs.According to the results of reverse Mendelian randomization analysis,Clostridiaceae1(family),Peptostreptococcaceae(family),Streptococcaceae(family),Clostridiumsensustricto1(genus)and Streptococcus(genus)showed negative causal effects on osteonecrosis due to drugs.However,Eisenbergiella(genus)showed protective causal effects on osteonecrosis due to drugs.None of the bidirectional sensitivity analysis revealed heterogeneity or horizontal pleiotropy.When gut microbiota were used as exposure and osteonecrosis due to drugs as the outcome,Mendelian randomization analysis found that seven bacterial traits were positively correlated to osteonecrosis due to drugs,nine bacterial traits were negatively related to osteonecrosis due to drugs.When osteonecrosis due to drugs were used as exposure and gut microbiota as the outcome,reverse Mendelian randomization analysis found a negative correlated relationship with five bacterial traits and a positive causal relationship with one bacterial trait.By changing the diversity and composition of gut microbiota,it is expected to improve the incidence and prognosis of osteonecrosis due to drugs,providing new ideas for the study of orthopedic diseases.
作者
柴金莲
李树栋
李威
杜海涛
董丽敏
梁学振
王平
Chai Jinlian;Li Shudong;Li Wei;Du Haitao;Dong Limin;Liang Xuezhen;Wang Ping(College of Pharmacy,Shandong University of Traditional Chinese Medicine,Jinan 250355,Shandong Province,China;First College of Clinical Medicine,Shandong University of Traditional Chinese Medicine,Jinan 250355,Shandong Province,China;College of Traditional Chinese Medicine,Shandong University of Traditional Chinese Medicine,Jinan 250355,Shandong Province,China;Shandong Provincial Research Institute of Traditional Chinese Medicine,Jinan 250014,Shandong Province,China)
出处
《中国组织工程研究》
CAS
北大核心
2024年第27期4325-4331,共7页
Chinese Journal of Tissue Engineering Research
基金
国家自然科学基金资助项目(82205154),项目负责人:梁学振
山东省中央引导地方科技发展资金项目(YDZX20203700002055),项目负责人:王平
山东省自然科学基金面上项目(ZR2020MH386),项目负责人:王平
山东省自然科学基金青年项目(ZR2021QH004),项目负责人:梁学振
山东省医药卫生科技发展计划项目(2019WS577),项目负责人:梁学振
山东省中医药科技项目(2020Q009),项目负责人:梁学振
济南市临床医学科技创新计划(202019056),项目负责人:梁学振。
关键词
药物相关性骨坏死
肠道菌群
孟德尔随机化
单核苷酸多态性
全基因组关联分析
因果关系
逆方差加权法
异质性
水平多效性
敏感性分析
osteonecrosis due to drugs
gut microbiota
Mendelian randomization
single-nucleotide polymorphism
Genome-Wide Association Study
causality
inverse variance weighted
heterogeneity
horizontal pleiotropy
sensitivity analysis
