title: CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids.
abstract: Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case-control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10(-05)). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03-1.11; joint P = 2.3 × 10(-06)). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.
authors.affiliation: Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
authors.forename: Amber
authors.initials: A
authors.lastname: Dahlin
authors.affiliation: Department of Medical BioinformaticsVanderbilt University School of MedicineNashvilleTennessee37235; Department of MedicineVanderbilt UniversityNashvilleTennessee37235.
authors.forename: Joshua
authors.initials: J
authors.lastname: Denny
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine Vanderbilt University School of Medicine Nashville Tennessee 37235.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Center for Human Genetics Marshfield Clinic Research Foundation Marshfield Wisconsin 54449.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Department of Medicine Vanderbilt University Nashville Tennessee 37235.
authors.forename: Christie
authors.initials: C
authors.lastname: Ingram
authors.affiliation: Center for Human Genetics Marshfield Clinic Research Foundation Marshfield Wisconsin 54449.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Kitchner
authors.affiliation: Biomedical Informatics Research Center Marshfield Clinic Research Foundation Marshfield Wisconsin 54449.
authors.forename: James G
authors.initials: JG
authors.lastname: Linneman
authors.affiliation: Department of Medicine Vanderbilt University Nashville Tennessee 37235.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Shaffer
authors.affiliation: Department of MedicineVanderbilt UniversityNashvilleTennessee37235; Department of CardiologyCopenhagen, University HospitalGentofteDenmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.affiliation: School of Biomedical Informatics The University of Texas Health Science Center at Houston Houston Texas 77030.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Riken Center for Genomic Medicine Kanagawa Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Riken Center for Genomic Medicine Kanagawa Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
authors.affiliation: Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
authors.forename: George L
authors.initials: GL
authors.lastname: Clemmer
authors.affiliation: Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
authors.forename: John
authors.initials: J
authors.lastname: Ziniti
authors.affiliation: Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGeachie
authors.affiliation: Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.affiliation: Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.affiliation: Channing Division of Network Medicine, Department of MedicineBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusetts02115; Center for Child Health Care Studies, Department of Population MedicineHarvard Pilgrim Health Care Institute and Harvard Medical SchoolBostonMassachusetts02115.
authors.forename: Ann Chen
authors.initials: AC
authors.lastname: Wu
keywords: Asthma; EMR; GWAS; exacerbations; inhaled corticosteroids; pharmacogenomics