Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast

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Abstract
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. 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. 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. 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.