TY - JOUR
T1 - Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism
T2 - A meta-analysis stratified by treatment
AU - Turner, S.
AU - Francis, Ben
AU - Vijverberg, Susanne
AU - Pino-Yanes, Maria
AU - Maitland-van der Zee, Anke H.
AU - Basu, Kaninika
AU - Bignell, Lauren
AU - Mukhopadhyay, Somnath
AU - Tavendale, Roger
AU - Palmer, Colin
AU - Hawcutt, Daniel
AU - Pirmohamed, Munir
AU - Burchard, Esteban G.
AU - Lipworth, Brian
N1 - ndividual cohorts were funded as follows: BREATHE was funded by Scottish Enterprise Tayside, the Gannochy Trust, the Perth and Kinross City Council, and Brighton and Sussex Medical School. The contribution from GALA II to this work was supported by grants from the National Institutes of Health to E.G.B.: the National Heart, Lung, and Blood Institute (HL088133, HL078885, HL004464, HL104608, and HL117004); the National Institute of Environmental Health Sciences (ES015794); the National Institute on Minority Health and Health Disparities (MD006902); and the National Institute of General Medical Sciences (GM007546). E.G.B. was also funded by the American Asthma Foundation, the RWJF Amos Medical Faculty Development Award, the Sandler Foundation, and the Flight Attendant Medical Research Institute. M.P.-Y. was supported by a postdoctoral fellowship from Fundacion Ramon Areces (www.fundacionareces.es). PACMAN was funded by a strategic alliance between GlaxoSmithKline and the Utrecht Institute for Pharmaceutical Sciences. The Paediatric Asthma Gene Environment Study was funded by the Chief Scientist Officer for Scotland. The Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study was funded by the UK Department of Health through the NHS Chair of Pharmacogenomics.
PY - 2016/7
Y1 - 2016/7
N2 - Background: The Gly-to-Arg substitution at the 16 position (rs1042713) in the β2-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β2-receptors. Objectives: We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. Methods: Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined. Results: Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569).Conclusions: The use of a LABA but not an LTRA as an "add-on controller" is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children.
AB - Background: The Gly-to-Arg substitution at the 16 position (rs1042713) in the β2-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β2-receptors. Objectives: We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. Methods: Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined. Results: Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569).Conclusions: The use of a LABA but not an LTRA as an "add-on controller" is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children.
KW - Adrenergic receptors
KW - Asthma
KW - Child
KW - Disease exacerbation
KW - Therapeutics
UR - http://www.scopus.com/inward/record.url?scp=84953231094&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2015.10.045
DO - 10.1016/j.jaci.2015.10.045
M3 - Article
C2 - 26774659
AN - SCOPUS:84953231094
SN - 0091-6749
VL - 138
SP - 107
EP - 113
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -