Association between beta(2)-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics

Background In-vitro studies have suggested that polymorphisms of the beta(2)-adrenoceptor may influence the desensitisation induced by beta(2)-agonists. We investigated the influence of beta(2)-AR polymorphism on the development of bronchodilator desensitisation in asthma patients. Methods We carried out an analysis of 22 moderately severe stable asthmatics, mean age 38 years, FEV1 63% of predicted and FEF25-75 38% of predicted, who received a median inhaled corticosteroid dose of 1000 mu g/day. Patients were randomly assigned inhaled placebo or inhaled formoterol 24 mu g bid for 4 weeks each in a crossover study. Bronchodilator dose-response curves were made at the end of each treatment period by use of cumulative doses of formoterol (6-108 mu g) with FEV1 and FEF25-75 measured 30 min after each dose, and up to 6 h after the last dose. We calculated the degree of bronchodilator desensitisation by comparing the dose-response (for maximum and 6 h) after placebo with that after formoterol, and expressed this degree as percentage of placebo response. Patients were divided into groups according to genotype at codon 16: homozygous Arg 16 (n=4), heterozygous Arg 16/Gly 16 (n=8), and homozygous Gly 16 (n=10). At codon 27: homozygous Gin 27 (n=5), heterozygous Gin 27/Glu 27 (n=11), and homozygous Glu 27 (n=6). Findings We found a significantly (p<0.05) greater degree of bronchodilator desensitisation with homozygous Gly 16 than with homozygous Arg 16 for maximal FEV1 response: -8% (Arg 16) vs 46% (Gly 16); and for maximal FEF25-75 response: -32% (Arg 16) vs 74% (Gly 16; 95% CI 15-92% and 49-164%, respectively). Bronchodilator responses at 6 h were also significantly (p<0.05) different for FEV1 and FEF25-75 when Arg 16 and Gly 16 were compared and values for heterozygous Arg 16/Gly 16 were intermediate. There was significantly greater desensitisation with Glu 27 than with Gin 27 for maximal FEF25-75 response: -7% (Gin 27) vs 68% (Glu 27), p=0.05; and for 6 h FEF25-75 response: 43% (Gin 27) vs 93% (Glu 27), p<0.05 (95% CI 2-147% and 5-94%, respectively). All patients who were homozygous Glu 27 were also homozygous Gly 16. Interpretation We have found preliminary evidence that beta(2)-adrenoceptor polymorphism is associated with altered beta(2)-adrenoceptor expression in asthma patients. The homozygous Gly-16 form was significantly more prone to bronchodilator desensitisation than Arg 16, with the influence of Gly 16 dominating over any putative protective effects of Glu 27.