Published ahead of print on November 17, 2005, doi:10.1164/rccm.200509-1412OC Am. J. Respir. Crit. Care Med., Volume 173, Number 4, February 2006, 379-385 A more recent version of this article appeared on February 15, 2006
Submitted on September 9, 2005 Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in AsthmaJohn J Lima1*,1 The American Lung Associations Asthma Clinical Research Centers, USA; Pharmacogenetics Center, Nemours Children's Clinic, Jacksonville, FL, USA, 2 Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD, USA, 3 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA, 4 Department of Preventative Medicine and Institute for Genetic Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA, 5 Pharmacogenetics Center, Nemours Children's Clinic, Jacksonville, FL, USA, 6 Center for Clinical Trials, Johns Hopkins University, Baltimore, MD, USA * To whom correspondence should be addressed. E-mail: jlima{at}nemours.org.
Rationale: Inter-patient variability in montelukast response maybe related to variation in leukotriene pathway candidate genes. Objective: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in asthmatics taking montelukast for 6 months who participated in a clinical trial. Methods: Polymorphisms were typed using Sequenom MALDI-TOF mass array spectrometry and published methods; haplotypes were imputed using SNP-EM. ANOVA and logistic regression models were used to test for changes in outcomes by genotype. Chi-square 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. Measurements: Outcomes were asthma exacerbation rate and changes in FEV1 compared to baseline. Results: DNA was collected from 252 participants; 69% were White, 26% were African American. 28 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: montelukast, antiinflammatory, pharmacogenetic, pharmacodynamic
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