Plasma proteomics and lung function in four community-based cohorts

Abstract

Background: Underlying mechanism leading to impaired lung function are incompletely understood. Objectives: To investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function. Methods: We used four community-based studies (n = 2552) to investigate associations between 79 cardiovascular/inflammatory proteins and forced expiratory volume in 1 s percent predicted (FEV 1 %) assessed by spirometry. We divided the cohorts into discovery and replication samples and used risk factor-adjusted linear regression corrected for multiple comparison (false discovery rate of 5%). We performed Mendelian randomization analyses using genetic and spirometry data from the UK Biobank (n = 421,986) to assess causality. Measurements and main results: In cross-sectional analysis, 22 proteins were associated with lower FEV 1 % in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV 1 %. In longitudinal analyses (n = 681), higher plasma levels of growth differentiation factor 15 (GDF-15) and interleukin 6 (IL-6) predicted a more rapid 5-year decline in lung function (change in FEV 1 % per standard deviation of protein level − 1.4, (95% CI, − 2.5 to − 0.3) for GDF-15, and -0.8, (95% CI, − 1.5 to − 0.2) for IL-6. Mendelian randomization analysis in UK-biobank provided support for a causal effect of increased GDF-15 levels and reduced FEV 1 %. Conclusions: Our combined approach identified GDF-15 as a potential causal factor in the development of impaired lung function in the general population. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function.

Cardiovascular disease-linked plasma proteins are mainly associated with lung volume

“…Increased levels are associated with several disease states, e.g., insulin resistance, type 2 diabetes, and hypertension. FABP4 increased with decreasing lung function in COPD-stable patients [35] and with decreasing FEV 1 in our previous analyses [13]. This association could be mediated through MMP-9, as suggested in ischemic stroke animal models [36].…”

“…, insulin resistance, type 2 diabetes and hypertension. FABP4 increased with decreasing lung function in COPD-stable patients [ 35 ] and with decreasing FEV 1 in our previous analyses [ 13 ]. The association between FABP4 and lower lung function could be mediated through matrix metalloproteinase (MMP9), as suggested in ischaemic stroke animal models [ 36 ].…”

“…Formerly thought to only modulate body weight through decreased appetite, leptin has other important roles in the body, including both the immune and the endocrine system [ 32 ]. We previously reported an association between leptin and FEV 1 [ 13 ]. In this study, we replicated this association and extended it to FVC.…”

“…We have previously studied the association between forced expiratory volume in one second (FEV 1 ) and proteomics, focusing on inflammatory processes [13]. The primary aim of this paper was to study associations between broader proteomics data, focusing on CVDrelated proteins, and lung function in a large population.…”

Association of 71 cardiovascular disease-related plasma proteins with pulmonary function in the community

“…GDF-15 is an epithelial stress marker that is elevated in patients with idiopathic pulmonary fibrosis (IPF), a predictor of more severe disease and worse outcomes in IPF and associated with a greater odd of developing interstitial lung abnormalities (ILA) in both the FHS and COPDGene cohorts [ 38 , 39 ]. Higher levels of baseline GDF-15 have also been associated with a more rapid decline in FEV 1 over the span of 5 years in a community based sample [ 40 ]. Elevated levels of GDF-15 have been demonstrated to be an independent predictor of heart failure related rehospitalization as well as death in patients with both diastolic and systolic heart failure after adjusting for troponin and BNP levels [ 41 ].…”