Childhood asthma exacerbations and the Arg16 beta(2)-receptor polymorphism: A meta-analysis stratified by treatment

Background: The Gly-to-Arg substitution at the 16 position (rs1042713) in the beta(2)-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of beta(2)-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 beta-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 from4226 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 5 354) or ICSs plus LABAs plus LTRAs (n = 569). Conclusions: The use of a LABA but not an LTRA as an "addon 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