Influence of leukotriene pathway polymorphisms on response to montelukast in asthma.
BACKGROUND
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, chi(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.


METHODS
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 < 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.
Lima
John J
JJ
The American Lung Association Asthma Clinical Research Centers, Center for Pharmacogenetics, Nemours Children's Clinic, 807 Children's Way, Jacksonville, FL 32207, USA. jlima@nemours.org
Zhang
Shu
S
Grant
Audrey
A
Shao
Lianhe
L
Tantisira
Kelan G
KG
Allayee
Hooman
H
Wang
Jianwei
J
Sylvester
James
J
Holbrook
Janet
J
Wise
Robert
R
Weiss
Scott T
ST
Barnes
Kathleen
K
D000085:Acetates / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D003521:Cyclopropanes; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015289:Leukotrienes / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D011804:Quinolines / Q000627:therapeutic use*; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C093875:montelukast