Genome-wide association study of leukotriene modifier response in asthma.
Pharmacogenomics J
; 16(2): 151-7, 2016 Apr.
Article
in En
| MEDLINE
| ID: mdl-26031901
ABSTRACT
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 (ΔFEV1) 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 ΔFEV1 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Asthma
/
Leukotrienes
/
Anti-Asthmatic Agents
/
Genetic Loci
Type of study:
Clinical_trials
/
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Pharmacogenomics J
Journal subject:
BIOLOGIA MOLECULAR
/
FARMACOLOGIA
Year:
2016
Type:
Article
Affiliation country:
United States