Pathway discovery using transcriptomic profiles in adult-onset severe asthma

Hekking, Pieter-Paul; Loza, Matt J.; Pavlidis, Stelios; de Meulder, Bertrand; Lefaudeux, Diane; Baribaud, Fred; Auffray, Charles; Wagener, Ariane H.; Brinkman, Paul; Lutter, Rene; Bansal, Aruna T.; Sousa, Ana R.; Bates, Steve A.; Pandis, Yannis; Fleming, Louise J.; Shaw, Dominique E.; Fowler, Stephen J.; Guo, Y.; Meiser, Andrea; Sun, Kai; Corfield, Julie; Howarth, Peter H.; Bel, Elisabeth H.; Adcock, Ian M.; Chung, Kian Fan; Djukanovic, Ratko; Sterk, Peter J.

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 5 83), nasal brushings (n 5 41), and endobronchial brushings (n 5 65) and biopsies (n 5 47) (Affymetrix HT HG-U1331 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.

Citation

Hekking, P.-P., Loza, M. J., Pavlidis, S., de Meulder, B., Lefaudeux, D., Baribaud, F., Auffray, C., Wagener, A. H., Brinkman, P., Lutter, R., Bansal, A. T., Sousa, A. R., Bates, S. A., Pandis, Y., Fleming, L. J., Shaw, D. E., Fowler, S. J., Guo, Y., Meiser, A., Sun, K., …Sterk, P. J. (2018). Pathway discovery using transcriptomic profiles in adult-onset severe asthma. Journal of Allergy and Clinical Immunology, 141(4), 1280-1290. https://doi.org/10.1016/j.jaci.2017.06.037

• Journal Article Type: Article
• Acceptance Date: Jun 21, 2017
• Online Publication Date: Jul 26, 2017
• Publication Date: 2018-04
• Deposit Date: May 17, 2018
• Journal: Journal of Allergy and Clinical Immunology
• Print ISSN: 0091-6749
• Electronic ISSN: 1097-6825
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 141
• Issue: 4
• Pages: 1280-1290
• DOI: https://doi.org/10.1016/j.jaci.2017.06.037
• Keywords: Adult-onset asthma, severe asthma, gene set variation; analysis, phenotyping, transcriptomics, mechanisms, eosinophils, mast cells, ILC3
• Public URL: https://nottingham-repository.worktribe.com/output/929621
• Publisher URL: https://www.jacionline.org/article/S0091-6749(17)31195-8/abstract
• Contract Date: May 17, 2018