Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
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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-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 2100142 |
| Tidsskrift | European Respiratory Journal |
| Vol/bind | 59 |
| Udgave nummer | 2 |
| Antal sider | 17 |
| ISSN | 0903-1936 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Conflict of interest: M. Sparreman Mikus has nothing to disclose. J. Kolmert reports personal fees from Gesynta Pharma AB. L.I. Andersson has nothing to disclose. J. Östling has nothing to disclose. R.G. Knowles has nothing to disclose. C. Gómez has nothing to disclose. M. Ericsson has nothing to disclose. J-O. Thörngren has nothing to disclose. P. Emami Khoonsari has nothing to disclose. B. Dahlén reports personal fees from AstraZeneca, Teva, Sanofi and grants from Novartis and GlaxoSmithKline outside the submitted work. M. Kupczyk has nothing to disclose. B. De Meulder report grants from the Innovative Medicines Initiative during the conduct of the study. C. Auffray report grants from the Innovative Medicines Initiative during the conduct of the study. P.S. Bakke reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Chiesi outside the submitted work. B. Beghe reports personal fees from AstraZeneca, Boehringer Ingelheim, Menarini and GlaxoSmithKline outside the submitted work. E.H. Bel reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Novartis, TEVA, Sanofi/Regeneron, Chiesi, and Sterna outside the submitted work. M. Caruso has nothing to disclose. P. Chanez has nothing to disclose. B. Chawes has nothing to disclose. S.J. Fowler has nothing to disclose. M. Gaga reports grants and personal fees from Novartis, Menarini, Merck Sharp & Dohme, BMS, Galapagos, and AstraZeneca outside the submitted work. T. Geiser has nothing to disclose. M. Gjomarkaj has nothing to disclose. I. Horváth reports grants from EFPIA during the conduct of the study, and personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Boehringer-Ingelheim, Sandoz, Teva and Chiesi outside the submitted work. P.H. Howarth has nothing to disclose. S.L. Johnston reports personal fees from Virtus Respiratory Research, Myelo Therapeutics GmbH, Concert Pharmaceuticals, Bayer, Synairgen, Novartis, Boehringer Ingelheim, Chiesi, Gerson Lehrman Group, resTORbio, Bioforce, Materia Medical Holdings, PrepBio Pharma, Pulmotect, Virion Health, Lallemand Pharma and AstraZeneca outside the submitted work. In addition, Sebastian L. Johnston also has three patents (Anti-virus therapy for respiratory diseases, UK patent application No. GB 0405634.7, Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases, International Patent Application No. PCT/ GB05/50031 and Interferon Lambda therapy for the treatment of respiratory disease, UK patent application No.6779645.9). G. Joos reports grants and personal fees from AstraZeneca, Bayer, Chiesi, Eureca vzw, GlaxoSmithKline and Teva outside the submitted work. N. Krug has nothing to disclose. P. Montuschi has nothing to disclose. J. Musial has nothing to disclose. E. Niżankowska-Mogilnicka has nothing to disclose. H.K. Olsson reports other support from AstraZeneca outside the submitted work. A. Papi reports grants, personal fees, non-financial support and others from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Chiesi, Teva, Mundipharma, Zambon, Novartis, Menarini, Sanofi/Regeneron, Roche, Fondazione Salvatore Maugeri, Chiesi and Edmond pharma outside the submitted work. K.F. Rabe reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Sanofi Aventis, MERCK SHARP & DOHME, Novartis, Orion Cooperation, Berlin Chemie, Roche, Chiesi and grants for research from the Ministry of Education and Science, Germany. T. Sandström has nothing to disclose. D.E. Shaw reports personal fees and non-financial support from GlaxoSmithKline, Novartis and AstraZeneca outside the submitted work. N.M. Siafakas has nothing to disclose. M. Uhlen has nothing to disclose. J.H. Riley is an employee and shareholder in GlaxoSmithKline. S. Bates is an employee and shareholder in GlaxoSmithKline. R.J.M. Middelveld reports grants from the Swedish Strategic Research Foundation, AstraZeneca, the Swedish Heart Lung Foundation and the Swedish Asthma and Allergy Association outside the submitted work. C.E. Wheelock has nothing to disclose. K.F. Chung reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim, Roche and Shionogi outside the submitted work. I.M. Adcock has nothing to disclose. P.J. Sterk reports grants to Amsterdam UMC from the public private Innovative Medicines Initiative (IMI) covered by the European Union (EU) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) during the conduct of the study. R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, GlaxoSmithKline, AstraZeneca and Teva, consultation fees from Teva and Novartis; he is a co-founder and current consultant and has shares in Synairgen. P. Nilsson has nothing to disclose. S-E. Dahlén reports personal fees from AstraZeneca, Cayman Chemicals, GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva outside the submitted work. A. James has nothing to disclose.
Funding Information:
Support statement: This study was supported by grants from the ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium which is funded by the Swedish Foundation for Strategic Research, the Karolinska Institutet, AstraZeneca and Science for Life Laboratory Joint Research Collaboration, and the Vårdal Foundation, the Swedish Heart-Lung Foundation, the Swedish MRC, the Stockholm County Council Research Funds (ALF), the Swedish Asthma and Allergy Association’s Research Foundation, and Karolinska Institutet. This project has received funding from an Innovative Medicines Initiative (IMI) Joint Undertaking ( JU) under grant agreement number 115010 (U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes)), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Additional support from IMI 2 JU under grant agreement number 831434 (3TR (Taxonomy, Treatment, Targets and Remission)). This JU receives the support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The BIOAIR consortium was funded by the Fifth and Sixth Framework Programmes of the European Union, contract numbers: QLG1-CT-2000-01185 (BIOAIR) and FOOD-CT-2004-506378 (GA2LEN), and several national funding bodies. A. James and M. Kupczyk were supported by the Bernard Osher Initiative for Severe Asthma. P. Emami Khoonsari was financially supported by the Knut and Alice Wallenberg Foundation as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab. Funding information for this article has been deposited with the Crossref Funder Registry.
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