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Pathway discovery using transcriptomic profiles in adult-onset severe asthma

: Hekking, Pieter-Paul; Loza, Matt J.; Pavlidis, Stelios; Meulder, Bertrand de; Lefaudeux, Diane; Baribaud, Fred; Auffray, Charles; Wagener, Ariane H.; Brinkman, Paul; Lutter, René; 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; Djukanović, Ratko; Sterk, Peter J.


The journal of allergy and clinical immunology : JACI 141 (2018), Nr.4, S.1280-1290
ISSN: 0091-6749
ISSN: 1097-6825
ISSN: 1085-8725
Fraunhofer ITEM ()
adult-onset asthma; Severe asthma; gene set variation analysis; phenotyping; transcriptomics; mechanism; Eosinophil; mast cell; ILC3

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.