• 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; Population Sciences Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
• Chest. 2024 Nov 22.

BackgroundImpaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders.Research QuestionCan circulating protein biomarkers of pulmonary function provide insight into the pathophysiologic features of lung function impairment and links to comorbidities?.Study Design And MethodsWe analyzed plasma levels of 2,922 proteins in 32,493 UK Biobank participants (53% female; mean [SD] age, 57 [8] years) to investigate their associations with spirometry measures of lung function (FEV1, FVC, FEV1 to FVC ratio), and with obstructive (n = 4,713) and restrictive (n = 3,886) spirometry patterns. Significant protein signatures were annotated functionally and validated externally in 740 Framingham Heart Study (FHS) participants. We inferred causality using Mendelian randomization and examined colocalization of genetic signals of protein biomarkers with corresponding lung traits.ResultsIn the UK Biobank, we identified 1,240 proteins associated significantly (PUK Biobank < .000017) with FEV1, 1,310 proteins associated significantly with FVC, and 513 proteins associated significantly with FEV1 to FVC ratio. Of these, 44, 99, and 13 proteins, respectively, were nominally significant (PFHS < .01) in the FHS. Plasma levels of 737 proteins (seven with PFHS < .01) differed in individuals with an obstructive spirometry pattern (OSP), and 811 proteins (38 with PFHS < .01) differed in restrictive spirometry pattern compared with normal spirometry in the UK Biobank. Putatively causal relationships to FEV1, FVC, FEV1 to FVC ratio, and OSP were observed for 55, 63, 28, and 14 proteins, respectively. Of note, several circulating decoy receptors, including IL-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 identified proteomic signatures of reduced lung function linked to comorbidities, paving the way for improved diagnostics for and treatment of lung disease.Published by Elsevier Inc.

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