Abstract
BACKGROUND: Impaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders. RESEARCH QUESTION: Can circulating protein biomarkers of pulmonary function provide insight into the pathophysiologic features of lung function impairment and links to comorbidities? STUDY DESIGN AND METHODS: We 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 (FEV(1), FVC, FEV(1) 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. RESULTS: In the UK Biobank, we identified 1,240 proteins associated significantly (P < .000017 observed in the UK Biobank) with FEV(1), 1,310 proteins associated significantly with FVC, and 513 proteins associated significantly with FEV(1) to FVC ratio. Of these, 44, 99, and 13 proteins, respectively, were nominally significant (P < .01 obeserved in the FHS) in the FHS. Plasma levels of 737 proteins (seven with P < .01 obeserved in the FHS) differed in individuals with an obstructive spirometry pattern (OSP), and 811 proteins (38 with P < .01 obeserved in the FHS) differed in restrictive spirometry pattern compared with normal spirometry in the UK Biobank. Putatively causal relationships to FEV(1), FVC, FEV(1) 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. INTERPRETATION: This study identified proteomic signatures of reduced lung function linked to comorbidities, paving the way for improved diagnostics for and treatment of lung disease.