循环细胞因子水平与主动脉瘤和主动脉夹层风险的因果关系:双向两样本孟德尔随机化研究  

Causal relationships between the circulating levels of cytokines and risk of aortic aneurysm and aortic dissection:a bidirectional two‑sample Mendelian randomization study

作　　者：张秋雯 覃建颖 文宁 董建辉 李海滨 孙煦勇 ZHANG Qiuwen;QIN Jianying;WEN Ning;DONG Jianhui;LI Haibin;SUN Xuyong(Department of Immunology,School of Basic Medical Sciences,Guangxi Medical University,Nanning 530021,China;Institute of Transplantation Medicine,the Second Affiliated Hospital of Guangxi Medical University,Nanning 530007,China;Guangxi Clinical Research Center for Organ Transplantation,Nanning 530007,China;Guangxi Key Laboratory of Organ Donation and Transplantation,Nanning 530007,China)

机构地区：[1]广西医科大学基础医学院免疫学教研室,南宁530021 [2]广西医科大学第二附属医院移植医学研究所,南宁530007 [3]广西器官移植临床医学研究中心,530007 [4]广西器官捐献与移植研究重点实验室,南宁530007

出　　处：《广西医科大学学报》2024年第12期1619-1627,共9页Journal of Guangxi Medical University

基　　金：广西自然科学基金区域高发疾病研究联合专项资助(No.2024GXNSFAA010454)。

摘　　要：目的:采用两样本孟德尔随机化(MR)分析评估循环细胞因子(CCs)与主动脉瘤(AA)和主动脉夹层(AD)(统称AAD)的因果关系。方法:基于全基因组关联研究(GWASs)(n=8 293)的meta分析,获取与CCs相关的遗传变异作为工具变量;并从芬兰数据库中获得AAD相关的GWASs统计数据作为结局,所有样品均来自于欧洲人群。结局数据的对照组有349 539例,AD为881例,AA为7 395例,其中胸主动脉瘤(TAA)和腹主动脉瘤(AAA)分别为3 510例和3 548例。以逆方差加权法作为主要的分析方法,采用加权中位数法、MR-Egger回归、MR多效残差和和离群值检验作为补充,并进行相应的敏感性分析。应用反向MR分析评估反向因果关系。结果:在正向MR分析中,经Bonferroni校正后,显示TNF相关凋亡诱导配体(TRAIL)水平升高是AD的危险因素(OR=1.25, P=0.000 2),而其余阳性结果(0.000 2<P<0.05)提示以下两者之间存在潜在因果关系,其中包括:TRAIL与AA (OR=1.06)、TAA(OR=1.09)之间,单核细胞趋化蛋白-1(MCP-1)与AA(OR=1.13)、TAA(OR=1.18)、AD(OR=1.46)之间,干扰素-γ(IFN-γ)与AA(OR=0.82)和TAA(OR=0.75)之间,白细胞介素(IL)-16(OR=0.9)、IFN-γ诱导的单核因子(MIG)(OR=1.14)、巨噬细胞炎性蛋白-1β (MIP-1β)(OR=0.96)与TAA之间。在反向MR分析中,AAD与部分CCs存在潜在的因果关系,其中包括:AA与MCP-1呈正相关关系,TAA与嗜酸细胞活化趋化因子(EOTAXIN)呈正相关关系,而与IL-13呈负相关关系;AD分别与β神经生长因子(β-NGF)、IL-1β、IL-8和肿瘤坏死因子-α(TNF-α)呈正相关关系。敏感性分析结果提示CCs与AAD的因果效应无异质性和多效性。结论:循环中TRAIL、MCP-1水平与AD、AA、TAA发生风险具有潜在因果相关性,这可能为早期筛选AD、AA、TAA患者和治疗药物研发提供了潜在靶点。Objective:To evaluate the causal relationships between circulating cytokines(CCs)and aortic aneu‐rysm(AA)and aortic dissection(AD)collectively known as AAD using two-sample Mendelian randomization(MR)analysis.Methods:A meta-analysis based on genome-wide association studies(GWASs)involving 8,293 individuals was conducted to obtain genetic variations associated with CCs as instrumental variables.The AAD-related GWAS statistics data were obtained from the Finnish database as the outcome,with all samples originat‐ing from European populations.The control group for the outcome data comprised 349,539 individuals,with 881 cases of AD and 7,395 AA.Among these,thoracic aortic aneurysms(TAA)accounted for 3,510 cases,and ab‐dominal aortic aneurysms(AAA)for 3,548 cases.The study utilized inverse variance weighting as the primary analytical method,complemented by weighted median method,MR-Egger regression,MR pleiotropy residual sum and outlier test,and corresponding sensitivity analyses.Finally,reverse MR analysis was employed to assess reverse causal relationships.Results:In the forward MR analysis following Bonferroni correction,it was ob‐served that elevated levels of TNF-related apoptosis-inducing ligand(TRAIL)were identified as a risk factor for AD(OR=1.25,P=0.0002),while the other positive results(0.0002<P<0.05)indicated potential causal relation‐ships as follows:TRAIL with AA(OR=1.06)and TAA(OR=1.09);monocyte chemoattractant protein-1(MCP-1)with AA(OR=1.13),TAA(OR=1.18),and AD(OR=1.46);IFN-γwith AA(OR=0.82)and TAA(OR=0.75);inter‐leukin-16(IL-16)(OR=0.9),interferon-gamma-induced monocyte chemoattractant protein(MIG)(OR=1.14),and macrophage inflammatory protein-1 beta(MIP-1β)(OR=0.96)with TAA.In the reverse MR analysis,potential causal relationships were identified between AAD and some CCs,including a positive correlation between AA and MCP-1;a positive correlation between TAA and eosinophil activating chemotactic factor(EOTAXIN)and a negative correlation with IL-13;and positive correlations between AD and

关 键 词：主动脉瘤 主动脉夹层 细胞因子 生物标志物 孟德尔随机化 

分 类 号：R543.16[医药卫生—心血管疾病]