Genome-wide association study of leukotriene modifier response in asthma

Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and p...

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Bibliographic Details
Published in:The pharmacogenomics journal 2016-04, Vol.16 (2), p.151-157
Main Authors: Dahlin, A, Litonjua, A, Irvin, C G, Peters, S P, Lima, J J, Kubo, M, Tamari, M, Tantisira, K G
Format: Article
Language:English
Subjects:
45/43
631/208/205
Acetates - therapeutic use
Anti-Asthmatic Agents - therapeutic use
Asthma
Asthma - drug therapy
Asthma - genetics
Asthma - metabolism
Biomedical and Life Sciences
Biomedicine
Cohort Studies
Cyclopropanes
Dosage and administration
Drug metabolism
Drug therapy
Gene Expression
Gene-Environment Interaction
Genetic aspects
Genetic Loci
Genome-wide association studies
Genome-Wide Association Study
Genotype
Human Genetics
Humans
Hydroxyurea - analogs & derivatives
Hydroxyurea - therapeutic use
Identification and classification
Leukotrienes - metabolism
Oncology
Original
original-article
Pharmacotherapy
Phenotype
Polymorphism, Single Nucleotide
Psychopharmacology
Quinolines - therapeutic use
Sulfides
Zileuton
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Summary:Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N =526) of zileuton response were interrogated. Using a gene–environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV 1 ) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance ( P =6.28 × 10 −08 ); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV 1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P =1.25 × 10 −07 ). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.
ISSN:1470-269X
1473-1150
DOI:10.1038/tpj.2015.34