Novel Type 2-high gene clusters associated with corticosteroid sensitivity in COPD
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Rationale Severe asthma and COPD share common pathophysiologic traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the U-BIOPRED cohort with one Type 2-high signature (TAC1) and 2 Type 2-low signatures. Objective We examined whether gene-expression signatures obtained in asthma can be used to identify the subgroup of COPD patients with steroid sensitivity. Methods Using gene set variation analysis (GSVA), we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the GLUCOLD COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Measurements and main results Bronchial biopsies in COPD patients at baseline showed a wide range of expression of the 3 TACs. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 (sub)signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-seq and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription predicted change in FEV1 %predicted following 30-month ICS±LABA. Conclusions Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of COPD patients and identified airway wall mast cells as a predictor of those COPD patients who will benefit from inhaled corticosteroids.
Authors 15
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Alen Faiz corresponding
University of Technology Sydney · University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, Department of Pulmonary Diseases, University Medical Center Groningen - Groningen (Netherlands)
University of Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), University Medical Center Groningen - Groningen (Netherlands)
University of Technology Sydney, Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, Sydney, Australia
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Affiliation as printed
National Heart & Lung Institute, Imperial College London, London (United Kingdom),
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Affiliation as printed
National Heart & Lung Institute, Imperial College London, London (United Kingdom),
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Affiliation as printed
Janssen Research and Development - High Wycombe (United Kingdom)
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Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center, Department of Pulmonology - Leiden (Netherlands)
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, Department of Pathology and Medical Biology, University Medical Center Groningen - Groningen (Netherlands)
University of Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), University Medical Center Groningen - Groningen (Netherlands)
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, Department of Pathology and Medical Biology, University Medical Center Groningen - Groningen (Netherlands)
University of Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), University Medical Center Groningen - Groningen (Netherlands)
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, Department of Pathology and Medical Biology, University Medical Center Groningen - Groningen (Netherlands)
University of Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), University Medical Center Groningen - Groningen (Netherlands)
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Affiliation as printed
Dept of Computing and Data Science Institute, Imperial College London - London (United Kingdom)
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Affiliation as printed
Faculty of Medicine, Southampton University - Southampton (United Kingdom),
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Amsterdam (Netherlands)
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, Department of Pathology and Medical Biology, University Medical Center Groningen - Groningen (Netherlands)
University of Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), University Medical Center Groningen - Groningen (Netherlands)
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University Medical Center Groningen · University of Groningen · Imperial College London
Affiliation as printed
National Heart & Lung Institute, Imperial College London, London (United Kingdom),
University of Groningen, Department of Pathology and Medical Biology, University Medical Center Groningen - Groningen (Netherlands)
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University Medical Center Groningen · University of Groningen · Imperial College London
Affiliation as printed
National Heart & Lung Institute, Imperial College London, London (United Kingdom),
University of Groningen, Department of Pathology and Medical Biology, University Medical Center Groningen - Groningen (Netherlands)
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, Department of Pulmonary Diseases, University Medical Center Groningen - Groningen (Netherlands)
University of Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), University Medical Center Groningen - Groningen (Netherlands)
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