Polymorphism of the β2-adrenoceptor and the response to long-term β2-agonist therapy in asthma

In 1990 we reported a randomized controlled trial in which the administration of regular inhaled β2-agonist therapy was associated with a deterioration in asthma control in a majority of subjects when compared to as-required β-agonist treatment [1]. There were more asthma exacerbations, reductions in the forced expiratory volume in one second (FEV1) and morning peak expiratory flow rates (PEFRs) and increased bronchial responsiveness to methacholine during regular fenoterol therapy [2]. The mechanism responsible for the deterioration in asthma control during regular β-agonist therapy is unknown, but agonist-induced down-regulation of β2-adrenoceptor function is one possible explanation. In our study there was no evidence of loss of the acute bronchodilator response to β-agonist after prolonged therapy, suggesting that down-regulation of airway smooth muscle β2-receptors was not a significant problem [2]. However, tolerance to the nonbronchodilating properties of inhaled β2-agonists during regular treatment has been demonstrated in other studies [3–5]. It may be that down-regulation of β2receptors in other cells contributed to the overall deterioration in asthma control in our original study. Down regulation of the β2-adrenoceptor in vitro has been shown to be influenced by two common polymorphisms of the receptor gene which change the amino-acid sequence of the N-terminal domain of the receptor [6]. One results in the substitution of glycine (Gly) for arginine (Arg) at amino acid position 16 (Gly 16) of the receptor protein while the other results in the substitution of glutamic acid (Glu) for glutamine (Gln) at position 27 (Glu 27). In cell culture studies the Gly 16 variant of the receptor undergoes enhanced down-regulation during incubation with isoprenaline, whereas the Glu 27 variant is relatively resistant to down-regulation [7, 8]. Receptors with both Gly 16 and Glu 27 polymorphisms down-regulate to a similar extent to the Gly 16 variant alone [7]. Although these polymorphisms occur with similar frequency in asthmatics and nonasthmatics, among asthmatic patients they have been linked to certain clinical features. Gly 16 has been associated with an increased requirement for oral corticosteroids [6] and nocturnal asthma symptoms [9]. In contrast, Glu 27 has been associated with reduced bronchial responsiveness to methacholine [10]. Recently asthmatic patients homozygous for the Gly 16 polymorphism have been shown to undergo a greater loss of the bronchodilator response to β-agonist during treatment with formoterol. Subjects heterozygous for Arg 16/ Gly 16 showed intermediate desensitization [11]. There have been no reports on the influence of β2adrenoceptor polymorphism on changes in asthma control during prolonged β2-agonist therapy. We now report an analysis of the β2-adrenoceptor genotype in the subjects Polymorphism of the β2-adrenoceptor and the response to long-term β2-agonist therapy in asthma. R.J. Hancox, M.R. Sears, D.R. Taylor. ©ERS Journals Ltd 1998. ABSTRACT: Polymorphisms affecting amino acids 16 and 27 of the β2-adrenoceptor alter receptor regulation in vitro. Whether these polymorphisms alter the response to β2-agonist therapy in asthma is unknown. In a previous study of 64 asthmatics, most experienced a deterioration in asthma control during regular inhaled β2-agonist (fenoterol) treatment, while a minority improved. We have determined the β2-adrenoceptor genotypes in these subjects, to establish whether changes in asthma control during the earlier study were influenced by β2-adrenoceptor polymorphism. The genotypes coding for amino acids 16 and 27 were identified in 60 subjects using allele-specific polymerase chain reaction. The effects of regular β2-agonist treatment on asthma control were compared between genotypes. There was no association between genotype and change in overall asthma control during regular β2-agonist treatment. Only two of 10 markers of asthma control showed changes that were significantly associated with genotype: subjects homozygous for glycine at position 16 had no increase in bronchial responsiveness to methacholine during regular treatment; subjects homozygous for glutamic acid at position 27 had no increase in evening peak expiratory flow rates during regular treatment. These differences are the opposite of those that would have been predicted by the results of in vitro studies. In these subjects, the deleterious response to regular inhaled β2-agonist treatment was not related to β2-receptor polymorphism. Eur Respir J 1998; 11: 589–593. *Dept of Medicine, University of Otago, Dunedin, New Zealand. **Firestone Regional Chest and Allergy Unit, McMaster University, Hamilton, Ontario, Canada.