β2-Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy

The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with shortand long-acting β2-agonists and to evaluate any possible association with genetic polymorphism. Thirty-eight patients with stable mild to moderate asthma and receiving inhaled corticosteroids were randomized in a parallel group, double-blind, double-dummy fashion to receive 2 weeks of treatment with either formoterol (12 μg once daily, 6 μg twice daily or 24 μg twice daily) or terbutaline (500 μg four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expiratory volume in 1.0 s: PD20) was measured at baseline (unprotected) after an initial 1 week run-in without β2-agonist, and at 1 h after the first and last doses of each treatment. The PD20 values were log-transformed and calculated as change from baseline. Percentage desensitization of log PD20 for firstversus last-dose bronchoprotection was calculated and analysed according to effects of treatment and β2-adrenoceptor polymorphism at codon 16 or 27. The mean degree of desensitization for bronchoprotection was comparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values were (as μg of methacholine, geometric means3S.E.M.) : formoterol, 12 μg once daily, 99342 μg; formoterol, 6 μg twice daily, 107344 μg; formoterol, 24 μg twice daily, 108345 μg; terbutaline, 500 μg four times daily, 88337 μg. All patients receiving formoterol, 24 μg twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lower doses of formoterol (12 μg once daily or 6 μg twice daily) showed wider variability in the propensity for protection loss in patients who were heterozygous, in contrast to a more uniform protection loss seen with homozygous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean3S.E.M.) for percentage desensitization according to each genotype (pooled treatments) : Gly-16, 66311% ; Het-16, 5338% ; Arg-16, 69318% ; Glu-27, 68312% ; Het-27, 5838% ; Gln-27, 52312%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to shortor long-acting β2agonist exposure irrespective of β2-adrenoceptor polymorphism at codon 16 or 27. Further studies with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol.