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

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.