Influence of leukotriene pathway polymorphisms on response to montelukast in asthma

John J. Lima, Shu Zhang, Audrey Grant, Lianhe Shao, Kelan G. Tantisira, Hooman Allayee, Jianwei Wang, James Sylvester, Janet Holbrook, Robert Wise, Scott T. Weiss, Kathleen Barnes

Research output: Contribution to journalArticlepeer-review

Abstract

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, χ2 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 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.

Original languageEnglish (US)
Pages (from-to)379-385
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume173
Issue number4
DOIs
StatePublished - Feb 15 2006
Externally publishedYes

Keywords

  • Antiinflammatory
  • Montelukast
  • Pharmacodynamic
  • Pharmacogenetic

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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