Integrative GWAS and Mendelian Randomization Analysis Identifies IREB2 and CD27+ Memory B Cells as Core Drivers of COPD to Lung Cancer Progression

Chronic obstructive pulmonary disease (COPD) associates with increased lung cancer incidence and shares genetic susceptibility, yet its independent causal role and driver mechanisms are poorly understood. We integrated data from the National Health and Nutrition Examination Survey (NHANES) cohort with genome-wide association studies (GWAS) summary statistics and Mendelian randomization analyses to map genetic correlations and infer causality between COPD phenotypes and lung cancer. Post-GWAS methods-including transcriptome-wide association study, colocalization, partitioned heritability via heritability estimation from summary statistics (ρ-HESS), and cross-phenotype association (CPASSOC)-identified shared susceptibility loci, highlighting IREB2 and CD27⁺ B cells as potential mediators. Elevated IREB2 expression correlated with accelerated lung-function decline in COPD but predicted improved prognosis in lung cancer B cells, whereas higher CD27⁺ B cell levels in COPD were associated with protumorigenic activity. Single-cell transcriptomic analysis and in vitro knockdown experiments confirmed IREB2's role in modulating B-cell activation and apoptosis pathways within tumors. These results support COPD as an independent lung cancer risk factor and implicate IREB2 and CD27⁺ B cells in COPD-to-cancer progression, laying groundwork for early detection and targeted intervention in high-risk individuals.