T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED.
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 receptorsIL33R,CCR3andTSLPR), 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.
Airways Disease, National Heart and Lung Institute, Imperial College London, London, UK.|Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK.|Dept of Computing and Data Science Institute, Imperial College London, London, UK.
Chih-Hsi Scott
CS
Kuo
Janssen R&D, High Wycombe, UK.
Stelios
S
Pavlidis
Janssen R&D, High Wycombe, UK.
Matthew
M
Loza
Janssen R&D, High Wycombe, UK.
Fred
F
Baribaud
Janssen R&D, High Wycombe, UK.
Anthony
A
Rowe
Dept of Computing and Data Science Institute, Imperial College London, London, UK.
Iaonnis
I
Pandis
Respiratory Therapeutic Unit, GSK, Stockley Park, UK.
Ana
A
Sousa
AstraZeneca R&D, Mölndal, Sweden.|Areteva R&D, Nottingham, UK.
Julie
J
Corfield
Faculty of Medicine, Southampton University, Southampton, UK.
Ratko
R
Djukanovic
Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands.
Rene
R
Lutter
Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands.
Peter J
PJ
Sterk
Faculty of Medicine, Southampton University, Southampton, UK.|European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France.
Charles
C
Auffray
Dept of Computing and Data Science Institute, Imperial College London, London, UK.
Yike
Y
Guo
Airways Disease, National Heart and Lung Institute, Imperial College London, London, UK.|Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK.|These authors contributed equally to this work.
Ian M
IM
Adcock
Airways Disease, National Heart and Lung Institute, Imperial College London, London, UK f.chung@imperial.ac.uk.|Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK.|These authors contributed equally to this work.
Kian Fan
KF
Chung
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D015415:Biomarkers; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D004804:Eosinophils / Q000276:immunology*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D010641:Phenotype; D013183:Sputum; D018418:Th2 Cells / Q000276:immunology*; D059467:Transcriptome; D006113:United Kingdom
D000305:Adrenal Cortex Hormones; D015415:Biomarkers; D018793:Interleukin-13; D009569:Nitric Oxide; D002097:C-Reactive Protein