Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma

Koichiro Asano, Tetsuya Shiomi, Naoki Hasegawa, Hidetoshi Nakamura, Hiroyasu Kudo, Tatsu Matsuzaki, Haruhiko Hakuno, Koichi Fukunaga, Yusuke Suzuki, Minoru Kanazawa, Kazuhiro Yamaguchi

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Abstract

CysLT1 antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT1 antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C4 synthase (LTC4S) gene in Japanese patients with moderate asthma. The frequency of LTC4S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects (n = 349), A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 μg/day or fluticasone 200-400 μg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes (n = 31) [14.3 ± 5.3% vs. 3.1 ± 2.4% improvement of forced expiratory volume in one second (FEV1), P<0.01], while LTC4S genotype-stratified response to inhaled β-agonist salbutamol (200 μg) was not observed (17.5 ± 2.1% vs. 18.7 ± 2.2% improvement of FEV1). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV1) was correlated with LTC4S genotype (P<0.01) and pretreatment airway reversibility to salbutamol (P<0.01), but not with sex, age, atopic status, urinary leukotriene E4 excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC4S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P<0.05). We conclude that LTC4S genotype is predictive of the clinical response to a cysLT1 antagonist, pranlukast, in Japanese patients with moderate asthma.

Original languageEnglish
Pages (from-to)565-570
Number of pages6
JournalPharmacogenetics
Volume12
Issue number7
DOIs
Publication statusPublished - 2002 Oct

Fingerprint

Asthma
Albuterol
Genotype
Genes
Alleles
Adrenal Cortex Hormones
Leukotriene E4
Beclomethasone
Forced Expiratory Volume
Homozygote
pranlukast
leukotriene-C4 synthase
Multivariate Analysis
Regression Analysis
Population

Keywords

  • Asthma
  • CysLT antagonist
  • Leukotriene C synthase

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma. / Asano, Koichiro; Shiomi, Tetsuya; Hasegawa, Naoki; Nakamura, Hidetoshi; Kudo, Hiroyasu; Matsuzaki, Tatsu; Hakuno, Haruhiko; Fukunaga, Koichi; Suzuki, Yusuke; Kanazawa, Minoru; Yamaguchi, Kazuhiro.

In: Pharmacogenetics, Vol. 12, No. 7, 10.2002, p. 565-570.

Research output: Contribution to journalArticle

Asano, Koichiro ; Shiomi, Tetsuya ; Hasegawa, Naoki ; Nakamura, Hidetoshi ; Kudo, Hiroyasu ; Matsuzaki, Tatsu ; Hakuno, Haruhiko ; Fukunaga, Koichi ; Suzuki, Yusuke ; Kanazawa, Minoru ; Yamaguchi, Kazuhiro. / Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma. In: Pharmacogenetics. 2002 ; Vol. 12, No. 7. pp. 565-570.
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abstract = "CysLT1 antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT1 antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C4 synthase (LTC4S) gene in Japanese patients with moderate asthma. The frequency of LTC4S C(-444) allele was 21.6{\%} in the Japanese general population (n = 171) and 19.4{\%} in the asthmatic subjects (n = 349), A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 μg/day or fluticasone 200-400 μg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes (n = 31) [14.3 ± 5.3{\%} vs. 3.1 ± 2.4{\%} improvement of forced expiratory volume in one second (FEV1), P<0.01], while LTC4S genotype-stratified response to inhaled β-agonist salbutamol (200 μg) was not observed (17.5 ± 2.1{\%} vs. 18.7 ± 2.2{\%} improvement of FEV1). Univariate analysis demonstrated that the better response to pranlukast (more than 10{\%} improvement of FEV1) was correlated with LTC4S genotype (P<0.01) and pretreatment airway reversibility to salbutamol (P<0.01), but not with sex, age, atopic status, urinary leukotriene E4 excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC4S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P<0.05). We conclude that LTC4S genotype is predictive of the clinical response to a cysLT1 antagonist, pranlukast, in Japanese patients with moderate asthma.",
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AU - Nakamura, Hidetoshi

AU - Kudo, Hiroyasu

AU - Matsuzaki, Tatsu

AU - Hakuno, Haruhiko

AU - Fukunaga, Koichi

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AU - Kanazawa, Minoru

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N2 - CysLT1 antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT1 antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C4 synthase (LTC4S) gene in Japanese patients with moderate asthma. The frequency of LTC4S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects (n = 349), A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 μg/day or fluticasone 200-400 μg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes (n = 31) [14.3 ± 5.3% vs. 3.1 ± 2.4% improvement of forced expiratory volume in one second (FEV1), P<0.01], while LTC4S genotype-stratified response to inhaled β-agonist salbutamol (200 μg) was not observed (17.5 ± 2.1% vs. 18.7 ± 2.2% improvement of FEV1). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV1) was correlated with LTC4S genotype (P<0.01) and pretreatment airway reversibility to salbutamol (P<0.01), but not with sex, age, atopic status, urinary leukotriene E4 excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC4S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P<0.05). We conclude that LTC4S genotype is predictive of the clinical response to a cysLT1 antagonist, pranlukast, in Japanese patients with moderate asthma.

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