Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
Maria Mikus, Johan Kolmert, L. Andersson, Jörgen Östling, Richard G. Knowles, Cristina Gómez, Magnus Ericsson, John‐Olof Thörngren, Payam Emami Khoonsari, Barbro Dahlén, Maciej Kupczyk, Bertrand De Meulder, Charles Auffray, P Bakke, Bianca Beghé, Elisabeth H. Bel, Massimo Caruso, Pascal Chanez, Bo Chawes, Stephen J. Fowler, Mina Gaga, Thomas Geiser, Mark Gjomarkaj, Ildikó Horváth, Peter Howarth, Sebastian L. Johnston, Guy Joos, Norbert Krug, Paolo Montuschi, Jacek Musiał, Ewa Niżankowska‐Mogilnicka, Henric Olsson, Alberto Papi, Klaus F. Rabe, Thomas Sandström, Dominick Shaw, Nikolaos M. Siafakas, Mathias Uhlén, John Riley, Stewart Bates, Roelinde Middelveld, Craig E. Wheelock, Kian Fan Chung, Ian M. Adcock, Peter J. Sterk, Ratko Djukanović, Peter Nilsson, Sven‐Erik Dahlén, Anna James
Abstract
RATIONALE: Asthma phenotyping requires novel biomarker discovery. OBJECTIVES: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). METHODS: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. RESULTS: MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. CONCLUSIONS: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.