TY - JOUR
T1 - Genome-wide association studies of exacerbations in children using long-acting beta2-agonists
AU - Slob, Elise M. A.
AU - Richards, Levi B.
AU - Vijverberg, Susanne J. H.
AU - Longo, Cristina
AU - Koppelman, Gerard H.
AU - Pijnenburg, Mariëlle W. H.
AU - Bel, Elisabeth H. D.
AU - Neerincx, Anne H.
AU - Herrera Luis, Esther
AU - Perez-Garcia, Javier
AU - Chew, Fook Tim
AU - Sio, Yang Yie
AU - Andiappan, Anand K.
AU - Turner, Steve W.
AU - Mukhopadhyay, Somnath
AU - Palmer, Colin N. A.
AU - Hawcutt, Daniel
AU - Jorgensen, Andrea L.
AU - Burchard, Esteban G.
AU - Hernandez-Pacheco, Natalia
AU - Pino-Yanes, Maria
AU - Maitland-van der Zee, Anke H.
N1 - Funding Information:
EMA Slob, SJH Vijverberg, AH Maitland-van der Zee, GH Koppelman and MW Pijnenburg are conducting the PUFFIN trial that is supported by the Lung Foundation Netherlands, grant number 5.1.16.094. The PACMAN cohort study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The Genes-environments and Admixture in Latino Americans (GALA II) Study and the Study of African Americans, Asthma, Genes and Environments (SAGE) were supported in part by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung and Blood Institute of the National Institutes of Health R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL141992 and R01HL141845, National Institute of Health and Environmental Health Sciences R01ES015794 and R21ES24844, the National Institute on Minority Health and Health Disparities P60MD006902, RL5GM118984, R01MD010443 and R56MD013312, the Tobacco-Related Disease Research Program under Award Number 24RT-0025 and 27IR-0030 and the National Human Genome Research Institute U01HG009080. MP-Y was funded by the Ram?n y Cajal Program by the Spanish Ministry of Science, Innovation and Universities (MICIU) (RYC-2015-17205) and by a grant by MICIU, the State Research Agency and the European Regional Development Fund from the European Union (MINECO/AEI/FEDER, UE, SAF2017-83417R). Esther Herrera-Luis was supported by a MICIU fellowship (PRE2018-083837). Natalia Hernandez-Pacheco was supported by a fellowship (FI16/00136) from ISCIII and co-funded by the European Social Fund from the European Union (ESF) ?ESF invests in your future.?
Publisher Copyright:
© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
PY - 2021/8
Y1 - 2021/8
N2 - 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 associated 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 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10
−6) associated with exacerbations despite LABA use. Conclusion: No strong effects of single nucleotide polymorphisms (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.
AB - 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 associated 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 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10
−6) associated with exacerbations despite LABA use. Conclusion: No strong effects of single nucleotide polymorphisms (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.
KW - childhood asthma
KW - exacerbations
KW - genetic polymorphism
KW - long-acting beta2-agonist
KW - pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=85103199581&partnerID=8YFLogxK
U2 - 10.1111/pai.13494
DO - 10.1111/pai.13494
M3 - Article
C2 - 33706416
SN - 0905-6157
VL - 32
SP - 1197
EP - 1207
JO - Pediatric Allergy and Immunology
JF - Pediatric Allergy and Immunology
IS - 6
ER -