Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

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 matrixassisted 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, 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. Measurements: Outcomes were asthma exacerbation rate and changes in FEV 1 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 FEV 1 (p Ͻ 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. Keywords: antiinflammatory; montelukast; pharmacodynamic; pharmacogeneticMontelukast is a selective cysteinyl leukotriene 1 (cysLT 1 ) receptor antagonist (1). Montelukast is recommended as an alternative to low-dose inhaled corticosteroids for patients with mild persis- tent asthma and recommended as alternative add-on (to inhaled corticosteroids) treatment in patients with moderate persistent (step 3) and severe persistent (step 4) asthma (2). Numerous clinical trials in adults and children with asthma have established the efficacy and safety of montelukast (3, 4). However, interpatient variability in response to montelukast in both children and adults with asthma is significant, with 35 to 78% of patients receiving montelukast being classified as nonresponders (5-7). The mechanisms underlying interpatient variability in response are not clear but are believed to be due, in part, to genetic variability (8-11). Indeed, several studies have reported that promoter polymorphisms in the ALOX5 (12) and the LTC 4 synthase (LTC4S) genes contribute to variability in response to LT modifiers and LT selective antagonists (13)(14)(15)(16).Cy...

Leukotriene pathway genetics and pharmacogenetics in allergy

“…Mean FEV 1 improved by approximately 18.8 ± 3.6% (n = 64) for wild-type homozygotes and 23.3 ± 6% (n = 40) for heterozygotes compared with )1.2 ± 2.9% (n = 10) in homozygote mutant individuals (68). Similarly, Lima et al showed a significantly higher FEV 1 response to the LTRA montelukast for the ALOX5 rs2115819 SNP GG homozygotes compared to the AA and AG genotypes (p = 0.017) (142). Another study found no polymorphism specific bronchodilator responses between homozygous wildtypes and heterozygotes for the ALOX5 Sp1 polymorphism in 52 asthma subjects (143).…”

“…For a LTA4H rs2660845 G>A SNP, possession of the minor G allele gave a greater likelihood of experiencing an asthma exacerbation, which was further increased in the homozygote state (OR for GA and GG >4, p = <0.01) while taking LTRA (142).…”

Treatment response heterogeneity in asthma: the role of genetic variation

“…Another genetic variant in ALOX5, a SNP at position rs2115819, has been found to be associated with less improvement in lung function when treated with LTRA [57] or leukotriene inhibitor [60]. Nevertheless, smaller studies by Mougey et al (n = 65 patients) [46] and Kotani et al (n=21 patients) [61] did not find any pharmacogenetics effect of this variant in studies with montelukast.…”

“…In addition, Telleria et al showed that asthma patients with less than 5 tandem repeats more often suffered exacerbations and required albuterol to control symptoms when treated with montelukast [56]. In contrast, a study by Lima et al found that patients carrying 5 tandem repeats had an increased risk of exacerbations compared to patients carrying variant alleles [57]. Studies by Fowler et al and Klotsman et al reported no increased risk of poor montelukast response in patients carrying this genetic variant [54,58].…”

African Americans with Asthma: Genetic Insights

“…Not surprisingly, a number of target candidates that have been associated with asthma susceptibility are relevant to the mucosa and the bronchial epithelium (i.e., DPP10 [2], SPINK5 [3], GPRA [4]). Some of the earliest efforts in asthma genetics were directed-and efforts continue to be directedtoward candidate genes in pathways associated with treatment (i.e., ADRB2 [5,6], ALOX5 [7,8], CRHR1 [9]). As an outcome of what was, in the early 1990s, a relatively novel dichotomization of the cytokine milieu in the context of asthma, Th2 cytokines were a high priority set of priority candidate genes in some of the earliest association studies on asthma (i.e., IL4, IL13), and represent some of the most replicated associations to date (10)(11)(12).…”