COPD-associated proteins as biomarkers and drug targets: Insights from genetic and proteomic analyses

Chronic obstructive pulmonary disease (COPD) is a major global health burden with significant morbidity and mortality. Identifying circulating protein biomarkers may help understand COPD pathogenesis and develop novel therapeutic targets. We conducted a 2-sample Mendelian randomization (MR) analysis to assess the causal relationship between circulating proteins (cis-pQTLs) and COPD. Co-localization analysis confirmed shared genetic variants, while tissue-specific and pathway analyses provided insights into the biological roles of key proteins. Protein–protein interaction network analysis was conducted, and the impact of lifestyle factors on COPD-related proteins was also evaluated. Mendelian randomization analysis identified 18 proteins in the Decode dataset and 8 in the UK Biobank Pharmaceutical Proteomics Project dataset that were significantly associated with COPD after false discovery rate correction, with 4 proteins overlapping across datasets. Co-localization analysis provided strong evidence for proteins such as MMP12, KLC1, and apolipoprotein E being causally linked to COPD. Pathway analyses highlighted the involvement of these proteins in respiratory and inflammatory processes. Lifestyle factors, including dietary habits, were found to influence COPD-related proteins, suggesting avenues for lifestyle-based intervention. This study identified multiple circulating proteins associated with COPD, highlighting their potential as biomarkers and therapeutic targets. The findings suggest that targeted lifestyle interventions could modulate key proteins involved in COPD pathogenesis, providing opportunities for personalized management and prevention strategies.