Refractory neutrophilic asthma and ciliary genes - 03/06/22
, Laurie A. Manka, MD a, b, Camille M. Moore, PhD c, Elizabeth Wynn, MS e, Eszter K. Vladar, PhD f, Rafeul Alam, MD, PhD b, d, Tuyet-Hang Pham, MT, MS g, Tasha E. Fingerlin, PhD c, e, Richard J. Martin, MD a, bAbstract |
Background |
Refractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear.
Objective |
We sought to characterize and clinically correlate gene expression differences between refractory and nonrefractory (NR) asthma to uncover molecular mechanisms driving group distinctions.
Methods |
Microarray gene expression of paired airway epithelial brush and endobronchial biopsy samples was compared between 60 RA and 30 NR subjects. Subjects were hierarchically clustered to identify subgroups of RA, and biochemical and clinical traits (airway inflammatory molecules, respiratory pathogens, chest imaging) were compared between groups. Weighted gene correlation network analysis was used to identify coexpressed gene modules. Module expression scores were compared between groups using linear regression, controlling for age, sex, and body mass index.
Results |
Differential gene expression analysis showed upregulation of proneutrophilic and downregulation of ciliary function genes/pathways in RA compared to NR. A subgroup of RA with downregulated ciliary gene expression had increased levels of subclinical infections, airway neutrophilia, and eosinophilia as well as higher chest imaging mucus burden compared to other RA, the dominant differences between RA and NR. Weighted gene correlation network analysis identified gene modules related to ciliary function, which were downregulated in RA and were associated with lower pulmonary function and higher airway wall thickness/inflammation, markers of poorer asthma control.
Conclusions |
Identification of a novel ciliary-deficient subgroup of RA suggests that diminished mucociliary clearance may underlie repeated asthma exacerbations despite adequate treatment, necessitating further exploration of function, mechanism, and therapeutics.
Le texte complet de cet article est disponible en PDF.Key words : Refractory asthma, neutrophilic asthma, ciliary gene expression, asthma pathogenesis
Abbreviations used : BAL, BMI, C, CDRA, CT, DEG, GO, ICS, NR, OCS, RA, SBI, SBL, T2, WGCNA
Plan
| The first 3 authors contributed equally to this article, and all should be considered first author. |
|
| Supported by the Cohen Family Asthma Institute, Epstein Family Chair, and AstraZeneca. AstraZeneca assisted in initial sample collection and genetic analysis. |
|
| Disclosure of potential conflict of interest: R. J. Martin and institution have received a grant from MedImmune, and R. J. Martin has personally received consultancy fees from AstraZeneca and Merck. V. P. Guntur has participated in advisory board for AstraZeneca. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 6
P. 1970-1980 - juin 2022 Retour au numéro
Article précédent
- Ascaris exposure and its association with lung function, asthma, and DNA methylation in Northern Europe
- Nils O. Jõgi, Negusse Kitaba, Torgeir Storaas, Vivi Schlünssen, Kai Triebner, John W. Holloway, William G.C. Horsnell, Cecilie Svanes, Randi J. Bertelsen
- Multiomics analysis identifies BIRC3 as a novel glucocorticoid response–associated gene
- Mengyuan Kan, Avantika R. Diwadkar, Haoyue Shuai, Jaehyun Joo, Alberta L. Wang, Mei-Sing Ong, Joanne E. Sordillo, Carlos Iribarren, Meng X. Lu, Natalia Hernandez-Pacheco, Javier Perez-Garcia, Mario Gorenjak, Uroš Potočnik, Esteban G. Burchard, Maria Pino-Yanes, Ann Chen Wu, Blanca E. Himes
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?