• Gabrielle Y Liu, Andrew S Perry, George R Washko, Eric Farber-Eger, Laura A Colangelo, Quanhu Sheng, Quinn Wells, Xiaoning Huang, Bharat Thyagarajan, Weihua Guan, Shaina J Alexandria, San José EstéparRaúlR0000-0002-3677-1996Brigham and Women's Hospital, Radiology, Somerville, Massachusetts, United States., Russell P Bowler, Anthony J Esposito, Sadiya S Khan, Ravi V Shah, Bina Choi, and Ravi Kalhan.
• University of California Davis School of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Sacramento, California, United States.
• Am. J. Respir. Crit. Care Med. 2024 Sep 10.

RationaleAccelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice.ObjectiveTo determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality.MethodsIn CARDIA, a population-based cohort starting in young adulthood, longitudinal measurements of FEV1 percent predicted (up to six timepoints over 30 years) 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 regression. The proteomic respiratory susceptibility score was derived based on these circulating proteins and applied to the UK Biobank and COPDGene studies to examine associations with future respiratory morbidity and mortality.Measurements And ResultsHigher susceptibility score was independently associated with all-cause mortality (UKBB: HR 1.56, 95%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 1.83, 95%CI 1.33-2.51), incident COPD (UKBB: HR 1.84, 95%CI 1.71-1.98), incident respiratory exacerbation (COPDGene: OR 1.11, 95%CI 1.03-1.20), and incident exacerbation requiring hospitalization (COPDGene: OR 1.18, 95%CI 1.08-1.28).ConclusionsA proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is comprised 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.

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