Bidirectional mendelian randomization and single-cell sequencing reveal T cell-mediated causal links between COPD and lung adenocarcinoma

Background: Chronic obstructive pulmonary disease (COPD) and lung cancer are the leading causes of lung disease-related deaths globally, sharing common risk factors like smoking. While COPD is known to increase lung cancer risk, the exact underlying mechanism remains unclear. We aim to explore the potential relationship between lung adenocarcinoma (LA) and COPD by application of Mendelian randomization analysis and single-cell RNA sequencing. Methods: Single-cell RNA sequencing (scRNA-seq) data from the peripheral blood of patients with COPD and LA were collected to analyze the changes in the proportion of cell subpopulations under the two pathological conditions and screen out CD4 + T cell subpopulations as the focus of research. The causal relationship between the expression of key marker genes in COPD and LA was explored using Mendelian randomization (MR) analysis, combined with expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data. Results: Of the 38 genes screened by differential expression analysis in CD4 + T cell scRNA-seq data, CXCR4 showed a protective effect against LA in MR analysis (OR = 0.6806; 95% CI: 0.4653–0.9957). CXCR4 + CD4 + T cells showed significant interactions with endothelial cells and immune cells such as macrophages, suggesting its crucial role in the immune response. Conclusions: This study analyzed the role of CD4 + T cells in COPD and lung adenocarcinoma and found that the CXCR4 gene may affect lung adenocarcinoma development, providing new insights into the link between COPD and lung adenocarcinoma.