Association between β-adrenoceptor gene polymorphisms and relative response to β 2-agonists and anticholinergic drugs in Japanese asthmatic patients

Koichiro Asano, Wakako Yamada-Yamasawa, Hiroyasu Kudoh, Tatsu Matsuzaki, Takahiro Nakajima, Haruhiko Hakuno, Rika Hiraoka, Koichi Fukunaga, Tsuyoshi Oguma, Koichi Sayama, Kazuhiro Yamaguchi, Akira Nagabukuro, Yosuke Harada, Akitoshi Ishizaka

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background and objective: Whether 2-adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to 2-agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to 2-agonists. Methods: The increases in FEV 1 after inhalation of procaterol hydrochloride (FEV 1 procaterol) or oxitropium bromide (FEV 1 oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5′-flanking regions of ADRB2 were genotyped by direct sequencing and PCR-restriction fragment length polymorphism assay. Results: The mean age of the participants was 54 years, and 38 (47%) were smokers. Although FEV 1 procaterol and FEV 1 oxitropium adjusted for predicted FEV 1 were not associated with ADRB2 polymorphisms, the ratio of FEV 1 procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that FEV 1 procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). Conclusions: The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to 2-agonists even in elderly asthmatic patients and smokers.

Original languageEnglish
Pages (from-to)849-854
Number of pages6
JournalRespirology
Volume15
Issue number5
DOIs
Publication statusPublished - 2010 Jul

Fingerprint

Procaterol
Cholinergic Antagonists
Adrenergic Receptors
Pharmaceutical Preparations
Genes
Bronchodilator Agents
Alleles
Inhalation
Smoking
Airway Remodeling
5' Flanking Region
Pharmacogenetics
Restriction Fragment Length Polymorphisms
Glycine
Arginine
Linear Models
Asthma
Genotype
Regression Analysis
Amino Acids

Keywords

  • airway reversibility
  • anticholinergic agent
  • asthma
  • oxitropium bromide
  • procaterol hydrochloride

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Association between β-adrenoceptor gene polymorphisms and relative response to β 2-agonists and anticholinergic drugs in Japanese asthmatic patients. / Asano, Koichiro; Yamada-Yamasawa, Wakako; Kudoh, Hiroyasu; Matsuzaki, Tatsu; Nakajima, Takahiro; Hakuno, Haruhiko; Hiraoka, Rika; Fukunaga, Koichi; Oguma, Tsuyoshi; Sayama, Koichi; Yamaguchi, Kazuhiro; Nagabukuro, Akira; Harada, Yosuke; Ishizaka, Akitoshi.

In: Respirology, Vol. 15, No. 5, 07.2010, p. 849-854.

Research output: Contribution to journalArticle

Asano, K, Yamada-Yamasawa, W, Kudoh, H, Matsuzaki, T, Nakajima, T, Hakuno, H, Hiraoka, R, Fukunaga, K, Oguma, T, Sayama, K, Yamaguchi, K, Nagabukuro, A, Harada, Y & Ishizaka, A 2010, 'Association between β-adrenoceptor gene polymorphisms and relative response to β 2-agonists and anticholinergic drugs in Japanese asthmatic patients', Respirology, vol. 15, no. 5, pp. 849-854. https://doi.org/10.1111/j.1440-1843.2010.01786.x
Asano, Koichiro ; Yamada-Yamasawa, Wakako ; Kudoh, Hiroyasu ; Matsuzaki, Tatsu ; Nakajima, Takahiro ; Hakuno, Haruhiko ; Hiraoka, Rika ; Fukunaga, Koichi ; Oguma, Tsuyoshi ; Sayama, Koichi ; Yamaguchi, Kazuhiro ; Nagabukuro, Akira ; Harada, Yosuke ; Ishizaka, Akitoshi. / Association between β-adrenoceptor gene polymorphisms and relative response to β 2-agonists and anticholinergic drugs in Japanese asthmatic patients. In: Respirology. 2010 ; Vol. 15, No. 5. pp. 849-854.
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abstract = "Background and objective: Whether 2-adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to 2-agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to 2-agonists. Methods: The increases in FEV 1 after inhalation of procaterol hydrochloride (FEV 1 procaterol) or oxitropium bromide (FEV 1 oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5′-flanking regions of ADRB2 were genotyped by direct sequencing and PCR-restriction fragment length polymorphism assay. Results: The mean age of the participants was 54 years, and 38 (47{\%}) were smokers. Although FEV 1 procaterol and FEV 1 oxitropium adjusted for predicted FEV 1 were not associated with ADRB2 polymorphisms, the ratio of FEV 1 procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that FEV 1 procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). Conclusions: The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to 2-agonists even in elderly asthmatic patients and smokers.",
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AU - Asano, Koichiro

AU - Yamada-Yamasawa, Wakako

AU - Kudoh, Hiroyasu

AU - Matsuzaki, Tatsu

AU - Nakajima, Takahiro

AU - Hakuno, Haruhiko

AU - Hiraoka, Rika

AU - Fukunaga, Koichi

AU - Oguma, Tsuyoshi

AU - Sayama, Koichi

AU - Yamaguchi, Kazuhiro

AU - Nagabukuro, Akira

AU - Harada, Yosuke

AU - Ishizaka, Akitoshi

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N2 - Background and objective: Whether 2-adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to 2-agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to 2-agonists. Methods: The increases in FEV 1 after inhalation of procaterol hydrochloride (FEV 1 procaterol) or oxitropium bromide (FEV 1 oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5′-flanking regions of ADRB2 were genotyped by direct sequencing and PCR-restriction fragment length polymorphism assay. Results: The mean age of the participants was 54 years, and 38 (47%) were smokers. Although FEV 1 procaterol and FEV 1 oxitropium adjusted for predicted FEV 1 were not associated with ADRB2 polymorphisms, the ratio of FEV 1 procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that FEV 1 procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). Conclusions: The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to 2-agonists even in elderly asthmatic patients and smokers.

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KW - airway reversibility

KW - anticholinergic agent

KW - asthma

KW - oxitropium bromide

KW - procaterol hydrochloride

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