An integrative genetic and transcriptomic study reveals a causal link and candidate biomarkers between tuberculosis and asthma

IntroductionTuberculosis, caused by Mycobacterium tuberculosis, mainly affects the lungs, while asthma is a common chronic respiratory condition often linked with other health issues. Research on the connection between these two diseases is scarce, and their relationship needs more study.MethodsWe analyzed data from the Global Burden of Disease study to compare the impact of tuberculosis and asthma worldwide from 2013 to 2023. We used two-sample Mendelian randomization to explore the causal link between tuberculosis, asthma, and lung function. Transcriptomic data from active tuberculosis and asthma patients were obtained from the Gene Expression Omnibus database for differential expression, gene co-expression network, and functional enrichment analyses. The expression patterns of the identified candidate genes were validated using quantitative PCR in an independent clinical cohort of 40 tuberculosis patients and 40 healthy controls.ResultsThe global disease burden analysis shows that tuberculosis has a greater impact than asthma. Mendelian randomization indicates that pulmonary tuberculosis is a risk factor for asthma (Odds ratio = 1.58, 95% Confidence interval: 1.08–2.31, p = 0.018 for ebi-a-GCST90086044; Odds ratio = 1.74, 95% Confidence interval: 1.43–2.12, p < 0.001 for ebi-a-GCST90086047) and adversely affects lung function, including forced vital capacity and forced expiratory volume at one second. Transcriptome analysis reveals immune pathway activation and cellular function suppression in both diseases. Using weighted gene co-expression network analysis, five comorbidity genes: CRLF2, ETV5, LRRC1, OR10H1, and SENP2, were identified. These genes show significant expression changes in tuberculosis patients and demonstrate high discriminatory potential in the discovery cohort, with an area under the curve of up to 1.0, supporting their further investigation as candidate biomarkers. Clinical validation confirmed these expression patterns.ConclusionTuberculosis is identified as a causal risk factor for asthma based on genetic evidence from Mendelian randomization. The five key genes, including CRLF2 and ETV5, represent promising candidate biomarkers, providing new insights into their comorbidity.