Pathway discovery using transcriptomic profiles in adult-onset severe asthma - 05/04/18
, Matt J. Loza, PhD b, Stelios Pavlidis, PhD c, Bertrand de Meulder, PhD d, Diane Lefaudeux d, Fred Baribaud, PhD b, Charles Auffray, PhD d, Ariane H. Wagener, MD, PhD a, Paul Brinkman a, Rene Lutter, PhD a, Aruna T. Bansal, PhD e, Ana R. Sousa, PhD f, Steve A. Bates, PhD f, Yannis Pandis, PhD c, Louise J. Fleming, MD, PhD c, Dominique E. Shaw, MD, PhD g, Stephen J. Fowler, PhD h, Y. Guo, PhD c, Andrea Meiser, PhD c, Kai Sun, PhD c, Julie Corfield, PhD i, Peter H. Howarth, MD, PhD j, Elisabeth H. Bel, MD, PhD a, Ian M. Adcock, PhD k, Kian Fan Chung, MD, PhD k, Ratko Djukanovic, MD, PhD j, Peter J. Sterk, MD, PhD aand the
U-BIOPRED Study Group∗
Abstract |
Background |
Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples.
Objective |
We sought to identify gene profiles associated with adult-onset severe asthma.
Methods |
This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n = 83), nasal brushings (n = 41), and endobronchial brushings (n = 65) and biopsies (n = 47) (Affymetrix HT HG-U133+ PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways.
Results |
Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma.
Conclusions |
Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Adult-onset asthma, severe asthma, gene set variation analysis, phenotyping, transcriptomics, mechanisms, eosinophils, mast cells, ILC3
Abbreviations used : dES, ES, GSVA, ILC3
Plan
| U-BIOPRED was funded by a grant from the Innovative Medicines Initiative that was covered by the European Union and the European Federation of Pharmaceutical Industries and Associations. |
|
| Disclosure of potential conflict of interest: P.-P. Hekking, S. Pavlidis, B. de Meulder, D. Lefaudeux, C. Auffrey, A. H. Wagener, R. Lutter, A. T. Bansal, Y. Pandis, S. J. Fowler, J. Corfield, and P. J. Sterk receive grant support from Innovative Medicines Initiatives. M. J. Loza is an employee of Janssen R&D and holds stock options with Johnson & Johnson. F. Baribaud is an employee of Janssen R&D. S. A. Bates is an employee of GSK and holds stock options with GSK. L. J. Fleming receives grant support from Innovative Medicines Initiatives; serves as a consultant for Vectura and Boehringer Ingelheim; and received payment for lectures from Novartis. D. E. Shaw serves as a consultant for GSK and receives grant support from GSK and travel support from TEVA and Astra Zeneca. P. H. Howarth receives grant support from Innovative Medicines Initiatives; serves as a board member for Roche, Boehringer Ingelheim, and Novartis; is an employee of GSK; receives payment for lectures from Novartis and GSK; and holds stock options of GSK. E. H. Bel serves as a consultant for Sanofi, Novartis, Astra Zeneca, TEVA, GSK, Vectura, and Boehringer Ingelheim and receives grant support from GSK, AstraZeneca, Roche, and Novartis. I. M. Adcock receives grant support from Innovative Medicines Initiatives, MRC, BHF, and Dunhill Medical Trust and receives personal fees from Chiesi, GSK, Boehringer Ingelheim, Vectura, and Aztra Zeneca. K. F. Chung serves on the board for GSK, AstraZeneca, Novartis, TEVA, Boeringher Ingelheim, and Johnson & Johnson; receives grant support from Pfizer, GSK, MRC, Innovative Medicines Initiatives, and the National Institutes of Health; and receives payment for lectures from Aztra Zeneca and Merck. R. Djukanovic receives grant support from Innovative Medicines Initiatives and payment for lectures from TEVA and Novartis and holds stock options with Synairgen. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 4
P. 1280-1290 - avril 2018 Retour au numéro
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