Proteomic Risk Score of Increased Respiratory Susceptibility: A Multicohort Study

<b>Rationale:</b> Accelerated decline in lung function is associated with incident chronic obstructive pulmonary disease (COPD), hospitalization, and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice. <b>Objectives:</b> To determine whether a proteomic risk score trained on accelerated decline in lung function can assess the risk of future respiratory disease and mortality. <b>Methods:</b> In the Coronary Artery Risk Development in Young Adults Study, a population-based cohort starting in young adulthood, longitudinal measurements of FEV₁ percent predicted (up to six time points over 30 yr) were used to identify accelerated and normal decline trajectories. Protein aptamers associated with an accelerated decline trajectory were identified with multivariable logistic regression followed by LASSO (least absolute shrinkage and selection operator) regression. The proteomic respiratory susceptibility score was derived on the basis of these circulating proteins and applied to the U.K. Biobank (UKBB) and COPDGene studies to examine associations with future respiratory morbidity and mortality. <b>Measurements and Main Results:</b> Higher susceptibility score was independently associated with all-cause mortality (UKBB hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.50-1.61; COPDGene HR, 1.75 95% CI, 1.63-1.88), respiratory mortality (UKBB HR, 2.39; 95% CI, 2.16-2.64; COPDGene HR, 1.81; 95% CI, 1.32-2.47), incident COPD (UKBB HR, 1.84; 95% CI, 1.71-1.98), incident respiratory exacerbation (COPDGene odds ratio, 1.10; 95% CI, 1.02-1.19), and incident exacerbation requiring hospitalization (COPDGene OR, 1.17; 95% CI, 1.08-1.27). <b>Conclusions:</b> A proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is composed of proteins with well-known and novel associations with lung health and holds promise for the early detection of lung disease without requiring years of spirometry measurements.