Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.

Abstract

RATIONALE:

Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.

METHODS:

A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.

RESULTS:

10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10-6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.

CONCLUSIONS:

The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.

• Authors: Natalia Hernandez-Pacheco, Susanne J Vijverberg, Esther Herrera-Luis, Jiang Li, Yang Yie Sio, Raquel Granell, Almudena Corrales, Cyrielle Maroteau, Ryan Lethem, Javier Perez-Garcia, Niloufar Farzan, Katja Repnik, Mario Gorenjak, Patricia Soares, Leila Karimi, Maximilian Schieck, Lina Pérez-Méndez, Vojko Berce, Roger Tavendale, Celeste Eng, Olaia Sardon, Inger Kull, Somnath Mukhopadhyay, Munir Pirmohamed, Katia M C Verhamme, Esteban G Burchard, Michael Kabesch, Daniel B Hawcutt, Erik Melén, Uroš Potočnik, Fook Tim Chew, Kelan G Tantisira, Steve Turner, Colin N Palmer, Carlos Flores, Maria Pino-Yanes, Anke H Maitland-van der Zee, PiCA and SysPharmPedia consortia
• Journal: The European respiratory journal (Eur Respir J) Vol. 57 Issue 5 (05 2021) ISSN: 1399-3003 [Electronic] England
• PMID: 33303529 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2021.

Chemical References

• Adrenal Cortex Hormones
• Anti-Asthmatic Agents

Topics

• Administration, Inhalation
• Adrenal Cortex Hormones (therapeutic use)
• Anti-Asthmatic Agents (therapeutic use)
• Asthma (drug therapy)
• Child
• Genome-Wide Association Study
• Humans
• Young Adult