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首页> 外文期刊>Pharmacogenetics and genomics >Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast.
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Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast.

机译：5-脂氧合酶生物合成途径的药物遗传学和对孟鲁司特的可变临床反应。

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OBJECTIVE: Interindividual clinical response to leukotriene modifiers is highly variable, and less efficacious than inhaled corticosteroids in treating asthma. Genetic variability in 5-lipoxygenase biosynthetic and receptor pathway gene loci may influence cysteinyl-leukotriene production and subsequent response to leukotriene modifiers. METHODS: Using data from two clinical trials of 12-week duration, post-hoc analyses were performed in 174 patients randomized to montelukast. Associations between polymorphisms in 10 candidate genes (ALOX5, ALOX5AP, LTC4S, CYSLTR1, CYSLTR2, PLA2G4A, CYP2C9, CYP3A4, ADRB2, and NR3C1) and response to montelukast were modeled using change in morning peak expiratory flow and forced expiratory volume in 1 s (FEV1) to define the response phenotype. RESULTS: In our sample, eight out of 25 markers in 10 candidate genes were statistically associated with response to montelukast, with an estimated proportion of false discoveries of 16%. The strongest statistical evidence of clinically relevant pharmacogenetic effects peak expiratory flow were identified in CYSLTR2 (rs91227 and rs912278; P=0.02 and P=0.02, respectively) and ALOX5 (rs4987105 and rs4986832; P=0.01 and P=0.01, respectively). Patients with these variant genotypes, found in roughly 10-13% of patients, had an 18-25% improvement in peak expiratory flow. In contrast, the majority of patients with the wild-type alleles had only a marginal (8-10%) improvement. CONCLUSIONS: The overall mean response to montelukast may be skewed towards a response phenotype by a small subset (<15%) of asthma patients. CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations, yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy. These findings require replication to establish validity and clinical utility.
机译：目的：个体间对白三烯修饰剂的临床反应差异很大，与吸入性糖皮质激素治疗哮喘的疗效差。 5-脂氧合酶生物合成和受体途径基因位点的遗传变异性可能影响半胱氨酰-白三烯的产生以及随后对白三烯修饰剂的反应。方法：使用来自两个为期12周的临床试验的数据，对随机分配至孟鲁司特的174例患者进行事后分析。使用早晨峰值呼气流量变化和强制呼气量（1 s），模拟了10个候选基因（ALOX5，ALOX5AP，LTC4S，CYSLTR1，CYSLTR2，PLA2G4A，CYP2C9，CYP3A4，ADRB2和NR3C1）之间的多态性与对孟鲁司特的反应之间的关联。 FEV1）来定义反应表型。结果：在我们的样本中，在10个候选基因中的25个标记中有8个在统计学上与对孟鲁司特的反应相关，估计的错误发现比例为16％。在CYSLTR2（rs91227和rs912278;分别为P = 0.02和P = 0.02）和ALOX5（rs4987105和rs4986832; P = 0.01和P = 0.01）中鉴定出了临床相关药理作用峰值呼气流量的最强统计证据。在大约10％至13％的患者中发现了这些基因型变异的患者，其呼气峰值流量提高了18-25％。相反，大多数具有野生型等位基因的患者仅改善了少量（8-10％）。结论：一小部分（<15％）哮喘患者对孟鲁司特的总体平均反应可能偏向反应表型。 CYSLTR2和ALOX5多态性可能使少数人易患半胱氨酰-白三烯浓度过高，产生最可能对白三烯修饰剂药物疗法产生反应的独特哮喘表型。这些发现需要复制以建立有效性和临床实用性。

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