The influence of polymorphisms of the β2 - adrenoceptor (AR) gene and the β2 -AR upstream peptide (BUP) on bronchoprotective tolerance development in asthmatic patients
A. van Veen, E. A. Wierenga, F. R. Weller, H. M. Jansen, R. E. Jonkers (Amsterdam, The Netherlands)
Source: Annual Congress 2001 - Long-acting β2-agonists: clinical effects
Session: Long-acting β2-agonists: clinical effects
Session type: Oral Presentation
Number: 3475
Disease area: Airway diseases
Abstract Polymorphisms have been identified in the β2 -AR gene and in the 5'leader cistron encoding the BUP, which occur in only limited combinations due to linkage disequilibrium. We evaluated the in vivo impact of regular treatment with terbutaline on the bronchoprotective effect of increasing doses of fenoterol in six different genotypes. 45 asthmatic patients were included in a randomised, placebo controlled, double blind, cross-over designed study, with either terbutaline 500 qid or placebo. After two weeks of treatment, dose-response curves to inhaled fenoterol (200-3000μg) were constructed for PD20 methacholine. Data were stratified according to genotype. Results: Only 3 haplotypes were present in our population, leading to 6 different genotypes (table). These genotypes did not show any differences in baseline characteristics, nor in baseline responsiveness to β2 -agonists. However, significant tolerance development could only be demonstrated in 2 of the 6 genotypes. We conclude that genotype influences the degree of tolerance development after exposure to β2 -agonists. The in vivo impact of receptor polymorphism on response to medication should be evaluated in data stratified by genotypes actually present in the population instead of by one single polymorphism. Table: Mean (SEM) change in fenoterol response after terbutaline treatment as compared with placebo and expressed in doubling dose (DD).
dose fenoterol HetHetHet (n=12) ArgGlyGlu (n=10) HetGlyHet (n=5) CysArgGln (n=12) CysHetGln (n=4) CysGlyGln (n=2) baseline -0.09(0.50) -0.04(0.75) 0.72(0.54) -0.21(0.19) 0.05(0.31) 0.67 (0.13) 200 -0.56(0.62) 0.14 (0.44) -0.54(0.46) 0.24 (0.47) -0.31(0.19) 0.15 (2.44) 600 -1.23(0.37) -0.76(0.33) -2.00(0.56) 0.75(0.51) -1.25(0.34) -0.64(1.58) 1400 -1.16(0.55) -0.57(0.57) -2.14(0.52) -0.02(0.49) -0.85(0.50) -0.93(1.69) 3000 -0.63(0.51) -0.59(0.60) -2.10(0.57) -0.08(0.55) -1.02(0.70) -1.70(0.73)
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A. van Veen, E. A. Wierenga, F. R. Weller, H. M. Jansen, R. E. Jonkers (Amsterdam, The Netherlands). The influence of polymorphisms of the β2 - adrenoceptor (AR) gene and the β2 -AR upstream peptide (BUP) on bronchoprotective tolerance development in asthmatic patients. Eur Respir J 2001; 16: Suppl. 31, 3475
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