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.
Highlights
Asthma, a complex disease characterized by airway hyperresponsiveness, airway obstruction, inflammation and airway remodeling, confers substantial global financial burden and is a significant source of increasing morbidity and mortality worldwide [1, 2]
Our study identified six novel single nucleotide polymorphisms (SNPs) associated with differential risk of asthma exacerbations
We found that our top GWAS result, rs2395672, was present among the top-ranked discovery SNPs and replicated in Personalized Medicine Research Project (PMRP) (Tables 2 and 3)
Summary
A complex disease characterized by airway hyperresponsiveness, airway obstruction, inflammation and airway remodeling, confers substantial global financial burden and is a significant source of increasing morbidity and mortality worldwide [1, 2]. Some severely affected asthmatics, including patients with poorly controlled asthma, experience exacerbations, defined as the occurrence of hospitalizations, emergency department (ED) or intensive care unit (ICU) visit to receive treatment, and the requirement of oral corticosteroids. Clinical treatment of asthma exacerbations consumes significant healthcare resources, and patients who experience severe exacerbations have more ED and ICU visits, more frequent and longer hospitalizations related to their asthma, increased numbers of lost school and work days, more frequent unscheduled physician visits, diminished quality of life, and increased mortality risk [3, 4]. Recent GWAS and candidate gene studies have identified genetic risk factors for asthma exacerbations, the candidate genes ST13 [24], ADRB2 [10, 14, 25], P2X7 [26], FCER2 [21, 27], and IL13 [28], in patients taking ICS
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