Published ahead of print on November 17, 2005, doi:10.1164/rccm.200509-1412OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200509-1412OC
Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in AsthmaThe American Lung Association Asthma Clinical Research Centers; Pharmacogenetics Center, Nemours Children's Clinic, Jacksonville, Florida; Division of Allergy and Clinical Immunology; Center for Clinical Trials, Johns Hopkins University, Baltimore, Maryland; Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts; and Department of Preventive Medicine, and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California Correspondence and requests for reprints should be addressed to John J. Lima, Pharm.D., Centers for Clinical Pediatric Pharmacology and Pharmacogenetics, Nemours Children's Clinic, 807 Children's Way, Jacksonville, FL 32207. E-mail: jlima{at}nemours.org Rationale: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. Objective: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial.
Methods: Polymorphisms were typed using Sequenom matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism–expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, Measurements: Outcomes were asthma exacerbation rate and changes in FEV1 compared with baseline. Results: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV1 (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. Conclusions: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.
Key Words: antiinflammatory • montelukast • pharmacodynamic • pharmacogenetic This article has been cited by other articles:
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2 and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. 
