title: Genome-wide association study of leukotriene modifier response in asthma.
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.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dahlin
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Litonjua
authors.affiliation: Department of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Peters
authors.affiliation: Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lima
authors.affiliation: Center for Integrative Medical Sciences, Riken, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Center for Integrative Medical Sciences, Riken, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tamari
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Tantisira
mesh_terms: D000085:Acetates / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003521:Cyclopropanes; D059647:Gene-Environment Interaction; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000627:therapeutic use; D015289:Leukotrienes / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines / Q000627:therapeutic use; D013440:Sulfides
chemical_list: D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C093875:montelukast; C063449:zileuton; D006918:Hydroxyurea