Identifying causal genes of neutrophil extracellular traps in chronic obstructive pulmonary disease pathogenesis

Recent studies have highlighted the crucial role of Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD). However, the complex relationships between NETs-related genes and COPD risk remain largely unexplored. In this study, we utilized publicly available genome-wide association study (GWAS) and multi-omics quantitative trait loci (QTL) databases to identify 238 genes associated with NETs. We focused on genetic variants influencing gene expression, DNA methylation, and protein expression quantitative trait loci (cis-mQTL, cis-eQTL, and cis-pQTL, respectively), which were strongly associated with alterations in NETs-related genes. The causal associations between NETs-related genes and COPD were analyzed using the summary-data-based Mendelian randomization (SMR) method. Colocalization analysis was further performed to identify shared genetic variants between traits and validate the robustness of the SMR findings. Through SMR analysis, we identified two NETs-related genes ( AGER and SIGLEC9 ) and one protein ( CEACAM1 ) as causally associated with COPD. These findings supported by genetic predictions from blood-derived QTLs and colocalization analyses. Subsequent experimental validation in cigarette smoke extract (CSE)-treated BEAS-2B cells, a 12-week smoke-exposed mouse model, and clinical human lung tissue samples confirmed the involvement of these key molecules, revealing their dysregulated expression profiles in COPD-related conditions. Notably, although SMR analysis suggested protective effects of SIGLEC9 and CEACAM1 based on genetically predicted blood levels, experimental data demonstrated their upregulation in diseased lung tissues, indicating the involvement of complex regulatory mechanisms. This study identifies AGER , SIGLEC9 , and CEACAM1 as key causal mediators of the NETs-COPD axis, revealing their distinct roles in disease susceptibility and active pathogenesis. These molecules may represent promising therapeutic targets for modulating NETs-mediated inflammation and improving clinical outcomes in COPD.