• Mohit Aggarwal, Shih-Jen Hwang, Dong Heon Lee, Tianxiao Huan, Jenna N McNeill, Paul Courchesne, Roby Joehanes, Jennifer E Ho, Josée Dupuis, Åsa K Hedman, George O'Connor, and Daniel Levy.
• Framingham Heart Study, Framingham, MA, United States; Population Sciences Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States.
• Chest. 2024 Nov 21.

BackgroundImpaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders.Research QuestionCan circulating protein biomarkers of pulmonary function provide insights into the pathophysiology of lung function impairment and links to comorbidities?Study Design And MethodsWe analyzed plasma levels of 2922 proteins in 32,493 UK Biobank (UKB) participants (53% women, age=57±8 years) to investigate their associations with spirometry measures of lung-function (1-second forced-expiratory volume [FEV1], forced-vital capacity [FVC], FEV1/FVC ratio), and with obstructive (N=4713) and restrictive (N=3886) spirometry patterns. Significant protein signatures were functionally annotated and externally validated in 740 Framingham Heart Study participants (FHS). We inferred causality using Mendelian randomization and examined colocalization of genetic signals of protein biomarkers with corresponding lung traits.ResultsIn UKB, we identified 1240 proteins significantly associated (PUKB <0.000017) with FEV1, 1310 with FVC, and 513 with FEV1/FVC. Of these, 44, 99, and 13 proteins, respectively, were nominally significant (PFHS <0.01) in FHS. Plasma levels of 737 proteins (7 with PFHS <0.01) differed in individuals with an obstructive spirometry pattern (OSP), and 811 proteins (38 with PFHS <0.01) differed in restrictive spirometry pattern (RSP) compared to normal spirometry in the UKB. Putatively causal relations to FEV1, FVC, FEV1/FVC, and OSP were observed for 55, 63, 28, and 14 proteins, respectively. Of note, several circulating decoy receptors, including interleukin-1 receptor-like 1, tumor necrosis factor receptor superfamily member-6B, and macrophage scavenger receptor-1 emerged as causal and protective biomarkers of lung function. Enrichment analysis suggested a connection between reduced lung function and systemic inflammation driven by adipose tissue dysfunction and gut-dysbiosis. Protein biomarkers associated with lung function also were enriched for susceptibility to cardiovascular conditions and cancers.InterpretationThis study identifies proteomic signatures of reduced lung function linked to comorbidities, paving the way for improved diagnostics and treatment for lung disease.Copyright © 2024. Published by Elsevier Inc.

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