PT - JOURNAL ARTICLE AU - Natalia Hernandez-Pacheco AU - Susanne J. Vijverberg AU - Esther Herrera-Luis AU - Jiang Li AU - Yang Yie Sio AU - Raquel Granell AU - Almudena Corrales AU - Cyrielle Maroteau AU - Ryan Lethem AU - Javier Perez-Garcia AU - Niloufar Farzan AU - Katja Repnik AU - Mario Gorenjak AU - Patricia Soares AU - Leila Karimi AU - Maximilian Schieck AU - Lina Pérez-Méndez AU - Vojko Berce AU - Roger Tavendale AU - Celeste Eng AU - Olaia Sardon AU - Inger Kull AU - Somnath Mukhopadhyay AU - Munir Pirmohamed AU - Katia M.C. Verhamme AU - Esteban G. Burchard AU - Michael Kabesch AU - Daniel B. Hawcutt AU - Erik Melén AU - Uroš Potočnik AU - Fook Tim Chew AU - Kelan G. Tantisira AU - Steve Turner AU - Colin N. Palmer AU - Carlos Flores AU - Maria Pino-Yanes AU - Anke H. Maitland-van der Zee ED - , TI - Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use AID - 10.1183/13993003.03388-2020 DP - 2021 May 01 TA - European Respiratory Journal PG - 2003388 VI - 57 IP - 5 4099 - http://erj.ersjournals.com/content/57/5/2003388.short 4100 - http://erj.ersjournals.com/content/57/5/2003388.full SO - Eur Respir J2021 May 01; 57 AB - 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.A genome-wide association study of asthma exacerbations despite inhaled corticosteroid treatment in childhood asthma revealed a novel association at the CACNA2D3-WNT5A locus and suggested trichostatin A as a potential asthma therapy https://bit.ly/3nxWLPD