Effect of β2-Adrenergic Receptor Polymorphism in Asthma Control of Patients Receiving Combination Treatment

다국어 초록 (Multilingual Abstract)

Purpose: Combination treatment of inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA) is widely used as a
maintenance regimen for the management of asthma. This study evaluated the effect of the β2-adrenergic receptor (ADRB2)
polymorphism on lung function and asthma control with regular use of combination treatment of an inhaled ICS plus
LABA. Materials and Methods: 43 Korean asthmatics who were symptomatic despite regular ICS use for at least 3
months were enrolled. For a 2-week run-in period, they received ICS (budesonide 800 μg/day) plus terbutaline (5 μg prn). as
needed. During the 24-week active treatment period, they received budesonide 160 μg and formoterol 4.5 μg b.i.d. as
maintenance and rescue medication. Pulmonary function and quality of life scores were monitored every 8 weeks;
morning/evening peak expiratory flow meter (PEFR) was recorded daily. Patients were genotyped for ADRB2 Arg16Gly
using single base extension methodology. Results: During the run-in period, there were no significant between-group
differences in lung function; after 8 weeks of active treatment, Arg/Arg patients had significantly higher forced expiratory
volume in 1 secord (FEV1) and maximal mid-expiratory flow (MMEF) (p = 0.023 and p = 0.021, respectively), and better
asthma control and quality of life after 24 weeks (p = 0.016 and p = 0.028, respectively). During treatment, there was a
greater improvement in morning/evening PEFR in Arg/Arg patients. Conclusion: Asthmatic patients with the Arg/Arg
genotype at codon 16 of ADRB2 achieve better asthma control with long-term regular use of combined budesonide and
formoterol treatment, suggesting that the ADRB2 genotype may dictate choice of treatment strategy.

참고문헌 (Reference)

1 Wechsler ME, "beta-Adrenergic receptor polymorphisms and response to salmeterol" 173 : 519-526, 2006

2 Israel E, "Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial" 364 : 1505-1512, 2004

3 Israel E, "The effect of polymorphisms of the beta(2)- adrenergic receptor on the response to regular use of albuterol in asthma" 162 : 75-80, 2000

4 Lee DK, "The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol" 57 : 68-75, 2004

5 Green SA, "The Ile164 beta(2)- adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to G(s)" 421 : 141-147, 2001

6 Bleecker ER, "Salmeterol response is not affected by beta2- adrenergic receptor genotype in subjects with persistent asthma" 118 : 809-816, 2006

7 Liggett SB, "Polymorphisms of the beta2-adrenergic receptor and asthma" 156 : S156-S162, 1997

8 Hancox RJ, "Polymorphism of the beta2- adrenoceptor and the response to long-term beta2-agonist therapy in asthma" 11 : 589-593, 1998

9 Choudhry S, "Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma" 171 : 563-570, 2005

10 Reihsaus E, "Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects" 8 : 334-339, 1993

11 Munakata M, "Molecular-based haplotype analysis of the beta 2-adrenergic receptor gene (ADRB2) in Japanese asthmatic and non-asthmatic subjects" 55 : 191-198, 2006

12 Contopoulos-Ioannidis DG, "Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes" 115 : 963-972, 2005

13 Green SA, "Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells" 13 : 25-33, 1995

14 "Global initiative for asthma (gina) global strategy for asthma managemetn and prevention: National Instritutes of Health, National Heart" Lung and Blood Institute 2006

15 Rho HJ, "Factors influencing quality of life of asthmatic patients in Korea" 20 : 209-221, 2000

16 Pauwels RA, "Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group" 337 : 1405-1411, 1997

17 Bleecker ER, "Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies" 370 : 2118-2125, 2007

18 Drysdale CM, "Complex promoter and coding region beta 2- adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness" 10483-10488, 2000

19 O’Byrne PM, "Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma" 171 : 129-136, 2005

20 Taylor DR, "Bronchodilator response in relation to beta2-adrenoceptor haplotype in patients with asthma" 172 : 700-703, 2005

21 Taylor DR, "Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism" 55 : 762-767, 2000

22 Holloway JW, "Association of beta2-adrenergic receptor polymorphisms with severe asthma" 30 : 1097-1103, 2000

23 Martinez FD, "Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing" 100 : 3184-3188, 1997

24 Cho SH, "Association between bronchodilating response to short-acting betaagonist and non-synonymous single-nucleotide polymorphisms of beta-adrenoceptor gene" 35 : 1162-1167, 205

25 Palmer CN, "Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol" 61 : 940-944, 2006

26 Green SA, "Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonistpromoted regulatory properties" 33 : 9414-9419, 1994

27 Green SA, "A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor" 268 : 23116-23121, 1993