Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use
Natalia Hernandez‐Pacheco, Susanne J. H. Vijverberg, Esther Herrera‐Luis, Jiang Li, Yang Yie Sio, Raquel Granell, Almudena Corrales, Cyrielle Maroteau, Ryan Lethem, Javier Pérez-García, Niloufar Farzan, Katja Repnik, Mario Gorenjak, Patrícia Soares, Leila Karimi, Maximilian Schieck, Lina Pérez‐Méndez, Vojko Berce, Roger Tavendale, Celeste Eng, Olaia Sardón‐Prado, Inger Kull, Somnath Mukhopadhyay, Munir Pirmohamed, Katia 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
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: 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: 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.