Li Xianwen, Huang Dayin, Liu Chang, Yu Wei, Bi Lijun
State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China; Guangzhou National Laboratory, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Microb Pathog. 2025 Mar;200:107346. doi: 10.1016/j.micpath.2025.107346. Epub 2025 Jan 28.
The coexistence of tuberculosis (TB) and lung cancer (LC) is not rare, but their causal association are underexplored. This study aims to elucidate these bidirectional correlations and investigate the mediating effects of immunophenotypes and plasma metabolites.
Genetic variants for TB and LC were sourced from the IEU Open GWAS Project, while data for 731 immunophenotypes and 1400 plasma metabolites from previously published GWAS. Our core methodology centered on inverse-variance weighted method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode analyses to evaluate the bidirectional causal association between TB and LC. Additionally, a two-step Mendelian randomization analysis was performed to assess mediators of the association and calculate the mediated proportions. Multiple sensitivity analyses ensured the reliability of results.
Inverse-variance weighted results indicated a positive causal association between TB and LC (odds ratio: 1.072, 95 % confidence interval: 1.010-1.137, P < 0.05), with no reverse relationship. Causal associations were found between 30 immunophenotypes and 106 metabolites with LC (all P < 0.05). Among these, 1 immunophenotype, 6 metabolite levels, and 1 metabolite ratio were potential mediators of the TB-LC association. Specifically, CD4 on CD39 resting regulatory T cells showed an inverse association, suggesting a protective role, while pantoate, ethylparaben sulfate, dopamine 4-sulfate, pentose acid, N-formylmethionine, N6,N6,N6-trimethyllysine, and the tryptophan to pyruvate ratio exhibited positive correlations, indicating risk factors. No heterogeneity or horizontal pleiotropy was observed.
TB is a risk factor for LC at a genetically predicted level, potentially mediated through immune cell and metabolite regulation.
肺结核（TB）与肺癌（LC）并存并不罕见，但它们之间的因果关系尚未得到充分研究。本研究旨在阐明这些双向相关性，并研究免疫表型和血浆代谢物的中介作用。
TB和LC的基因变异来自IEU开放全基因组关联研究项目，而731种免疫表型和1400种血浆代谢物的数据来自先前发表的全基因组关联研究。我们的核心方法以逆方差加权法为中心，辅以MR-Egger、加权中位数、简单模式和加权模式分析，以评估TB和LC之间的双向因果关系。此外，进行了两步孟德尔随机化分析，以评估关联的中介因素并计算中介比例。多次敏感性分析确保了结果的可靠性。
逆方差加权结果表明，TB与LC之间存在正向因果关系（优势比：1.072，95%置信区间：1.010-1.137，P<0.05），不存在反向关系。在30种免疫表型和106种代谢物与LC之间发现了因果关系（所有P<0.05）。其中，1种免疫表型、6种代谢物水平和1种代谢物比率是TB-LC关联的潜在中介因素。具体而言，CD39静息调节性T细胞上的CD4呈负相关，表明具有保护作用，而泛酸、硫酸对羟基苯甲酸乙酯、硫酸多巴胺4、戊糖酸、N-甲酰甲硫氨酸、N6,N6,N6-三甲基赖氨酸以及色氨酸与丙酮酸的比率呈正相关，表明是危险因素。未观察到异质性或水平多效性。
在基因预测水平上，TB是LC的一个危险因素，可能通过免疫细胞和代谢物调节介导。
