Genome-wide association studies of exacerbations in children using long-acting beta2-agonists

Elise M. A. Slob, Levi B. Richards, Susanne J. H. Vijverberg, Cristina Longo, Gerard H. Koppelman, Mariëlle W. H. Pijnenburg, Elisabeth H. D. Bel, Anne H. Neerincx, Esther Herrera Luis, Javier Perez-Garcia, Fook Tim Chew, Yang Yie Sio, Anand K. Andiappan, Steve W. Turner, Somnath Mukhopadhyay, Colin N. A. Palmer, Daniel Hawcutt, Andrea L. Jorgensen, Esteban G. Burchard, Natalia Hernandez-PachecoMaria Pino-Yanes, Anke H. Maitland-van der Zee

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Abstract

Background: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associate with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium.

Methods: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma.

Results: Genome-wide association results for a total of 82,996common SNPs (MAF ≥ 1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (p-value threshold ≤ 5x10-6 ) associated with exacerbations despite LABA use.

Conclusion: No strong effects of SNPs on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7), that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Original languageEnglish
Number of pages11
JournalPediatric Allergy and Immunology
Early online date11 Mar 2021
DOIs
Publication statusE-pub ahead of print - 11 Mar 2021

Keywords

  • childhood asthma
  • exacerbations
  • genetic polymorphism
  • long-acting beta2-agonist
  • pharmacogenetics

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