免疫细胞与肺结核的因果关系:一项孟德尔随机化研究  

The causal relationship between immune cells and pulmonary tuberculosis:a mendelian randomization study

作　　者：文维农 安祯祥 何远利 何松 刘闯 孙凯 Wen Weinong;An Zhenxiang;He Yuanli;He Song;Liu Chuang;Sun Kai(The First Clinical Medical College of Guizhou University of Traditional Chinese Medicine,Guiyang 550002,China;Department of Gastroenterology,The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine,Guiyang 550001,China;Department of Geriatrics,The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine,Guiyang 550001,China)

机构地区：[1]贵州中医药大学第一临床医学院,贵阳550002 [2]贵州中医药大学第一附属医院消化内科,贵阳550001 [3]贵州中医药大学第一附属医院老年病科,贵阳550001

出　　处：《中国防痨杂志》2024年第12期1519-1526,共8页Chinese Journal of Antituberculosis

基　　金：国家自然科学基金(82160893);国家中医药管理局第五批全国中医临床优秀人才研修项目(国中医药人教函〔2022〕1号);贵州中医药大学国家与省级科技创新人才团队培育项目(贵中医TD合字〔2022〕005号)。

摘　　要：目的:运用孟德尔随机化(mendelian randomization,MR)分析评估免疫细胞与肺结核之间的因果关系,为肺结核病疫苗研制,以及结核病的防治和预后评估提供新思路。方法:利用大样本全基因关联研究(genome-wide association studies,GWAS)汇总数据,选择肺结核相关遗传位点作为工具变量,运用Egger回归法、加权中位数法、逆方差加权法、简单模式法、加权模式法等5种方法进行两样本MR分析。通过OR(95%CI)值评估免疫细胞和肺结核间因果关系,运用Cochran’s Q评估异质性、运用MR-多效残差及离群值与MR-Egger回归分析方法进行多效性评估,同时使用留一法评估结果的稳定性。结果:逆方差加权法分析得出肺结核发病风险与非同型转换记忆B细胞(β=-0.257,OR=0.773,95%CI:0.607~0.985,P=0.037)、IgD+CD38-B细胞表面CD19水平(β=-0.493,OR=0.610,95%CI:0.379~0.982,P=0.042)、CD39^(+)分泌型CD4^(+)调节性T细胞比例(β=0.425,OR=1.532,95%CI:1.099~2.135,P=0.012)、非调节性CD45RA-CD4T细胞表面CD25水平(β=-0.719,OR=0.487,95%CI:0.262~0.904,P=0.023)、CD33高表达HLA-DR+细胞表面CD45水平(β=-0.364,OR=0.695,95%CI:0.508~0.949,P=0.022)、CD33-HLA-DR+细胞表面HLA-DR水平(β=0.153,OR=1.166,95%CI:1.024~1.323,P=0.020)、CD14^(-)CD16^(-)细胞表面HLA-DR水平(β=0.134,OR=1.144,95%CI:1.006~1.300,P=0.040)、单核细胞中的程序性细胞死亡配体1(β=0.379,OR=1.462,95%CI:1.056~2.026,P=0.022)有较强关联性。通过异质性检验及多效性检验得出无异质性也无明显多效性的结果。结论:非同型转换记忆B细胞、IgD+CD38-B细胞表面CD19水平、非调节性CD45RA-CD4T细胞表面CD25水平、CD33高表达HLA-DR+细胞表面CD45水平这4种免疫细胞表型水平的升高可能降低肺结核发病风险;CD39^(+)分泌型CD4^(+)调节性T细胞比例、CD33-HLA-DR+细胞表面HLA-DR水平、单核细胞中的程序性细胞死亡配体1、CD14^(-)CD16^(-)细胞表面HLA-DR水平这4种免疫细胞表型水平的升高可�Objective:This study aims to evaluate the causal relationship between immune cells and pulmonary tuberculosis(TB)using Mendelian Randomization(MR)analysis.This approach provides novel insights into vaccine development,TB prevention strategies,and prognosis evaluation.Methods:Summary data from genome-wide association studies(GWAS)were utilized,with genetic loci related to pulmonary TB selected as instrumental variables.Five methods were applied for two-sample MR analysis:MR-Egger regression,weighted median,inverse variance weighted,simple mode,and weighted mode.The causal relationship between immune cells and pulmonary TB was assessed using odds ratios(OR,95%CI).Heterogeneity was evaluated using Cochran’s Q,and pleiotropy was examined through the MR-pleiotropy residual sum and outlier(MR-PRESSO)test and MR-Egger regression.The leave-one-out method was employed to verify the stability of the results.Results:The inverse variance weighted analysis revealed a strong association between pulmonary TB risk and Unsw mem%B cell(β=-0.257,OR=0.773,95%CI:0.607 to 0.985,P=0.037),CD19 on IgD+CD38-(β=-0.493,OR=0.610,95%CI:0.379 to 0.982,P=0.042),CD39^(+)secreting Treg%CD4 Treg(β=0.425,OR=1.532,95%CI:1.099 to 2.135,P=0.012),CD25 on CD45RA-CD4 not Treg(β=-0.719,OR=0.487,95%CI:0.262 to 0.904,P=0.023),CD45 on CD33br HLA-DR+(β=-0.364,OR=0.695,95%CI:0.508 to 0.949,P=0.022),HLA-DR on CD33-HLA-DR+(β=0.153,OR=1.166,95%CI:1.024 to 1.323,P=0.020),HLA-DR on CD14^(-)CD16^(-)(β=0.134,OR=1.144,95%CI:1.006 to 1.300,P=0.040),and PDL-1 on monocyte(β=0.379,OR=1.462,95%CI:1.056 to 2.026,P=0.022).No significant heterogeneity or pleiotropy was found.Conclusion:Elevated levels of four immune cell phenotypes—unswitched memory B cells,CD19 on IgD+CD38-cells,CD25 on CD45RA-CD4 non-Treg cells,and CD45 on CD33bright HLA-DR+cells—may be associated with a reduced risk of developing tuberculosis.In contrast,increased levels of four other immune cell phenotypes—CD39^(+)secreting regulatory T cells(%CD4 Treg),HLA-DR on CD33-HLA-DR+cells,PDL-1 on

关 键 词：分枝杆菌 结核 感染 免疫系统 孟德尔随机化 因果律 

分 类 号：R52[医药卫生—内科学]