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

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 emergenc...

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Autores principales: Dahlin, Amber, Denny, Joshua, Roden, Dan M., Brilliant, Murray H., Ingram, Christie, Kitchner, Terrie E., Linneman, James G., Shaffer, Christian M., Weeke, Peter, Xu, Hua, Kubo, Michiaki, Tamari, Mayumi, Clemmer, George L., Ziniti, John, McGeachie, Michael J., Tantisira, Kelan G., Weiss, Scott T., Wu, Ann Chen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693729/
https://www.ncbi.nlm.nih.gov/pubmed/26734457
http://dx.doi.org/10.1002/iid3.73
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author Dahlin, Amber
Denny, Joshua
Roden, Dan M.
Brilliant, Murray H.
Ingram, Christie
Kitchner, Terrie E.
Linneman, James G.
Shaffer, Christian M.
Weeke, Peter
Xu, Hua
Kubo, Michiaki
Tamari, Mayumi
Clemmer, George L.
Ziniti, John
McGeachie, Michael J.
Tantisira, Kelan G.
Weiss, Scott T.
Wu, Ann Chen
author_facet Dahlin, Amber
Denny, Joshua
Roden, Dan M.
Brilliant, Murray H.
Ingram, Christie
Kitchner, Terrie E.
Linneman, James G.
Shaffer, Christian M.
Weeke, Peter
Xu, Hua
Kubo, Michiaki
Tamari, Mayumi
Clemmer, George L.
Ziniti, John
McGeachie, Michael J.
Tantisira, Kelan G.
Weiss, Scott T.
Wu, Ann Chen
author_sort Dahlin, Amber
collection PubMed
description 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.
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spelling pubmed-46937292016-01-05 CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids Dahlin, Amber Denny, Joshua Roden, Dan M. Brilliant, Murray H. Ingram, Christie Kitchner, Terrie E. Linneman, James G. Shaffer, Christian M. Weeke, Peter Xu, Hua Kubo, Michiaki Tamari, Mayumi Clemmer, George L. Ziniti, John McGeachie, Michael J. Tantisira, Kelan G. Weiss, Scott T. Wu, Ann Chen Immun Inflamm Dis Original Research 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. John Wiley and Sons Inc. 2015-07-14 /pmc/articles/PMC4693729/ /pubmed/26734457 http://dx.doi.org/10.1002/iid3.73 Text en © 2015 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Dahlin, Amber
Denny, Joshua
Roden, Dan M.
Brilliant, Murray H.
Ingram, Christie
Kitchner, Terrie E.
Linneman, James G.
Shaffer, Christian M.
Weeke, Peter
Xu, Hua
Kubo, Michiaki
Tamari, Mayumi
Clemmer, George L.
Ziniti, John
McGeachie, Michael J.
Tantisira, Kelan G.
Weiss, Scott T.
Wu, Ann Chen
CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
title CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
title_full CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
title_fullStr CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
title_full_unstemmed CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
title_short CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
title_sort cmtr1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693729/
https://www.ncbi.nlm.nih.gov/pubmed/26734457
http://dx.doi.org/10.1002/iid3.73
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