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

doi:10.1016/j.rmed.2020.106282

Abstract

BackgroundUnderlying mechanism leading to impaired lung function are incompletely understood. ObjectivesTo investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function. MethodsWe 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 resultsIn 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%. ConclusionsOur 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

Individuals with reduced lung function and chronic obstructive pulmonary disease (COPD) have increased risks of cardiovascular dis ease and mortality [1,2,3,4,5] that cannot entirely be attributed to estab lished risk factors, like smoking, hypertension and diabetes [5,6,7]
As the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD are insufficient for predicting the long-term outcomes in these patients [9], new diagnostic tools are needed to identify high-risk individuals that would benefit from targeted prevention
Replication stage Two independent cohorts were selected from the Study of Atherosclerosis in Vastmanland, a healthy control group (SaVa-controls) and patients with peripheral artery disease (Peripheral Arterial Disease in Vastmanland, PADVa)

Summary

Introduction

Individuals with reduced lung function and chronic obstructive pulmonary disease (COPD) have increased risks of cardiovascular dis ease and mortality [1,2,3,4,5] that cannot entirely be attributed to estab lished risk factors, like smoking, hypertension and diabetes [5,6,7]. These individuals represent a heterogenous group with differences in disease severity, rate of progression and impact on the quality of life [8]. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function

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