ArticlesEffect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial
Introduction
Combination therapy with longacting β2 agonists and inhaled corticosteroids is one of the most widely prescribed treatments for the control of asthma in the world. Some studies suggest that, on average, this combination improves lung function and asthma control;1 others suggest that a subpopulation of patients with asthma could be at risk for severe exacerbations or death with use of longacting β2 agonists.2, 3
β2 agonists act primarily at the β2-adrenergic receptor (ADRB2). A common single nucleotide polymorphism in the coding region of ADRB2 codes for arginine instead of glycine at the 16th aminoacid of the receptor (allele frequency 0·4 in white people4). In retrospective and prospective studies in patients with asthma not taking inhaled corticosteroids, regular use of shortacting β2 agonists, such as salbutamol (albuterol), was associated with lower lung function in individuals homozygous for arginine at the 16th aminoacid position (B16 Arg/Arg) than in individuals homozygous for glycine at that position (B16 Gly/Gly).5, 6 Another study showed increased risk of exacerbations with regular use of salbutamol but not salmeterol in patients with the B16 Arg/Arg genotype.7
In view of these genotype-specific findings, we undertook a genotype-stratified retrospective analysis of patients with asthma who had participated in randomised trials of the longacting β2 agonist salmeterol.8 Patients with the B16 Arg/Arg genotype did not benefit from treatment with salmeterol, even when used with a concomitant inhaled corticosteroid. We have therefore examined prospectively whether there is a genotype-specific difference in the response to longacting β2 agonists, by undertaking a randomised controlled trial that compared the effects of salmeterol plus inhaled corticosteroid with inhaled corticosteroid alone in B16 Arg/Arg patients with asthma versus B16 Gly/Gly patients with asthma.
Section snippets
Participants
Seven centres recruited participants for the LARGE trial. Patients with asthma were recruited from the clinical practices of each study site and through community advertising by use of a variety of media. After patients had given written informed consent (approved by participating site institutional review boards), their medical history was reviewed (eg, medication use and history of asthma exacerbations) and they were screened for eligibility on the basis of the inclusion and exclusion
Results
Figure 2 shows the trial profile. Between 2004 and 2006, 474 patients were screened for the trial. The B16 alleles were in Hardy–Weinberg equilibrium (p=0·95) in this population. 244 patients had eligible genotypes. Several of these patients (Arg/Arg, n=9; Gly/Gly, n=42) withdrew consent after screening because no appropriate match was identified and they no longer wanted to participate in the pre-match protocol. 42 participants with the B16 Arg/Arg genotype and 45 with the B16 Gly/Gly genotype
Discussion
Over the past decade, several studies have investigated the effect of specific mutations of the β-adrenergic receptor gene on response to β2 agonists.6, 7 A previous retrospective analysis of ACRN trials suggested that individuals with the ADRB2 B16 Arg/Arg genotype might not benefit from treatment with longacting β2 agonists, with or without inhaled corticosteroids.8 However, in this prospective, randomised controlled trial, the addition of a longacting β2 agonist to inhaled corticosteroid for
References (26)
- et al.
The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol
Chest
(2006) - et al.
Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial
Lancet
(2004) - et al.
Arg16Gly polymorphism of the [beta]2-adrenergic receptor gene does not modulate cinical response to salmeterol in subjects with asthma
J Allergy Clin Immunol
(2008) - et al.
Effect of ADRB2 polymorphisms on response to longacting β2-agonist therapy: a pharmacogenetic analysis of two randomised studies
Lancet
(2007) - et al.
Effects of treatment with formoterol on bronchoprotection against methacholine
Am J Med
(1998) - et al.
Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group
N Engl J Med
(1997) - et al.
Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment
BMJ
(1993) - et al.
Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study
Am J Respir Crit Care Med
(2006) - et al.
The effect of polymorphisms of the beta2-adrenergic receptor on the response to regular use of albuterol in asthma
Am J Respir Crit Care Med
(2000) - et al.
Asthma exacerbations during long term beta-agonist use: influence of beta2 adrenoceptor polymorphism
Thorax
(2000)
Beta-adrenergic receptor polymorphisms and response to salmeterol
Am J Respir Crit Care Med
Comparison of regularly scheduled with as-needed use of albuterol in mild asthma
N Engl J Med
Long-acting β2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial
JAMA
Cited by (204)
Optimizing asthma management: Role of long-acting muscarinic antagonists
2022, Journal of Allergy and Clinical ImmunologyUncovering Outcome Disparities of β<inf>2</inf> Adrenergic Agonists in Blacks: A Systematic Review
2021, Journal of the National Medical AssociationCitation Excerpt :Blacks tended to have higher hospital admission rates than Whites in both the formoterol (1.57% vs 0.65%) and the non-LABA treated (2.63% vs. 0.67%) groups. In addition to these subgroup effects by race and ethnicity, we identified four papers exploring effects of interaction between genomic variation and race on response to β2 adrenergic agonists in asthma, including one meta-analysis,29 one cross-sectional study,12 one secondary analysis of randomized controlled trial (RCT) data,30 and one genome-wide association study (GWAS)31 (Table 3). One paper analyzed race by both self-report category (including biologic parents and grandparents) and ancestry informative markers,12 one defined race by participant report that included both biologic parents and all four biologic grandparents,31 and the other two papers did not provide operational definitions for race and ethnicity categories.29,30
Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials
2019, Journal of Allergy and Clinical ImmunologyNovel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity
2019, Pharmacology and TherapeuticsCitation Excerpt :Genetic variability in ADRB2, the gene encoding the β2-adrenergic receptor, has long been considered as a promising biomarker to predict the response to β-agonists in the management of asthma (Kersten & Koppelman, 2017; Ortega & Meyers, 2014). However, results of different trials were conflicting and could, if at all, only explain a minor fraction of the observed variability in drug response (Israel et al., 2004; Wechsler et al., 2009; Wechsler et al., 2015). Thus, the implementation of genotype-guided therapies for asthma utilizing β2-adrenergic receptor variants in the near future appears unlikely.
Genetic underpinnings of asthma and related traits
2019, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders45 - Wheezing in Older Children: Asthma
2019, Kendig's Disorders of the Respiratory Tract in Children
- ‡
For other study contributors see end of paper