Comments
Rationale: 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.
Objectives: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess the risk of future respiratory disease and mortality.
Methods: 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.
Measurements and Main Results: 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).
Conclusions: 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.
* These authors contributed equally to this work.
‡ These authors contributed equally to this work.
Supported by National Institutes of Health grant F32-HL162318 (G.Y.L.). B.C. is supported by National Institutes of Health grant F32-HL167486 and the American Lung Association. R.K. is supported in part by National Heart, Lung, and Blood Institute grant R01 HL122477 (CARDIA Lung Study). The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I, HHSN268201800007I), Northwestern University (HHSN268201800003I), the University of Minnesota (HHSN268201800006I), and the Kaiser Foundation Research Institute (HHSN268201800004I). The COPDGene study is supported by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an industry advisory committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. This article has been reviewed by CARDIA for scientific content. Analyses from the U.K. Biobank were conducted under approved Research Proposal 5749.
Author Contributions: Concept and design: G.Y.L., A.S.P., G.R.W., R.V.S., B.C., and R.K. Data acquisition, analysis, or interpretation: G.Y.L., A.S.P., G.R.W., E.F.-E., Q.S., Q.W., X.H., B.T., W.G., S.J.A., R.S.J.E., R.P.B., A.J.E., S.S.K., R.V.S., B.C., and R.K. Drafting of the manuscript: G.Y.L. and A.S.P. Statistical analysis: G.Y.L., A.S.P., E.F.-E., L.A.C., and B.C. Supervision: G.R.W., R.V.S., B.C., and R.K. Critical revision of the manuscript for important intellectual content and final approval: all authors.
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Originally Published in Press as DOI: 10.1164/rccm.202403-0613OC on September 10, 2024
Author disclosures are available with the text of this article at www.atsjournals.org.
