免疫细胞与肺结核的因果关系:一项孟德尔随机化研究

doi:10.19982/j.issn.1000-6621.20240270

中国防痨杂志 ›› 2024, Vol. 46 ›› Issue (12): 1519-1526.doi: 10.19982/j.issn.1000-6621.20240270

免疫细胞与肺结核的因果关系:一项孟德尔随机化研究

文维农¹, 安祯祥¹^,²(), 何远利¹^,³, 何松¹^,², 刘闯¹^,², 孙凯¹^,²

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

收稿日期:2024-07-01 出版日期:2024-12-10 发布日期:2024-12-03
通信作者: 安祯祥,Email:anzhenxiang057@gzy.edu.cn
基金资助:
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)

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

Wen Weinong¹, An Zhenxiang¹^,²(), He Yuanli¹^,³, He Song¹^,², Liu Chuang¹^,², Sun Kai¹^,²

¹The First Clinical Medical College of Guizhou University of Traditional Chinese Medicine, Guiyang 550002, China
²Department of Gastroenterology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China
³Department of Geriatrics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China

Received:2024-07-01 Online:2024-12-10 Published:2024-12-03
Contact: An Zhenxiang, Email:anzhenxiang057@gzy.edu.cn
Supported by:
National Natural Science Foundation of China(82160893);The Fifth Batch of National Traditional Chinese Medicine Clinical Outstanding Talent Training Project of the National Administration of Traditional Chinese Medicine(〔2022〕1);National and Provincial Science and Technology Innovation Talent Team Cultivation Project of Guizhou University of Traditional Chinese Medicine(Guizhou TCM TD〔2022〕005)

摘要/Abstract

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能增加肺结核发病风险。

关键词: 分枝杆菌,结核, 感染, 免疫系统, 孟德尔随机化, 因果律

Abstract:

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 monocytes, and HLA-DR on CD14^-CD16^- cells—may be linked to an elevated risk of tuberculosis.

Key words: Mycobacterium tuberculosis, Infection, Immune system, Mendelian randomization, Causality

中图分类号:

文维农, 安祯祥, 何远利, 何松, 刘闯, 孙凯. 免疫细胞与肺结核的因果关系:一项孟德尔随机化研究[J]. 中国防痨杂志, 2024, 46(12): 1519-1526. doi: 10.19982/j.issn.1000-6621.20240270

Wen Weinong, An Zhenxiang, He Yuanli, He Song, Liu Chuang, Sun Kai. The causal relationship between immune cells and pulmonary tuberculosis: a mendelian randomization study[J]. Chinese Journal of Antituberculosis, 2024, 46(12): 1519-1526. doi: 10.19982/j.issn.1000-6621.20240270

图/表 4

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免疫细胞表型	多效残差及离群值检验	Egger 回归检验	Cochran’s Q值
非同型转换记忆B细胞	P=0.619	P=0.355	逆方差加权法:P=0.587;Egger回归:P=0.582
IgD⁺CD38^- B细胞表面CD19水平	P=0.510	P=0.724	逆方差加权法:P=0.300;Egger回归:P=0.184
非调节性CD45RA^-CD4T细胞表面CD25水平	P=0.521	P=0.092	逆方差加权法:P=0.499;Egger回归:P=0.351
CD33高表达HLA-DR⁺细胞表面CD45水平	P=0.300	P=0.375	逆方差加权法:P=0.242;Egger回归:P=0.259
CD39⁺分泌型CD4⁺调节性T细胞比例	P=0.843	P=0.754	逆方差加权法:P=0.913;Egger回归:P=0.821
CD33^-HLA-DR⁺细胞表面HLA-DR水平	P=0.949	P=0.579	逆方差加权法:P=0.935;Egger回归:P=0.932
单核细胞中的程序性细胞死亡配体1	P=0.998	P=0.821	逆方差加权法:P=0.995;Egger回归:P=0.986
CD14^-CD16^-细胞表面HLA-DR水平	P=0.570	P=0.623	逆方差加权法:P=0.529;Egger回归:P=0.455

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

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