Hernandez-Pacheco, Natalia and Vijverberg, Susanne J. and Herrera-Luis, Esther and Li, Jiang and Sio, Yang Yie and Granell, Raquel and Corrales, Almudena and Maroteau, Cyrielle and Lethem, Ryan and Perez-Garcia, Javier and Farzan, Niloufar and Repnik, Katja and Gorenjak, Mario and Soares, Patricia and Karimi, Leila and Schieck, Maximilian and Perez-Mendez, Lina and Berce, Vojko and Tavendale, Roger and Eng, Celeste and Sardon, Olaia and Kull, Inger and Mukhopadhyay, Somnath and Pirmohamed, Munir and Verhamme, Katia M. C. and Burchard, Esteban G. and Kabesch, Michael and Hawcutt, Daniel B. and Melen, Erik and Potocnik, Uros and Chew, Fook Tim and Tantisira, Kelan G. and Turner, Steve and Palmer, Colin N. and Flores, Carlos and Pino-Yanes, Maria and Maitland-van der Zee, Anke H. (2021) Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use. EUROPEAN RESPIRATORY JOURNAL, 57 (5): 2003388. ISSN 0903-1936, 1399-3003
Full text not available from this repository. (Request a copy)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 x 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 |
|---|---|
| Uncontrolled Keywords: | DEACETYLASE INHIBITOR TRICHOSTATIN; CHILDHOOD; VARIANTS; WNT; PHARMACOGENOMICS; INFLAMMATION; GENES; EOSINOPHILS; EXPRESSION; RESPONSES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2022 08:43 |
| Last Modified: | 04 Oct 2022 08:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48207 |
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