CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids

Amber Dahlin; Joshua Denny; Dan M Roden; Murray H Brilliant; Christie Ingram; Terrie E Kitchner; James G Linneman; Christian M Shaffer; Peter Weeke; Hua Xu; Michiaki Kubo; Mayumi Tamari; George L Clemmer; John Ziniti; Michael J McGeachie; Kelan G Tantisira; Scott T Weiss; Ann Chen Wu

doi:10.1002/iid3.73

CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids

Immun Inflamm Dis. 2015 Jul 14;3(4):350-9. doi: 10.1002/iid3.73. eCollection 2015 Dec.

Authors

Amber Dahlin¹, Joshua Denny², Dan M Roden³, Murray H Brilliant⁴, Christie Ingram⁵, Terrie E Kitchner⁴, James G Linneman⁶, Christian M Shaffer⁵, Peter Weeke⁷, Hua Xu⁸, Michiaki Kubo⁹, Mayumi Tamari⁹, George L Clemmer¹, John Ziniti¹, Michael J McGeachie¹, Kelan G Tantisira¹, Scott T Weiss¹, Ann Chen Wu¹⁰

Affiliations

¹ Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115.
² Department of Medical BioinformaticsVanderbilt University School of MedicineNashvilleTennessee37235; Department of MedicineVanderbilt UniversityNashvilleTennessee37235.
³ Division of Clinical Pharmacology, Department of Medicine Vanderbilt University School of Medicine Nashville Tennessee 37235.
⁴ Center for Human Genetics Marshfield Clinic Research Foundation Marshfield Wisconsin 54449.
⁵ Department of Medicine Vanderbilt University Nashville Tennessee 37235.
⁶ Biomedical Informatics Research Center Marshfield Clinic Research Foundation Marshfield Wisconsin 54449.
⁷ Department of MedicineVanderbilt UniversityNashvilleTennessee37235; Department of CardiologyCopenhagen, University HospitalGentofteDenmark.
⁸ School of Biomedical Informatics The University of Texas Health Science Center at Houston Houston Texas 77030.
⁹ Riken Center for Genomic Medicine Kanagawa Japan.
¹⁰ 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.

PMID: 26734457
PMCID: PMC4693729
DOI: 10.1002/iid3.73

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.

Keywords: Asthma; EMR; GWAS; exacerbations; inhaled corticosteroids; pharmacogenomics.

Abstract

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