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

U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium

doi:10.1183/13993003.00142-2021

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

U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium

KTH Royal Institute of Technology
Karolinska Institutet
Knowles Consulting, Stevenage Bioscience Catalyst, Stevenage, United Kingdom;
Science for Life Laboratory
Medical University of Łódź
European Institute of Systems Biology and Medicine, 69390 Lyon, France
University of Bergen
University of Modena and Reggio Emilia
University of Catania
AP-HM Assistance Publique - Hôpitaux de Marseille
University of Copenhagen
Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK
National and Kapodistrian University of Athens
University of Bern
National Research Council of Italy
Semmelweis University
University Hospital Southampton NHS Foundation Trust
Imperial College London
Ghent University
Fraunhofer Institute for Toxicology and Experimental Medicine
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
AstraZeneca
University of Ferrara
Kiel University
Umeå University
University of Nottingham
University of Crete
GlaxoSmithKline
Knowles Consulting
Karolinska University Hospital
European Institute for Systems Biology and Medicine
University of Amsterdam
University of Manchester
Bern University Hospital ‘Inselspital’
Consiglio Nazionale delle Ricerche
1st Department of Cardiology, Interventional Electrocardiology and Hypertension, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
AstraZeneca Sweden

Research output: Contribution to journal › Article › Academic › peer-review

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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: 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.

Original language	English
Article number	2100142
Journal	European respiratory journal
Volume	59
Issue number	2
DOIs	https://doi.org/10.1183/13993003.00142-2021
Publication status	Published - 1 Feb 2022

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SDG 3 Good Health and Well-being

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10.1183/13993003.00142-2021

Plasma-proteins-elevated-in-severe-asthma-despite-oral-steroid-use-and-unrelated-to-type-2-inflammation.pdfFinal published version, 1.39 MBLicence: CC BY

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U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium (2022). Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation. European respiratory journal, 59(2), Article 2100142. https://doi.org/10.1183/13993003.00142-2021

U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium. / Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation. In: European respiratory journal. 2022 ; Vol. 59, No. 2.

@article{3acca53ed4104b2ca39cbcb44662c60c,

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

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: 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.",

author = "\{Sparreman Mikus\}, Maria and Johan Kolmert and Andersson, \{Lars I.\} and {\"O}stling, \{J. rgen\} and Knowles, \{Richard G.\} and Cristina G{\'o}mez and Magnus Ericsson and John-Olof Th{\"o}rngren and \{Emami Khoonsari\}, Payam and Barbro Dahl{\'e}n and Maciej Kupczyk and \{de Meulder\}, Bertrand and Charles Auffray and Bakke, \{Per S.\} and Bianca Beghe and Bel, \{Elisabeth H.\} and Massimo Caruso and Pascal Chanez and Bo Chawes and Fowler, \{Stephen J.\} and Mina Gaga and Thomas Geiser and Mark Gjomarkaj and Ildik{\'o} Horv{\'a}th and Howarth, \{Peter H.\} and Johnston, \{Sebastian L.\} and Guy Joos and Norbert Krug and Paolo Montuschi and Jacek Musial and Ewa Ni{\.z}ankowska-Mogilnicka and Olsson, \{Henric K.\} and Alberto Papi and Rabe, \{Klaus F.\} and Thomas Sandstr{\"o}m and Shaw, \{Dominick E.\} and Siafakas, \{Nikolaos M.\} and Mathias Uhl{\'e}n and Riley, \{John H.\} and Stewart Bates and Middelveld, \{Roelinde J. M.\} and \{U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium\} and Wheelock, \{Craig E.\} and Chung, \{Kian Fan\} and Adcock, \{Ian M.\} and Sterk, \{Peter J.\} and Ratko Djukanovic and Peter Nilsson and Sven-Erik Dahl{\'e}n and Anna James",

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. {\"O}stling has nothing to disclose. R.G. Knowles has nothing to disclose. C. G{\'o}mez has nothing to disclose. M. Ericsson has nothing to disclose. J-O. Th{\"o}rngren has nothing to disclose. P. Emami Khoonsari has nothing to disclose. B. Dahl{\'e}n 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. Horv{\'a}th 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. Ni{\.z}ankowska-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. Sandstr{\"o}m 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. Dahl{\'e}n 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 V{\aa}rdal Foundation, the Swedish Heart-Lung Foundation, the Swedish MRC, the Stockholm County Council Research Funds (ALF), the Swedish Asthma and Allergy Association{\textquoteright}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{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} 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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2022 European Respiratory Society. All rights reserved.",

year = "2022",

month = feb,

day = "1",

doi = "10.1183/13993003.00142-2021",

language = "English",

volume = "59",

journal = "European respiratory journal",

issn = "0903-1936",

publisher = "European Respiratory Society",

number = "2",

}

U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium 2022, 'Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation', European respiratory journal, vol. 59, no. 2, 2100142. https://doi.org/10.1183/13993003.00142-2021

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation. / U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium.
In: European respiratory journal, Vol. 59, No. 2, 2100142, 01.02.2022.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

AU - Sparreman Mikus, Maria

AU - Kolmert, Johan

AU - Andersson, Lars I.

AU - Östling, J. rgen

AU - Knowles, Richard G.

AU - Gómez, Cristina

AU - Ericsson, Magnus

AU - Thörngren, John-Olof

AU - Emami Khoonsari, Payam

AU - Dahlén, Barbro

AU - Kupczyk, Maciej

AU - de Meulder, Bertrand

AU - Auffray, Charles

AU - Bakke, Per S.

AU - Beghe, Bianca

AU - Bel, Elisabeth H.

AU - Caruso, Massimo

AU - Chanez, Pascal

AU - Chawes, Bo

AU - Fowler, Stephen J.

AU - Gaga, Mina

AU - Geiser, Thomas

AU - Gjomarkaj, Mark

AU - Horváth, Ildikó

AU - Howarth, Peter H.

AU - Johnston, Sebastian L.

AU - Joos, Guy

AU - Krug, Norbert

AU - Montuschi, Paolo

AU - Musial, Jacek

AU - Niżankowska-Mogilnicka, Ewa

AU - Olsson, Henric K.

AU - Papi, Alberto

AU - Rabe, Klaus F.

AU - Sandström, Thomas

AU - Shaw, Dominick E.

AU - Siafakas, Nikolaos M.

AU - Uhlén, Mathias

AU - Riley, John H.

AU - Bates, Stewart

AU - Middelveld, Roelinde J. M.

AU - U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium

AU - Wheelock, Craig E.

AU - Chung, Kian Fan

AU - Adcock, Ian M.

AU - Sterk, Peter J.

AU - Djukanovic, Ratko

AU - Nilsson, Peter

AU - Dahlén, Sven-Erik

AU - James, Anna

N1 - 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. Publisher Copyright: © 2022 European Respiratory Society. All rights reserved.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85124850563

U2 - 10.1183/13993003.00142-2021

DO - 10.1183/13993003.00142-2021

M3 - Article

C2 - 34737220

SN - 0903-1936

VL - 59

JO - European respiratory journal

JF - European respiratory journal

IS - 2

M1 - 2100142

ER -

U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation. European respiratory journal. 2022 Feb 1;59(2):2100142. doi: 10.1183/13993003.00142-2021

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

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