Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

doi:10.1111/all.14016

Multicenter Study

. 2020 Feb;75(2):370-380.

doi: 10.1111/all.14016. Epub 2019 Sep 10.

Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

Leena George¹, Adam R Taylor², Anna Esteve-Codina³, María Soler Artigas^{1

3

4

5}, Gian Andri Thun³, Stewart Bates², Stelios Pavlidis^{6

7}, Scott Wagers⁸, Anne Boland⁹, Antje Prasse¹⁰, Piera Boschetto¹¹, David G Parr¹², Adam Nowinski¹³, Imre Barta¹⁴, Jens Hohlfeld¹⁵, Timm Greulich^{16

17}, Maarten van den Berge¹⁸, Pieter S Hiemstra¹⁹, Wim Timens²⁰, Timothy Hinks²¹, Sally Wenzel^{22

23}, Salman Siddiqui¹, Matthew Richardson¹, Per Venge²⁴, Simon Heath³, Ivo Gut^{3

25}, Martin D Tobin¹, Lindsay Edwards², John H Riley², Ratko Djukanovic²⁶, Charles Auffray²⁷, Bertrand De-Meulder²⁷, Sven Erik-Dahlen²⁸, Ian M Adcock⁵, Kian Fan Chung⁵, Loems Ziegler-Heitbrock²⁹, Peter J Sterk³⁰, Dave Singh^{31

32}, Christopher E Brightling¹; U-BIOPRED and the EvA study teams

Affiliations

¹ Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK.
² GSK Respiratory Therapeutic Area Unit, Stevenage, UK.
³ Centre for Genomic Regulation, CNAG-CRG Centre Nacional d'Anàlisi Genòmica, Barcelona Institute for Science and Technology, Barcelona, Spain.
⁴ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁵ Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
⁶ Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, UK.
⁷ Data Science Institute, Imperial College London, London, UK.
⁸ Biosci Consulting, Maasmechelen, Belgium.
⁹ Institut de Génomique, CEA, CNG Centre National de Génotypage, Evry, France.
¹⁰ Department of Pneumology, University Medical Center, Freiburg, Germany.
¹¹ Department of Medical Sciences, University of Ferrara and Ferrara City Hospital, Ferrara, Italy.
¹² Department of Respiratory Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
¹³ Department of Respiratory Medicine, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
¹⁴ Department of Pathophysiology, National Koranyi Institute for TB and Pulmonology, Budapest, Hungary.
¹⁵ Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
¹⁶ Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany.
¹⁷ Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
¹⁸ Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁹ Department of Pulmonary Diseases, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands.
²⁰ Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²¹ University of Oxford, Oxford, UK.
²² Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
²³ Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
²⁴ Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
²⁵ Universitat Pompeu Fabra, Barcelona, Spain.
²⁶ NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, UK.
²⁷ European Institute for Systems Biology and Medicine (EISBM), CNRS-ENS-UCBL, Université de Lyon, Lyon cedex 07, France.
²⁸ Karolinska Institute, Stockholm, Sweden.
²⁹ EvA Study Center, Helmholtz Zentrum Muenchen and Asklepios-Klinik, Gauting, Germany.
³⁰ Department Respiratory Medicine, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.
³¹ Centre for Respiratory Medicine and Allergy, The University of Manchester, Manchester, UK.
³² Medicines Evaluation Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.

PMID: 31506971
PMCID: PMC7064968
DOI: 10.1111/all.14016

Multicenter Study

Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

Leena George et al. Allergy. 2020 Feb.

. 2020 Feb;75(2):370-380.

doi: 10.1111/all.14016. Epub 2019 Sep 10.

Authors

Affiliations

¹ Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK.
² GSK Respiratory Therapeutic Area Unit, Stevenage, UK.
³ Centre for Genomic Regulation, CNAG-CRG Centre Nacional d'Anàlisi Genòmica, Barcelona Institute for Science and Technology, Barcelona, Spain.
⁴ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁵ Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
⁶ Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, UK.
⁷ Data Science Institute, Imperial College London, London, UK.
⁸ Biosci Consulting, Maasmechelen, Belgium.
⁹ Institut de Génomique, CEA, CNG Centre National de Génotypage, Evry, France.
¹⁰ Department of Pneumology, University Medical Center, Freiburg, Germany.
¹¹ Department of Medical Sciences, University of Ferrara and Ferrara City Hospital, Ferrara, Italy.
¹² Department of Respiratory Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
¹³ Department of Respiratory Medicine, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
¹⁴ Department of Pathophysiology, National Koranyi Institute for TB and Pulmonology, Budapest, Hungary.
¹⁵ Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
¹⁶ Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany.
¹⁷ Member of the German Center for Lung Research (DZL), Großhansdorf, Germany.
¹⁸ Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁹ Department of Pulmonary Diseases, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands.
²⁰ Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²¹ University of Oxford, Oxford, UK.
²² Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
²³ Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
²⁴ Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
²⁵ Universitat Pompeu Fabra, Barcelona, Spain.
²⁶ NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, UK.
²⁷ European Institute for Systems Biology and Medicine (EISBM), CNRS-ENS-UCBL, Université de Lyon, Lyon cedex 07, France.
²⁸ Karolinska Institute, Stockholm, Sweden.
²⁹ EvA Study Center, Helmholtz Zentrum Muenchen and Asklepios-Klinik, Gauting, Germany.
³⁰ Department Respiratory Medicine, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands.
³¹ Centre for Respiratory Medicine and Allergy, The University of Manchester, Manchester, UK.
³² Medicines Evaluation Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.

PMID: 31506971
PMCID: PMC7064968
DOI: 10.1111/all.14016

Abstract

Background: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.

Methods: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).

Results: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.

Conclusion: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

Keywords: T2-immunity; asthma; chronic obstructive pulmonary disease; eosinophil; gene expression.

PubMed Disclaimer

Conflict of interest statement

The authors acknowledge the contributions from the wider EvA and UBIOPRED consortia.

Figures

**Figure 1**
Principal component analysis plots derived from the top 100, 250 and 1000 genes determined by the regression analysis from the COPD (EvA) and asthma (U‐BIOPRED) subjects. Blue dots and red dots represent individual subjects dichotomized by the blood eosinophil count (>200 eosinophils/μL)

See this image and copyright information in PMC

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References

1. George L, Brightling CE. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther Adv Chronic Dis. 2016;7(1):34‐51. - PMC - PubMed
1. http://www.GOLD.org GOLD guidelines. Accessed 17th May 2019.
1. Brightling CE, Greening N. Airway inflammation in COPD‐ progress to precision medicine. Eur Respir J. 2019;54(2):1900651. - PubMed
1. Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;21:29‐40. - PubMed
1. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662‐671. - PubMed

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[1] George L, Brightling CE. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther Adv Chronic Dis. 2016;7(1):34‐51. - PMC - PubMed

[2] George L, Brightling CE. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther Adv Chronic Dis. 2016;7(1):34‐51. - PMC - PubMed

[3] http://www.GOLD.org GOLD guidelines. Accessed 17th May 2019.

[4] http://www.GOLD.org GOLD guidelines. Accessed 17th May 2019.

[5] Brightling CE, Greening N. Airway inflammation in COPD‐ progress to precision medicine. Eur Respir J. 2019;54(2):1900651. - PubMed

[6] Brightling CE, Greening N. Airway inflammation in COPD‐ progress to precision medicine. Eur Respir J. 2019;54(2):1900651. - PubMed

[7] Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;21:29‐40. - PubMed

[8] Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;21:29‐40. - PubMed

[9] Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662‐671. - PubMed

[10] Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662‐671. - PubMed

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Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

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Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

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