Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Maria Sparreman Mikus , Johan Kolmert , Lars Andersson , Jörgen Östling , Richard Knowles , Cristina Gómez , Magnus Ericsson , John-Olof Thörngren , Payam Emami Khoonsari , Barbro Dahlén , Maciej Kupczyk , Bertrand de Meulder , Charles Auffray , Per Bakke , Bianca Beghe , Elisabeth Bel , Massimo Caruso , Pascal Chanez (1) , Bo Chawes , Stephen Fowler , Mina Gaga , Thomas Geiser , Mark Gjomarkaj , Ildikó Horváth , Peter Howarth , Sebastian Johnston , Guy Joos , Norbert Krug , Paolo Montuschi , Jacek Musial , Ewa Niżankowska-Mogilnicka , Henric Olsson , Alberto Papi , Klaus Rabe , Thomas Sandström , Dominick Shaw , Nikolaos Siafakas , Mathias Uhlén , John Riley , Stewart Bates , Roelinde J.M. Middelveld , Craig Wheelock , Kian Fan Chung , Ian Adcock , Peter Sterk , Ratko Djukanovic , Peter Nilsson , Sven-Erik Dahlén , Anna James

1 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research

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 In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus 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.

Domains: Life Sciences [q-bio]

Maria Sparreman Mikus, Johan Kolmert, Lars Andersson, Jörgen Östling, Richard Knowles, et al.. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation. European Respiratory Journal, 2022, 59 (2), pp.2100142. ⟨10.1183/13993003.00142-2021⟩. ⟨hal-03654460⟩