Proteomic Mediators of Chronic Obstructive Pulmonary Disease Phenotypes and Coronary Artery Calcification Burden in Ever Smokers

Background Chronic obstructive pulmonary disease (COPD) increases cardiovascular disease risk. Coronary artery calcification (CAC) predicts cardiovascular events and mortality in COPD. We hypothesized that plasma proteins linked to pulmonary phenotypes mediate CAC burden. Methods Pulmonary function, emphysema, airway wall thickening, Agatston CAC scores (inverse normal transformed), and relative abundance of 1305 plasma proteins (log‐transformed) were assessed in 989 Phase 1 COPDGene (Genetic Epidemiology of COPD) participants. Proteins associated with both pulmonary phenotypes (FEV 1 [forced expiratory volume in 1 second]%predicted, FVC [forced vital capacity], FEV 1 /FVC, emphysema, airway wall thickness, wall area percentage) and CAC (false discovery rate P ≤0.20) were evaluated using multivariable mediation. Model adjustments included sex, age, race, body mass index, smoking, comorbidities, and medications. Adjustment for pulmonary artery‐to‐aortic diameter ratio—a marker of pulmonary vascular pressure—was also explored. The95% bootstrap CIs that excluded zero were considered significant. Results FEV 1 %predicted ( P =0.026) and FEV 1 /FVC ( P =0.010) were associated with CAC. After adjusting for FEV 1 , visual emphysema, and visual airway wall thickening remained associated with CAC. Five proteins (TSP2 [thrombospondin‐2], renin, MMP‐7 [matrix metalloproteinase‐7], ERBB1 [epidermal growth factor receptor], MIC‐1 [macrophage inhibitory cytokine‐1]) mediated the FEV 1 %predicted and CAC association. All except MIC‐1 mediated FEV 1 /FVC and CAC. All except renin mediated quantitative airway wall thickness or wall area percentage and CAC. Additionally, α2‐antiplasmin (alpha‐2 antiplasmin) mediated airway wall thickness and CAC. ERBB1 mediated visual paraseptal emphysema and CAC. Pulmonary artery‐to‐aortic diameter ratio adjustment reduced or eliminated some mediation effects. ERBB1 remained an independent mediator across multiple phenotypes. Conclusions Six plasma proteins mediated associations between COPD phenotypes and CAC burden. These effects were partially influenced by pulmonary artery‐to‐aortic diameter ratio A, suggesting shared molecular pathways linking lung dysfunction to cardiovascular risk in COPD.