Project 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.

Project description:Asthma is a polygenic disease that may onset during childhood. Inhaled corticosteroids (ICS) are the main therapy in asthma, although their efficacy varies among individuals. Nuclear factor κB (NF-κB) is an important target of ICS treatment of asthma. Recent research has reported that GRB2 associated binding protein 1 (GAB1) gene may participate in the pathogenesis of asthma by regulating the NF-κB pathway. Therefore, we used the technique of an improved multiplex ligation detection reaction to sequence GAB1 gene and investigated the involvement of Single-nucleotide variants (SNVs) in GAB1 gene in asthma and ICS efficacy in asthmatic children. We found no differences between asthma cases and controls in allele or genotype frequencies of GAB1. Haplotype analysis showed an increased tendency for AGGAGC frequency in asthma patients compared with controls (OR = 2.69, p = 0.018). The percentage of EOS and genotype distribution of rs1397527 were associated (p = 0.007). The EOS percentage was higher in GT genotype when compared to the GG genotype (5.50 vs 3.00, Bonferroni adjusted p = 0.005). After 12-weeks ICS treatment, GAB1 rs1397527 TT and GT genotype carriers had a smaller change in forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) than GG carriers (p = 0.009), and rs3805236 GG and AG genotype carriers also had a smaller change in FEV1/FVC than AA carriers (p = 0.025). For ICS response, the frequency of GG genotype of rs1397527 was significantly higher in good responders (p = 0.038). The generalized multifactor dimensionality reduction (GMDR) analysis showed a best significant four-order model (rs1397527, allergen exposure, environmental tobacco smoke exposure, and pet exposure) involving gene-environment interactions (p = 0.001). In summary, we found that GAB1 SNVs were not associated with asthma susceptibility. Haplotype AGGAGC was a risk factor for asthma. GAB1 variants were associated with eosinophils and ICS response in asthmatics. Furthermore, gene-environment interaction was observed.

Project description:BackgroundFor children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.MethodsWe randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.ResultsA differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).ConclusionsNearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)

Project description:BACKGROUND:Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS:We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS:The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS:In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

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IL1RL1 gene variations are associated with asthma exacerbations in children and adolescents using inhaled corticosteroids.

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