Integrating immunophenotypes reveals causal relationship between tuberculosis and lung cancer: Mendelian randomization study

BackgroundTuberculosis (TB) and lung cancer (LC) are major respiratory diseases causing significant deaths worldwide. Both primarily affect the lungs and share similar clinical symptoms. The comorbidity rate between TB and LC is high, and epidemiological data suggest a potential association between the two diseases. However, the detailed causal relationships and potential mediators remain underexplored due to limited evidence from observational studies. This study aims to elucidate the relationship between TB and LC, including the pathological subtypes of LC, and to investigate the potential mediating effects of immune cells. Materials and MethodsThe genetic variants for TB and LC were sourced from the IEU Open GWAS Project, while the data for the 731 immunocyte phenotypes were obtained from their genome-wide association studies (GWAS). The inverse variance-weighted (IVW), MR-Egger, weighted median, simple mode and weighted mode were used to evaluate the causal relationship between TB and LC. We then applied a two-step Mendelian randomization (MR) analysis to examine the roles of immunocyte phenotypes as mediators. Additionally, multiple sensitivity analyses were conducted to ensure the reliability of the MR results. ResultsThe results of the IVW methods of the MR analysis indicated a causal relationship between TB and LC, demonstrating a positive correlation (OR = 1.072, 95% CI: 1.010-1.137, P < 0.05). The immune phenotype CD4 on CD39+ resting regulatory T cell is implicated in the linkage between TB and LC as well (mediation proportion: 9.09%). Additionally, no evidence was found to support a reverse causal relationship between TB and LC, nor a causal relationship between TB and the pathological subtypes of LC. There was no observed heterogeneity or horizontal pleiotropy in our MR results. ConclusionOur study suggests the causal effect of TB on increased LC risk, with immune phenotype playing a mediating role. These insights provide a significant basis for the prevention and concurrent management of LC and TB.