Asthma is known to display different phenotypes across the life-course, suggesting that age related changes are particularly relevant to understanding asthma pathogenesis and remission. We have ...previously demonstrated that a lung function phenotype associated with asthma, bronchodilator response, is reduced with age, at rate of 0.24 percent per year.
In this study, we interrogated the serum metabolome, to determine whether circulating metabolites mediate age-related changes in bronchodilator response (BDR) for individuals with asthma. We used data on 295 participants from the follow-up phase of the CAMP clinical trial (age 12.2-25.9 years; mean BDR of 8%, standard deviation 7%). Using a counterfactual framework, we analyzed over 500 pareto-scaled metabolites using mediation analysis to identify indirect effects of age through potential metabolite mediators.
There was a significant indirect effect of age on BDR through 4 plasmalogens (C36:1 PC and related metabolites) (Indirect Effect Beta = -0.001,
= 0.006).
Our findings suggest that plasmalogens may contribute to age-related asthma phenotypes, and may also serve as potential pharmacologic targets for enhancement of lung function in individuals with asthma.
This work uses data from the previous clinical trial of asthma, the Childhood Asthma Management Program (CAMP), registered at ClinicalTrials.gov, # NCT00000575.
Although accurate measures of heritability are required to understand the pharmacogenetic basis of drug treatment response, these are generally not available, as it is unfeasible to give medications ...to individuals for which treatment is not indicated. Using a polygenic linear mixed modeling approach, we estimated lower bounds on the heritability of asthma and the heritability of two related drug-response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide single nucleotide polymorphism (SNP) data from existing asthma cohorts. Our estimate of the heritability for bronchodilator response is 28.5% (SE 16%, P=0.043) and airway hyperresponsiveness is 51.1% (SE 34%, P=0.064), whereas we estimate asthma genetic liability at 61.5% (SE 16%, P<0.001). Our results agree with the previously published estimates of the heritability of these traits, suggesting that the linear mixed modeling method is useful for computing the heritability of other pharmacogenetic traits. Furthermore, our results indicate that multiple SNP main effects, including SNPs as yet unidentified by genome-wide association study methods, together explain a sizable portion of the heritability of these traits.
Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction ...and chronic obstructive pulmonary disease.
To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.
We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.
An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10
; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.
Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).
Asthma patient response to inhaled corticosteroids (ICS) is variable and difficult to quantify. We aimed to define a measure of steroid response suitable for pharmacogenetic research in longitudinal ...and cross-sectional cohorts. Using longitudinal data from the Childhood Asthma Management Program (CAMP) asthma cohort, we defined the Cross-sectional Asthma STEroid Response (CASTER) measure in cross-sectional data. We then applied this to cross-sectional slices of four independent asthma cohorts: The Improving Asthma Control Trial (IMPACT), the Salmeterol or Corticosteroids Study (SOCS), the Pediatric Asthma Controller Trial (PACT), and the Genetics of Asthma in Costa Rica Study (GACRS). CASTER achieved high accuracy on the childhood asthma cohorts: GACRS, PACT, and also on cross-sectional data from CAMP (AUCs 82%, 71%, 63%, respectively). This demonstrates that select cross-sectional clinical information is sufficient to identify good and poor responders to ICS treatment in childhood asthma. Thus, CASTER represents a major improvement in the usability and applicability of steroid response measures in asthma research.
The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in ...modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (
-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = -0.004,
; GACRS: β = -0.015,
), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005,
GACRS: β = 0.023,
) Five additional metabolites had a
-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response.
Asthma affects more than 300 million people in the world, costs over $80 billion annually in the United States, and is efficaciously treated with inhaled corticosteroids (ICS). To our knowledge, no ...studies have examined the real-world effectiveness of ICS, including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), and patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. Data included longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS-LABA combination. Asthma exacerbations were defined as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We used an expected-value approach to determine ICS and ICS-LABA coverage over exacerbation events. We compared rates of exacerbation of subjects on ICS or ICS-LABAs to their own rates of exacerbation when off controller medications. We found ICS-LABA therapy had significant effects, reducing all types of exacerbations per day by a factor of 1.76 (95% CI (1.06, 2.93),
= 0.03) and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53),
= 0.037). In conclusion, ICS-LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.
Several reports have shown that statin treatment benefits patients with asthma; however, inconsistent effects have been observed. The mir-152 family (148a, 148b and 152) has been implicated in ...asthma. These microRNAs suppress HLA-G expression, and rs1063320, a common SNP in the HLA-G 3'UTR that is associated with asthma risk, modulates miRNA binding. We report that statins upregulate mir-148b and 152, and affect HLA-G expression in an rs1063320-dependent fashion. In addition, we found that individuals who carried the G minor allele of rs1063320 had reduced asthma-related exacerbations (emergency department visits, hospitalizations or oral steroid use) compared with non-carriers (P=0.03) in statin users ascertained in the Personalized Medicine Research Project at the Marshfield Clinic (n=421). These findings support the hypothesis that rs1063320 modifies the effect of statin benefit in asthma, and thus may contribute to variation in statin efficacy for the management of this disease.
Inhaled corticosteroids (ICS) are the most commonly used controller medications prescribed for asthma. Two single-nucleotide polymorphisms (SNPs), rs1876828 in corticotrophin releasing hormone ...receptor 1 and rs37973 in GLCCI1, have previously been associated with corticosteroid efficacy. We studied data from four existing clinical trials of asthmatics, who received ICS and had lung function measured by forced expiratory volume in 1 s (FEV1) before and after the period of such treatment. We combined the two SNPs rs37973 and rs1876828 into a predictive test of FEV1 change using a Bayesian model, which identified patients with good or poor steroid response (highest or lowest quartile, respectively) with predictive performance of 65.7% (P=0.039 vs random) area under the receiver-operator characteristic curve in the training population and 65.9% (P=0.025 vs random) in the test population. These findings show that two genetic variants can be combined into a predictive test that achieves similar accuracy and superior replicability compared with single SNP predictors.
Many microRNAs (miRNAs) have been associated with asthma and chronic obstructive pulmonary disease (COPD). Longitudinal lung function growth trajectories of children with asthma-normal growth, ...reduced growth (RG), early decline (ED), and RG with an ED (RGED)-have been observed, with RG and RGED associated with adverse outcomes, including COPD.
Our aim was to determine whether circulating miRNAs from an early age in children with asthma would be prognostic of reduced lung function growth patterns over the next 16 years.
We performed small RNA sequencing on sera from 492 children aged 5 to 12 years with mild-to-moderate asthma from the CAMP clinical trial, who were subsequently followed for 12 to 16 years. miRNAs were assessed for differential expression between previously assigned lung function growth patterns.
We had 448 samples and 259 miRNAs for differential analysis. In a comparison of the normal and the most severe group (ie, normal growth compared with RGED), we found 1 strongly dysregulated miRNA, hsa-miR-145-5p (P < 8.01E-05). This miR was downregulated in both ED groups (ie, ED and RGED). We verified that miR-145-5p was strongly associated with airway smooth muscle cell growth in vitro.
Our results showed that miR-145-5p is associated with the ED patterns of lung function growth leading to COPD in children with asthma and additionally increases airway smooth muscle cell proliferation. This represents a significant extension of our understanding of the role of miR-145-5p in COPD and suggests that reduced expression of miR-145-5p is a risk factor for ED of long-term lung function.
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.
We present a genome‐wide association study and demonstrate that genetic variability contributes to the risk of asthma exacerbations in patients taking inhaled corticosteroids.
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