Genome-wide association study of asthma exacerbations despite inhaled corticosteroids use

Hernandez-Pacheco, Natalia, Vijverberg, Susanne J, Herrera-Luis, Esther, Li, Jiang, Sio, Yang Yie, Granell, Raquel, Corrales, Almudena, Maroteau, Cyrielle, Lethem, Ryan, Perez-Garcia, Javier, Farzan, Niloufar, Repnik, Katja, Gorenjak, Mario, Soares, Patricia, Mukhopadhyay, Somnath, PiCA and SysPharmPedia consortia, and others, (2021) Genome-wide association study of asthma exacerbations despite inhaled corticosteroids use. European Respiratory Journal, 57 (1). pp. 1-93. ISSN 0903-1936

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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 European-descent children 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 Ten 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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 17 Nov 2020 10:16
Last Modified: 08 Feb 2021 09:20
URI: http://sro.sussex.ac.uk/id/eprint/95118

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