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

• DOI: 10.1097/fpc.0b013e3280120043
• Publication Date: 2008-05-04T18:16:28Z
• Authors: Michael Klotsman; Timothy P. York; Sreekumar G. Pillai; Cristina Vargas-I...; Sanjay S. Sharma; Edwin J.C.G. van ...; Wayne H. Anderson
• Keywords: Leukotriene E4; Leukotriene C4

Objective Interindividual clinical response to leukotriene modifiers is highly variable, and less efficacious than inhaled corticosteroids in treating asthma. Genetic variability 5-lipoxygenase biosynthetic receptor pathway gene loci may influence cysteinyl-leukotriene production subsequent modifiers. Methods Using data from two trials of 12-week duration, post-hoc analyses were performed 174 patients randomized montelukast. Associations between polymorphisms 10 candidate genes (ALOX5, ALOX5AP, LTC4S, CYSLTR1, CYSLTR2, PLA2G4A, CYP2C9, CYP3A4, ADRB2, NR3C1) montelukast modeled using change morning peak expiratory flow forced volume 1 s (FEV1) define the phenotype. Results In our sample, eight out 25 markers statistically associated with montelukast, an estimated proportion false discoveries 16%. The strongest statistical evidence clinically relevant pharmacogenetic effects identified CYSLTR2 (rs91227 rs912278; P=0.02 P=0.02, respectively) ALOX5 (rs4987105 rs4986832; P=0.01 P=0.01, respectively). Patients these variant genotypes, found roughly 10–13% patients, had 18–25% improvement flow. contrast, majority wild-type alleles only a marginal (8–10%) improvement. Conclusions overall mean be skewed towards phenotype by small subset (<15%) asthma patients. predispose minority individuals excessive concentrations, yielding distinct most likely respond modifier pharmacotherapy. These findings require replication establish validity utility.