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T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED

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Title: T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED
Authors: Kuo, C-HS
Pavlidis, S
Loza, M
Baribaud, F
Rowe, A
Pandis, I
Sousa, A
Corfield, J
Djukanovic, R
Lutter, R
Sterk, PJ
Auffray, C
Guo, Y
Adcock, IM
Chung, KF
Item Type: Journal Article
Abstract: Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects. After filtering on the differentially expressed genes between eosinophil- and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets. We defined three transcriptome-associated clusters (TACs): TAC1 (characterised by immune receptors IL33R, CCR3 and TSLPR), TAC2 (characterised by interferon-, tumour necrosis factor-α- and inflammasome-associated genes) and TAC3 (characterised by genes of metabolic pathways, ubiquitination and mitochondrial function). TAC1 showed the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2 (Th2) and innate lymphoid cell type 2. TAC1 had the highest sputum eosinophilia and exhaled nitric oxide fraction, and was restricted to severe asthma with oral corticosteroid dependency, frequent exacerbations and severe airflow obstruction. TAC2 showed the highest sputum neutrophilia, serum C-reactive protein levels and prevalence of eczema. TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1 s. Gene–protein coexpression networks from TAC1 and TAC2 extended this molecular classification. We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome-associated and metabolic/mitochondrial pathways, respectively.
Issue Date: 8-Feb-2017
Date of Acceptance: 3-Nov-2016
URI: http://hdl.handle.net/10044/1/51554
DOI: http://dx.doi.org/10.1183/13993003.02135-2016
ISSN: 0903-1936
Publisher: European Respiratory Society
Journal / Book Title: European Respiratory Journal
Volume: 49
Issue: 2
Copyright Statement: © 2016 ERS. This is an author-submitted, peer-reviewed version of a manuscript that has been accepted for publication in the European Respiratory Journal, prior to copy-editing, formatting and typesetting. This version of the manuscript may not be duplicated or reproduced without prior permission from the copyright owner, the European Respiratory Society. The publisher is not responsible or liable for any errors or omissions in this version of the manuscript or in any version derived from it by any other parties. The final, copy-edited, published article, which is the version of record, is available without a subscription 18 months after the date of issue publication.
Sponsor/Funder: National Institute for Health Research
Medical Research Council (MRC)
Commission of the European Communities
Medical Research Council (MRC)
National Institute for Health Research
Funder's Grant Number: NF-SI-0509-10080
G1000758
115010
G1000758
NF-SI-0515-10016
Keywords: Science & Technology
Life Sciences & Biomedicine
Respiratory System
INNATE LYMPHOID-CELLS
GENE-EXPRESSION
AIRWAY INFLAMMATION
NLRP3 INFLAMMASOME
NEUTROPHILIC ASTHMA
SUBTYPES
BIOMARKERS
DISCOVERY
DISEASE
U-BIOPRED Study Group
11 Medical And Health Sciences
Publication Status: Published
Article Number: ARTN 1602135
Appears in Collections:Faculty of Engineering
Computing
National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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