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Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma.

ABSTRACT: While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10-05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10-08) (rs34631960 [OR 2.3±1.6-3.3] in thrombospondin type 1 domain-containing protein 4 (THSD4) and rs2328386 [OR 0.5±0.3-0.7] in human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.

SUBMITTER: Dahlin A

PROVIDER: S-EPMC7051058 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma.

Dahlin Amber A Sordillo Joanne E JE McGeachie Michael M Kelly Rachel S RS Tantisira Kelan G KG Lutz Sharon M SM Lasky-Su Jessica J Wu Ann Chen AC

PloS one 20200302 3

While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide ...[more]

PMID: 32119686

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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: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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Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma.

Publications

Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma.

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