ASSOCIATION BETWEEN BETA(2)-ADRENOCEPTOR POLYMORPHISM AND SUSCEPTIBILITY TO BRONCHODILATOR DESENSITIZATION IN MODERATELY SEVERE STABLE ASTHMATICS

Background In-vitro studies have suggested that polymorphisms of the b eta(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 patient s. Methods We carried out an analysis of 22 moderately severe stable a sthmatics, mean age 38 years, FEV1 63% of predicted and FEF25-75 38% o f 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. Bronchod ilator dose-response curves were made at the end of each treatment per iod by use of cumulative doses of formoterol (6-108 mu g) with FEV1 an d FEF25-75 measured 30 min after each dose, and up to 6 h after the la st 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 plac ebo 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). Findin gs 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 signifi cantly (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 intermed iate. There was significantly greater desensitisation with Glu 27 than with Gin 27 for maximal FEF25-75 response: -7% (Gin 27) vs 68% (Glu 2 7), 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 we re homozygous Glu 27 were also homozygous Gly 16. Interpretation We ha ve found preliminary evidence that beta(2)-adrenoceptor polymorphism i s associated with altered beta(2)-adrenoceptor expression in asthma pa tients. The homozygous Gly-16 form was significantly more prone to bro nchodilator desensitisation than Arg 16, with the influence of Gly 16 dominating over any putative protective effects of Glu 27.