Steve Turner1, Ben Francis2, Susanne Vijverberg3, Maria Pino-Yanes4, Anke H Maitland-van der Zee3, Kaninika Basu5, Lauren Bignell5, Somnath Mukhopadhyay6, Roger Tavendale7, Colin Palmer7, Daniel Hawcutt8, Munir Pirmohamed9, Esteban G Burchard10, Brian Lipworth11. 1. Child Health, University of Aberdeen, Aberdeen, United Kingdom. Electronic address: s.w.turner@abdn.ac.uk. 2. Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom. 3. Division of Pharmacoepidemiology and Clinical Pharmacology, University of Utrecht, Utrecht, The Netherlands. 4. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain. 5. Academic Department of Paediatrics, Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, United Kingdom. 6. Academic Department of Paediatrics, Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, United Kingdom; Population Pharmacogenetics Group, University of Dundee, Dundee, United Kingdom. 7. Population Pharmacogenetics Group, University of Dundee, Dundee, United Kingdom. 8. Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. 9. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. 10. Department of Bioengineering and Therapeutic Sciences and Medicine, University of California, San Francisco, Calif; Center for Genes, Environment and Health, University of California, San Francisco, Calif. 11. Asthma and Allergy Research Group, University of Dundee, Dundee, United Kingdom.
Abstract
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.
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.
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