Polymorphism of the ADRB2 Gene and Response to Inhaled Beta- agonists in Children with Asthma: A Meta-analysis

Abstract

Background. About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the β₂-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the β₂-adrenergic receptor (β₂AR), induce resistance to the smooth-muscle relaxing effect of β₂-adrenergic agonists. Methods. We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled β₂-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined as ≥ 15% improvement in forced expiratory volume in 1 second (FEV₁) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the β₂AR. Individual and summary odds ratios were calculated using a random effects model. Results. We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative β₂-bronchodilator response, defined as < 15% improvement in FEV₁ and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled β₂-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the β₂AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the β₂AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to β₂-agonists and polymorphism at amino acid position 27 of the β₂AR (OR = 1.04; 95% CI [0.76,1.42]). Conclusions. Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the β₂-adrenergic receptor. Genetic typing for β₂AR polymorphism may help identify children with drug-resistant asthma.

Keywords :

• β₂-adrenergic receptor (β₂AR)
• polymorphism
• asthma
• meta-analysis
• children