Early ReportAssociation between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics
Introduction
Since the β2-adrenoceptor (β2-AR) gene was cloned in 1987,1 there has been intense interest in the relation between β2-AR structure and function. Polymorphisms at codons 16 and 27 are quite common in both heterozygous and homozygous states in asthmatic and non-asthmatic people alike, and have been a focus of research.2, 3 In-vitro studies in transfected cell lines and primary cultures of human-airway smooth-muscle cells have shown that the Gly-16 form of the receptor becomes more down-regulated and desensitised after exposure to a β2-agonist than the Arg-16 form.4, 5 By contrast, the Glu-27 form confers more protection against down-regulation and desensitisation than the Gln-27 form.4, 5 To date, there have been few in-vivo studies in humans. In one study, however, high doses of nebulised metaproterenol produced down-regulation of alveolar macrophage and bronchial epithelial β2-AR in normal volunteers with the homozygous Gly-16 polymorphism.6 Other studies have shown an association between Gly 16 and nocturnal asthma,7 as well as lower bronchial hyperreactivity and Glu 27.8
We have previously carried out three similar clinical studies of patients with asthma in which bronchodilator desensitisation was shown after chronic exposure to inhaled formoterol 24 μg bid.9, 10, 11 We therefore decided to investigate whether β2-AR polymorphism might influence the development of brochodilator desensitisation. We did an analysis of these three randomised, double-blind, placebo-controlled, crossover studies9, 10, 11 to assess the relation of β2-AR polymorphism to the development of bronchodilator desensitisation.
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Patients
The three studies were done between 1992 and 1996.9, 10, 11 35 patients were originally recruited to all three studies, which comprised 29 individuals. We were able to recall 22 (76%) of the 29 patients to the department to have a blood sample taken for genotype analysis. Of the remaining seven patients, one declined to return, and six had moved from the area and could not be contacted. Of the 22 recalled patients, four participated in two studies, and one in three studies; these five patients
Results
For codon-16 polymorphism, maximum FEV1 and FEF25-75 responses showed a significantly greater degree of bronchodilator desensitisation with homozygous Gly 16 than with homozygous Arg 16. This result was mirrored by significantly greater densensitisation with homozygous Gly 16 than with homozygous Arg 16 for 6-h FEV1 and FEF25-75 responses. Mean values for the heterozygote form (Arg 16/Gly 16) were intermediate between homozygous Arg 16 and Gly 16, except for the maximum FEV1 response, in which
Discussion
Our results suggest that β2-AR polymorphism may be associated with altered β2-AR expression in asthmatic patients, in terms of susceptibility to bronchodilator desensitisation after chronic exposure to a long-acting β2-agonist. Those asthmatic patients who were homozygous Gly 16 developed significantly greater bronchodilator desensitisation than those who were homozygous Arg 16; whereas heterozygote patients developed desensitisation to a degree intermediate between the two kinds of homozygote
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