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.
Clustering of transcriptomic genes from sputum cells defined one Th2- and two non-Th2-associated phenotypes http://ow.ly/UEkA3069ZYL
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Support statement: The U-BIOPRED consortium receives funding from the European Union and from the European Federation of Pharmaceutical Industries and Associations as an Innovative Medicines Initiative Joint Undertaking funded project (115010) on behalf of the U-BIOPRED Study Group with input from the U-BIOPRED Patient Input Platform and patient representatives from the Ethics Board and Safety Management Board. C-H.S. Kuo is supported by the Dept of Thoracic Medicine, Linkou Chang-Gung Memorial Hospital through a grant from Chang-Gung Medical Foundation, Taoyuan, Taiwan. This project was also supported by the National Institute for Health Research Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. K.F. Chung is a Senior Investigator of the UK National Institute for Health Research. Funding information for this article has been deposited with the Open Funder Registry.
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received November 1, 2016.
- Accepted November 3, 2016.
- Copyright ©ERS 2017