Plasma proteomics and lung function in four community-based cohorts. (January 2021) - Rydell, Andreas
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 (FEV1 %) 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 FEV1 % in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV1 %. 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 FEV1 % 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 FEV1 %. 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. Highlights: Protein profiling may provide new insights into mechanisms for impaired lung function. Twenty-two proteins were cross-sectionally associated with FEV1 % in four cohorts. Mendelian randomization analysis provided support for a causal effect of GDF-15. GDF-15 could be a suitable target for interventions to prevent lung function decline.