Asano Koichiro, Shiomi Tetsuya, Hasegawa Naoki, Nakamura Hidetoshi, Kudo Hiroyasu, Matsuzaki Tatsu, Hakuno Haruhiko, Fukunaga Kouichi, Suzuki Yusuke, Kanazawa Minoru, Yamaguchi Kazuhiro
Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Pharmacogenetics. 2002 Oct;12(7):565-70. doi: 10.1097/00008571-200210000-00009.
CysLT(1) 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 cysLT(1) antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C(4) synthase (LTC(4) S) gene in Japanese patients with moderate asthma. The frequency of LTC(4) S 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 microg/day or fluticasone 200-400 microg/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 (FEV(1) ), 0.01], while LTC(4) S genotype-stratified response to inhaled beta-agonist salbutamol (200 microg) was not observed (17.5 2.1% vs. 18.7 2.2% improvement of FEV(1) ). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV(1) ) was correlated with LTC(4) S genotype (P < 0.01) and pretreatment airway reversibility to salbutamol (P < 0.01), but not with sex, age, atopic status, urinary leukotriene E(4) excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC(4) S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P < 0.05). We conclude that LTC(4) S genotype is predictive of the clinical response to a cysLT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.
半胱氨酰白三烯1（CysLT(1)）拮抗剂对部分哮喘患者有效；然而，一直没有很好的方法来预测某一特定患者的反应。我们研究了日本中度哮喘患者中，CysLT(1)拮抗剂普仑司特的临床反应与白三烯C4合成酶（LTC(4) S）基因中DNA序列变异A(-444)C之间的相互作用。LTC(4) S C(-444)等位基因在日本普通人群（n = 171）中的频率为21.6%，在哮喘患者（n = 349）中为19.4%。对50名使用吸入性糖皮质激素（倍氯米松400 - 800微克/天或氟替卡松200 - 400微克/天）病情得到良好控制的中度哮喘患者进行了一项为期4周的普仑司特（每日两次，每次225毫克）前瞻性开放试验。与A(-444)等位基因纯合子（n = 31）相比，C(-444)等位基因携带者（n = 16）对普仑司特反应更好[一秒用力呼气量（FEV(1)）改善率为14.3±5.3% vs. 3.1±2.4%，P = 0.01]，而未观察到LTC(4) S基因型分层的对吸入性β受体激动剂沙丁胺醇（200微克）的反应差异（FEV(1)改善率为17.5±2.1% vs. 18.7±2.2%）。单因素分析表明，对普仑司特更好的反应（FEV(1)改善超过10%）与LTC(4) S基因型（P < 0.01）和对沙丁胺醇的预处理气道可逆性（P < 0.01）相关，但与性别、年龄、特应性状态、尿白三烯E4排泄率或吸入性糖皮质激素的每日剂量无关。此外，多因素回归分析表明，LTC(4) S基因型和沙丁胺醇的支气管舒张作用是预测对普仑司特临床反应的独立变量（P < 0.05）。我们得出结论，在日本中度哮喘患者中，LTC(4) S基因型可预测对CysLT(1)拮抗剂普仑司特的临床反应。
