Effect of ADRB2 Polymorphisms on Response to Longacting β2-Agonist Therapy: A Pharmacogenetic Analysis of Two Randomised Studies
Authors: Simons Elinor 
Published: October 2008

Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Lancet. 2007;370(9605):2118–2125

PURPOSE OF THE STUDY. To determine if polymorphisms at amino acid 16 of the β2-adrenergic receptor (ADRB2) affect response to long-acting β2-agonists in combination with inhaled corticosteroids (ICSs).

STUDY POPULATION. The study included individuals at least 12 years old (2225 in study 1 and 405 in study 2) who had asthma for at least 6 months and used ICSs.

METHODS. In study 1, individuals with at least 12% reversibility of their forced expiratory volume in 1 second received 6 months of double-blind treatment with budesonide plus formoterol for maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol. The primary outcome was the time to first severe asthma exacerbation. In study 2, participants received 7 months of open-label treatment with an adjustable regimen of budesonide plus formoterol, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol. Primary outcomes included the number of asthma exacerbations, time to first exacerbation, and percentage of participants with at least 1 exacerbation. Participants were stratified according to ADRB2 genotype, and the relation between genotype and asthma outcome was determined.

RESULTS. Baseline characteristics were similar among all Gly16Arg genotypes, and the genotypes were equally distributed across treatment groups. A combination of the 3 treatment groups showed a similar likelihood of having &gt;1 severe asthma exacerbation for each genotype in study 1 (Gly/Gly, 12%; Gly/Arg, 11%; and Arg/Arg, 9%) and study 2 (Gly/Gly, 9%; Gly/Arg, 8%; and Arg/Arg, 9%). The time to first exacerbation was similar among genotype groups (study 1 P = .31, study 2 P = .94). In study 1, there was no interaction among treatment group, genotype, and time to first severe exacerbation (P = .88). Improvement of morning peak expiratory flow and other secondary end points was similar for all genotypes in both studies. In study 2, differences in response according to genotype were not seen between participants with and without baseline reversibility of forced expiratory volume in 1 second.

CONCLUSIONS. Individuals with asthma may continue to receive ICSs plus long-acting bronchodilators regardless of their Gly16Arg genotype.

REVIEWER COMMENTS. Study results have varied regarding the effectiveness of long-acting β2-agonists, with or without the concomitant use of ICSs, in individuals with the Arg/Arg genotype relative to the Gly/Gly genotype. This large and long-term randomized study, including participants taking different long-acting β2-agonists, adds to the evidence suggesting that combination ICS/long-acting bronchodilator therapy may be equally effective in people with the Arg/Arg genotype. Given the overall effectiveness and prevalence of ICS/long-acting bronchodilator use and the increasing focus on individualization of asthma management, responses of subgroups of people with asthma to these medications will continue to be an important area of research.