欧洲人种新型冠状病毒感染与结核病发病风险因果关系:一项双样本孟德尔随机化研究

doi:10.19982/j.issn.1000-6621.20240474

摘要/Abstract

摘要：

目的: 利用孟德尔随机化分析方法探寻新型冠状病毒感染(coronavirus disease 2019, COVID-19)与结核病之间的因果关系。方法: 从IEU Open GWAS数据库(https://gwas.mrcieu.ac.uk/)获取COVID-19 GWAS汇总数据,从UKB数据库(https://www.ukbiobank.ac.uk/)获取结核病GWAS数据。使用5种孟德尔随机化分析方法,逆方差加权法(IVW)为主要方法,加权中位数法、MR-Egger回归、简单众数法、加权众数法作为补充(COVID-19样本:626151例,病例组:3886例,对照组:622265例;结核病样本:462933例,病例组:2277例,对照组:460656例),采用Cochran Q检验、MR-Egger截距、留一法检测多效性和敏感度,最后再做反向孟德尔随机化分析。结果: 从GWAS数据库中筛选出14个与COVID-19显著相关的独立的单核苷酸多态性(single nucleotide polymorphism, SNP)作为工具变量,SNP位点编号分别为rs1064213、rs10875713、rs113488799、rs11634857、rs13050728、rs1566837、rs2269899、rs2277732、rs2597569、rs2781267、rs28815269、rs4782434、rs622568、rs787642。逆方差加权分析显示,COVID-19与结核病发病风险没有相关性(OR_IVW=1.001,95%CI:0.995~1.002,P=0.527)。MR-Egger回归显示,水平多效性影响结果的可能性小(截距=0.0002435,P=0.101),逆方差加权和MR-Egger回归没有发现异质性(Q=13.205,P=0.432;Q=10.040,P=0.612)。“留一法”分析显示,孟德尔随机化整体估计结果较为可靠,未出现显著偏差,漏斗图未显示不对称。反向孟德尔随机化分析表明,结核病与COVID-19发病风险无因果关系[P(IVW)=0.805]。结论: 基于欧洲人群遗传数据的双向孟德尔随机化分析表明,欧洲人群COVID-19与结核病之间可能没有双向因果关系。

关键词: 冠状病毒感染, 结核, 孟德尔随机化, 因果律

Abstract:

Objective: To investigate the causality between coronavirus disease 2019 (COVID-19) and tuberculosis (TB) using Mendelian randomization analysis. Methods: Summary data on COVID-19 was extracted from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Studies (GWAS) pool (https://gwas.mrcieu.ac.uk/). GWAS data on TB was also retrieved from the UK Biobank database (https://www.ukbiobank.ac.uk/). The relationship between COVID-19 and TB was examined using five methods, the major method being inverse variance weighting (IVW), while additional methods included weighted median, MR-Egger regression, simple mode and weighted mode (626151 cases of COVID-19, including 3886 cases and 622265 controls; 462933 cases of TB, including 2277 cases and 460656 controls). Cochran’s Q statistic, MR-Egger regression analysis, and the “leave-one-out-method” analysis were used to evaluate heterogeneity and sensitivity, and finally inverse Mendelian randomization was done. Results: Fourteen independent single nucleotide polymorphisms (SNPs) associated with COVID-19 were selected as instrumental variables from GWAS (SNP IDs: rs1064213, rs10875713, rs113488799, rs11634857, rs13050728, rs1566837, rs2269899, rs2277732, rs2597569, rs2781267, rs28815269, rs4782434, rs622568, and rs787642). IVW showed no significant correlation between COVID-19 and TB (IVW odds ratio=1.001, 95% confidence interval=0.995-1.002, P=0.527). MR-Egger regression showed that horizontal pleiotropy was unlikely to influence the results (intercept=0.0002435, P=0.101), neither IVW nor MR-Egger regression revealed heterogeneity (Q=13.205, P=0.432; Q=10.040, P=0.612). The “leave-one-out-method” analysis revealed that Mendelian randomization overall estimates were reliable, with no significant bias, and the funnel plot did not exhibit asymmetry. Reverse MR analysis also confirmed the absence of a causality between COVID-19 and TB risk (P (IVW)=0.805). Conclusion: Bidirectional MR analysis based on genetic data of European population revealed no significant bidirectional relationship between COVID-19 and TB in this population.

Key words: Coronavirus infections, Tuberculosis, Mendelian randomization, Causality

中图分类号:

王雷, 陈迟到, 宿连政, 李凌玮, 王欣淼, 王鹏, 黄忠浩. 欧洲人种新型冠状病毒感染与结核病发病风险因果关系:一项双样本孟德尔随机化研究[J]. 中国防痨杂志, 2025, 47(5): 653-659. doi: 10.19982/j.issn.1000-6621.20240474

Wang Lei, Chen Chidao, Su Lianzheng, Li Lingwei, Wang Xinmiao, Wang Peng, Huang Zhonghao. Causality between coronavirus disease 2019 and tuberculosis in Europeans: a two-sample Mendelian randomization study[J]. Chinese Journal of Antituberculosis, 2025, 47(5): 653-659. doi: 10.19982/j.issn.1000-6621.20240474

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孟德尔随机化分析方法	单核苷酸多态性	风险指数	OR值	95%CI值	P值
MR-Egger回归法	14	―2.000×10^-3	0.998	0.985~1.001	0.087
加权中位数法	14	―2.557×10^-4	0.990	0.935~1.021	0.410
逆方差加权法	14	―1.489×10^-4	1.001	0.995~1.002	0.527
加权众数法	14	―3.172×10^-4	1.000	0.999~1.001	0.481
简单众数法	14	―1.744×10^-4	1.002	0.973~1.032	0.580

多效性检测	数值
MR-Egger回归法
Egger截距	2.435×10^-4
P值	0.101
异质性检测(Cochran Q检验)	数值
MR Egger回归法
统计量	10.040
P值	0.612
逆方差加权法
统计量	13.205
P值	0.432

孟德尔随机化分析方法	单核苷酸多态性	风险指数	P值
MR-Egger回归法	9	-1.350×10^-2	0.652
加权中位数法	9	-5.271×10^-4	0.128
逆方差加权法	9	-2.860×10^-4	0.805
加权众数法	9	-3769×10^-4	0.123
简单众数法	9	-5804×10^-4	0.736