Hepatitis B virus infection and lung cancer risk: evidence from meta-analysis, Mendelian randomization, and integrative transcriptomic analyses

Epidemiological studies have suggested an association between hepatitis B virus (HBV) infection and lung cancer, but the potential causal relationship and shared molecular features remain unclear. This study integrated epidemiological, genetic, and transcriptomic evidence to investigate the relationship between HBV infection and lung cancer. We conducted a systematic review and meta-analysis to evaluate the association between HBV infection and lung cancer risk. Two-sample Mendelian randomization analyses were performed using genome-wide association study data from East Asian and European populations, including reverse and multivariable analyses to assess the direction and robustness of the association. We further analyzed transcriptomic datasets using differential expression analysis, weighted gene co-expression network analysis, functional enrichment analysis, and machine-learning algorithms to identify candidate molecular signatures shared between HBV infection and lung cancer. Ten publications contributed 11 independent effect estimates to the primary meta-analysis. The pooled analysis showed a modest positive association between HBV infection and lung cancer risk (pooled relative effect = 1.18, 95% confidence interval (CI): 1.07–1.30; P = 0.003). In geographic subgroup analysis, the pooled relative effect was 1.19 (95% CI: 1.10–1.29; P = 0.001) in East Asian populations, whereas no statistically significant association was observed in the European/US subgroup. In East Asian populations, genetically predicted susceptibility to HBV infection was associated with a higher risk of lung cancer in the inverse-variance weighted analysis (odds ratio (OR) = 1.226, 95% CI: 1.152–1.305; P < 0.0001). This association remained significant after adjustment for smoking and major pulmonary comorbidities (OR = 1.131, 95% CI: 1.077–1.188; P < 0.001). No corresponding association was observed in European datasets. Exploratory transcriptomic and machine-learning analyses identified PTTG1, DTL, and TPX2 as candidate cross-disease expression signatures. These genes were upregulated in both datasets and were predominantly associated with cell-cycle regulation and proliferative processes. This study provides epidemiological and complementary genetic evidence supporting an association between HBV infection susceptibility and lung cancer risk, with the clearest evidence observed in East Asian populations. Exploratory transcriptomic analyses identified overlapping molecular signatures between HBV infection and lung cancer, providing candidate directions for further investigation of their biological relationship.