A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes. METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement. RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity.
Date Issued
2017-02-15
Date Acceptance
2016-08-20
Citation
American Journal of Respiratory and Critical Care Medicine, 2017, 195 (4), pp.443-455
ISSN
1535-4970
Publisher
American Thoracic Society
Start Page
443
End Page
455
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
195
Issue
4
Copyright Statement
© 2016 American Thoracic Society. All Rights Reserved.
Sponsor
Commission of the European Communities
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Grant Number
115010
MR/L01632X/1
MR/L01632X/1
NF-SI-0509-10080
G1000758
G1000758
NF-SI-0515-10016
Subjects
Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
severe asthma
corticosteroid insensitivity
T-helper type 2
exhaled nitric oxide
gene set variation analysis
CLINICAL PHENOTYPES
OXIDATIVE STRESS
CLUSTER-ANALYSIS
GENE-EXPRESSION
HUMAN AIRWAY
CELLS
INTERLEUKIN-5
INFLAMMATION
MICROARRAY
CYTOKINES
T-helper type 2
corticosteroid insensitivity
exhaled nitric oxide
gene set variation analysis
severe asthma
Adrenal Cortex Hormones
Adult
Asthma
Biomarkers
Biopsy
Breath Tests
Bronchi
Bronchoscopy
Cohort Studies
Drug Resistance
Eosinophils
Female
Gene Expression Profiling
Humans
Inflammation
Leukocyte Count
Male
Middle Aged
Phenotype
Severity of Illness Index
Sputum
Th2 Cells
U-BIOPRED Project Team ‡
Bronchi
Eosinophils
Th2 Cells
Sputum
Humans
Asthma
Inflammation
Adrenal Cortex Hormones
Breath Tests
Bronchoscopy
Biopsy
Leukocyte Count
Severity of Illness Index
Cohort Studies
Gene Expression Profiling
Drug Resistance
Phenotype
Adult
Middle Aged
Female
Male
Biomarkers
11 Medical and Health Sciences
Respiratory System
Publication Status
Published
Date Publish Online
2016-08-31