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

• Published in: The Lancet (British edition) 1997-10, Vol.350 (9083), p.995-999
• Main Authors: Tan, Soong, Hall, Ian P, Dewar, Jane, Dow, Eleanor, Lipworth, Brian
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Adrenergic beta-Agonists - administration & dosage; Adrenergic beta-Agonists - therapeutic use; Adult; Asthma - drug therapy; Asthma - genetics; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - therapeutic use; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Ethanolamines - administration & dosage; Ethanolamines - therapeutic use; Female; Formoterol Fumarate; Humans; Male; Polymorphism, Genetic; Receptors, Adrenergic, beta-2 - genetics; Time Factors
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(97)03211-X

In-vitro studies have suggested that polymorphisms of the β 2-adrenoceptor may influence the desensitisation induced by β 2-agonists. We investigated the influence of β 2-AR polymorphism on the development of bronchodilator desensitisation in asthma patients. We carried out an analysis of 22 moderately severe stable asthmatics, mean age 38 years, FEV 1 63% of predicted and FEF 25-75 38% of predicted, who received a median inhaled corticosteroid dose of 1000 μg/day. Patients were randomly assigned inhaled placebo or inhaled formoterol 24 ug bid for 4 weeks each in a cross-over study. Bronchodilator dose-response curves were made at the end of each treatment period by use of cumulative doses of formoterol (6-108 μg) with FEV 1 and FEF 25-75 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 a 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). We found a significantly (p < 0·05) greater degree of bronchodilator desensitisation with homozygous Gly 16 than with homozygous Arg 16 for maximal FEV 1 response: -8% (Arg 16) vs 46% (Gly 16); and for maximal FEF 25-75 response: -32% (Arg 16) vs 74% (Gly 16; 95% Cl 15-92% and 49-164%, respectively). Bronchodilator responses at 6 h were also significantly (p < 0·05) different for FEV 1 and FEF 25-75 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 FEF 25-75 response: -7% (Gin 27) vs 68% (Glu 27), p=0·05; and for 6 h FEF 25-75 response: 43% (Gin 27) vs 93% (Glu 27), p < 0·05 (95% Cl 2-147% and 5-94%, respectively). All patients who were homozygous Glu 27 were also homozygous Gly 16. We have found preliminary evidence that β 2-adrenoceptor polymorphism is associated with altered β 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.