Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma
Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. 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 clini...
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| Published in: | American journal of respiratory and critical care medicine Vol. 173; no. 4; pp. 379 - 385 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
New York, NY
Am Thoracic Soc
15-02-2006
American Lung Association American Thoracic Society |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes.
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.
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.
Outcomes were asthma exacerbation rate and changes in FEV(1) compared with baseline.
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.
Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supported by the American Lung Association, the Nemours Research Foundation, and National Institutes of Health grants R01 HL071394 (J.J.L.) and U01 HL65899 (S.T.W.). This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: J.J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.G.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.W. received consulting fees from GlaxoSmithKline, Pfizer, Sanofi-Aventis, Emphasys, and Spiration in the past 3 yr for research oversight and review committees. He has served on advisory boards for Boehringer-Ingelheim, Pfizer, GlaxoSmithKline, Hill-Rom, Otsuka, Ortho, and Amgen. S.T.W. has also received research grants from Boehringer-Ingelheim, Otsuka, and Pfizer. Conflicts of interest regarding human research are managed by Johns Hopkins University. S.T.W. received a grant for $900,065, Asthma Policy Modeling Study, from AstraZeneca for 1997–2003. He has been a coinvestigator on a grant from Boehringer-Ingelheim to investigate a COPD natural history model, which began in 2003. He has received no funds for his involvement in this project. He had been an advisor to the TENOR Study for Genentech and has received $5,000 for 2003–2004. He received a grant from Glaxo-Wellcome for $500,000 for genomic equipment for 2000–2003. He was a consultant for Roche Pharmaceuticals in 2000 and received no financial remuneration for this consultancy. K.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Originally Published in Press as DOI: 10.1164/rccm.200509-1412OC on November 17, 2005 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@nemours.org |
| ISSN: | 1073-449X 1535-4970 |
| DOI: | 10.1164/rccm.200509-1412OC |