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

CMTR1 Is Associated With Increased Asthma Exacerbations in Patients Taking Inhaled Corticosteroids

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Free PMC article

CMTR1 Is Associated With Increased Asthma Exacerbations in Patients Taking Inhaled Corticosteroids

Amber Dahlin et al. Immun Inflamm Dis. .
Free PMC article

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.

Figures

Figure 1
Figure 1
GWAS results. Plots of –log10 transformed, two‐sided P values (expected vs. observed) for (A) BioVU and (B) PMRP are shown (λ [SE]: in [A] 1.03 [5.4 × 10−05]; in [B] 1.01 [7.6 × 10−06]). (C) The Manhattan plot shows –log10‐transformed association P values for the meta‐analysis, plotted versus chromosome position (x axis). The results were adjusted for age at reported exacerbation event, gender, and the first four principal components. The blue line indicates the P value threshold for suggestive genome‐wide significance (10−05) whereas the red line indicates the genome‐wide significance threshold (10−07).
Figure 2
Figure 2
Differential Expression of CMTR1. The expression of CMTR1 mRNA transcripts was evaluated using a publicly available dataset (GEO accession GSE30326) from a microarray analysis of nasal lavage samples obtained from asthmatic children during and after asthma exacerbation 35. The y axis represents normalized expression values of CMTR1 from 32 paired mRNA samples.

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