β 2-Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy

Abstract

The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with short- and long-acting beta2-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 microg once daily, 6 microg twice daily or 24 microg twice daily) or terbutaline (500 microg 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 beta2-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 first- versus last-dose bronchoprotection was calculated and analysed according to effects of treatment and beta2-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 microg of methacholine, geometric means+/-S. E.M.): formoterol, 12 microg once daily, 99+/-42 microg; formoterol, 6 microg twice daily, 107+/-44 microg; formoterol, 24 microg twice daily, 108+/-45 microg; terbutaline, 500 microg four times daily, 88+/-37 microg. All patients receiving formoterol, 24 microg 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 microg once daily or 6 microg 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 (mean+/-S.E.M.) for percentage desensitization according to each genotype (pooled treatments): Gly-16, 66+/-11%; Het-16, 53+/-8%; Arg-16, 69+/-18%; Glu-27, 68+/-12%; Het-27, 58+/-8%; Gln-27, 52+/-12%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to short- or long-acting beta2-agonist exposure irrespective of beta2-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.

Pharmacogenetics of Beta-1- and Beta-2-Adrenergic Receptors

“…Plasma albuterol concentrations were identified between the two groups. Several studies, though, have failed to reveal any relationship between the ß 2 AR polymorphisms at position 16 and 27 and the acute response to ß-agonists [26][27][28]. The designs (including the choice of ß-agonist) were quite different in these studies, and this may explain the discrepancies.…”

“…The small sample size in the Arg16 homogeneous group and the extensive variability within each group raised some concern that a more comprehensive study is needed. Indeed, a subsequent study by some of the investigators in the Tan et al [29] study revealed no effect of ß 2 AR genotype at positions 16 or 27 on tachyphylaxis to the bronchoprotective effect of formoterol and terbutaline [27]. We recently published a study [30] that utilized data from an albuterol tachyphylaxis collaborative study [31] originally designed to evaluate effects of regular vs as needed use of albuterol on asthma outcome in mild asthmatics.…”

Complex promoter and coding region β 2 -adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness

“…Indeed, some studies have shown that an individual ␤ 2 AR SNP correlates with the bronchodilatory response to ␤ agonists (12)(13)(14) or the extent of tachyphylaxis to repeated use of these agents (15,16). Other studies, although, have failed to show any such correlations (17) or have shown discordant results (15,16).…”

Autonomic Nervous System Pharmacogenomics: A Progress Report

“…Overall, the data suggest that ␤ 2 -AR polymorphisms, especially Arg16Gly, may play a role in airway hyperresponsiveness, bronchodilator sensitivity and response to ␤-agonist, long-term use of ␤-agonist, and tolerance (Table 11) Martinez et al, 1997;Tan et al, 1997;D'Amato et al, 1998;Kotani et al, 1999;Fowler et al, 2000;Israel et al, 2000;Lima et al, 2000;Taylor et al, 2000a). Future studies will need to identify individuals at risk for the development of asthma in addition to patient populations that are likely or unlikely to respond to treatment or experience adverse side effects (Silver- Albuterol-evoked FEV 1 was higher and more rapid in Arg16 homozygotes vs. Gly16 carriers Lima et al, 1999 Arg16Gly Lower airway responsiveness to salbutamol in Gly16 vs. Arg16 homozygotes or Arg16Gly heterozygotes Kotani et al, 1999 Arg16Gly, Gln27Glu No association between genotype and desensitization to short-or long-acting ␤ 2 -agonists (formoterol vs. terbutaline) Lipworth et al, 1999a Arg16Gly Poor FEV 1 vs. albuterol concentration relationship associated with Gly16 Lima et al, 2000 Arg16Gly No association between functional antagonism of methacholine-induced bronchoconstriction with formoterol or salmeterol and genotype Lipworth et al, 2000 Arg16Gly Decline in peak expiratory flow with regular albuterol use in Arg16 vs. Gly16 homozygotes Israel et al, 2000 Arg16Gly No association between tolerance to regular salmeterol and genotype Taylor et al, 2000b Arg16Gly More frequent exacerbations during salbutamol treatment of Arg16 vs. Gly16 homozygotes or Arg16Gly heterozygotes Taylor et al, 2000a Haplotype pairs Albuterol-evoked FEV 1 improvement related to haplotype pairs (i.e., Arg19Cys (Ϫ47), Arg16Gly, Gln27Glu) Drysdale et al, 2000 FEV 1 , forced expiratory volume in 1 s.…”