Plasma proteomics and lung function in four community-based cohorts
Andreas Rydell, Christoph Nowak, Christer Janson, Karin Lisspers, Björn Ställberg, David Iggman, Jerzy Leppert, Pär Hedberg, Johan Sundström, Erik Ingelsson, Lars Lind, Johan Ärnlöv
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.