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
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