Effect of β2-Adrenergic Receptor Polymorphism on Response to Longacting β2 Agonist in Asthma (LARGE Trial): A Genotype-Stratified, Randomised, Placebo-Controlled, Crossover Trial

Abstract

Background Combined long-acting β2-agonist and inhaled corticosteroid (LABA/ICS) therapy improves outcomes in many asthmatics. Some studies suggest that patients homozygous for arginine at the 16th amino-acid position of the β2 adrenergic receptor (B16 Arg/Arg) benefit less than those with B16 Gly/Gly.

Methods In an NIH-funded, B16 genotype-stratified, prospective, randomized, double-blind, placebo-controlled, cross-over trial (www.ClinicalTrials.gov registration ID NCT00200967), we compared adding salmeterol or placebo to ICS in patients with moderate asthma, using AM PEF as the primary outcome.

Findings After 18 weeks, Arg/Arg (n=42) and Gly/Gly (n=45) subjects had greater AM PEF with salmeterol than placebo, with no difference in improvement by genotype (Arg/Arg 21.4 (p<0.0001) vs. Gly/Gly 21.5 L/min (p<0.0001); 0.1 L/min difference between genotypes, 95% CI (−14.2, 14.4), p=0.99). In Gly/Gly subjects, methacholine PC20 (a secondary outcome) doubled when salmeterol was added to ICS (p<0.0001), but remained unchanged in Arg/Arg subjects (p=0.87) (1.32 doubling dose difference between genotypes (95%CI 0.43,2.21), p=0.0038). An exploratory posthoc subset analysis of African Americans showed that salmeterol improved the AM and PM PEF for the 8 Gly/Gly subjects (29 L/min, p=0.013 and 45 L/min, p= 0.0005, respectively) but not for the 9 Arg/Arg subjects (−12 L/min, p=0.57 and−2.2 L/min, p=0.92, respectively).

Interpretation B16 Arg/Arg and Gly/Gly patients experience improved airway function with salmeterol added to moderate-dose ICS. While these data provide reassurance that in the general population these polymorphisms should not alter the use of LABA with moderate-dose ICS, the significance of the genotype-differentiated response in airway reactivity favoring Gly/Gly subjects and the post-hoc analysis in African Americans require further investigation.