Childhood Asthma Exacerbations and the Arg16 β2-receptor Polymorphism: A Meta-Analysis Stratified by Treatment

J Allergy Clin Immunol. 2016 Jul;138(1):107-113.e5. doi: 10.1016/j.jaci.2015.10.045. Epub 2016 Jan 7.

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.

Keywords: Adrenergic receptors; asthma; child; disease exacerbation; therapeutics.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adrenergic beta-2 Receptor Agonists / therapeutic use
  • Alleles
  • Anti-Asthmatic Agents / therapeutic use
  • Arginine / chemistry
  • Arginine / genetics*
  • Asthma / diagnosis*
  • Asthma / drug therapy
  • Asthma / epidemiology
  • Asthma / genetics*
  • Child
  • Child, Preschool
  • Codon*
  • Cross-Sectional Studies
  • Disease Progression
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Leukotriene Antagonists / therapeutic use
  • Male
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Receptors, Adrenergic, beta-2 / chemistry
  • Receptors, Adrenergic, beta-2 / genetics*
  • Risk Factors

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Anti-Asthmatic Agents
  • Codon
  • Leukotriene Antagonists
  • Receptors, Adrenergic, beta-2
  • Arginine