Few data exist on the predictors of asthma remission by early adulthood in North America.
The predictors of adult asthma remission were determined in a multiethnic population of patients with ...mild-to-moderate persistent childhood asthma.
Asthma remission in early adulthood was measured by using 2 definitions: a clinical and a strict definition. Both included normal lung function and the absence of symptoms, exacerbations, and medication use. The strict definition also included normal airways responsiveness. Predictors were identified from 23 baseline measures by using multivariate logistic regression. The probability of remission was modeled by using decision tree analysis.
In 879 subjects the mean ± SD baseline age was 8.8 ± 2.1 years, 59.4% were male, and 68.7% were white. By adulthood, 229 (26.0%) of 879 participants were in clinical remission, and 111 (15.0%) of 741 participants were in strict remission. The degree of FEV1/forced vital capacity (FVC) ratio impairment was the largest predictor of asthma remission. More than half of boys and two thirds of girls with baseline FEV1/FVC ratios of 90% or greater were in remission at adulthood. Decreased airways responsiveness was also a predictor for both remission definitions (clinical remission odds ratio, 1.23 95% CI, 1.09-1.39; strict remission odds ratio, 1.52 95% CI, 1.26-1.84). The combination of normal FEV1/FVC ratio, airways responsiveness, and serum eosinophil count at baseline yielded greater than 80% probability of remission by adulthood.
A considerable minority of patients with persistent childhood asthma will have disease remission by adulthood. Clinical prognostic indicators of asthma remission, including baseline lung function, can be seen from an early age.
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Asthma is a chronic inflammatory respiratory disease that affects over 300 million people worldwide. Glucocorticoids are a mainstay therapy for asthma because they exert anti-inflammatory effects in ...multiple lung tissues, including the airway smooth muscle (ASM). However, the mechanism by which glucocorticoids suppress inflammation in ASM remains poorly understood. Using RNA-Seq, a high-throughput sequencing method, we characterized transcriptomic changes in four primary human ASM cell lines that were treated with dexamethasone--a potent synthetic glucocorticoid (1 µM for 18 hours). Based on a Benjamini-Hochberg corrected p-value <0.05, we identified 316 differentially expressed genes, including both well known (DUSP1, KLF15, PER1, TSC22D3) and less investigated (C7, CCDC69, CRISPLD2) glucocorticoid-responsive genes. CRISPLD2, which encodes a secreted protein previously implicated in lung development and endotoxin regulation, was found to have SNPs that were moderately associated with inhaled corticosteroid resistance and bronchodilator response among asthma patients in two previously conducted genome-wide association studies. Quantitative RT-PCR and Western blotting showed that dexamethasone treatment significantly increased CRISPLD2 mRNA and protein expression in ASM cells. CRISPLD2 expression was also induced by the inflammatory cytokine IL1β, and small interfering RNA-mediated knockdown of CRISPLD2 further increased IL1β-induced expression of IL6 and IL8. Our findings offer a comprehensive view of the effect of a glucocorticoid on the ASM transcriptome and identify CRISPLD2 as an asthma pharmacogenetics candidate gene that regulates anti-inflammatory effects of glucocorticoids in the ASM.
Circulating microRNAs have shown promise as non-invasive biomarkers and predictors of disease activity. Prior asthma studies using clinical, biochemical and genomic data have not shown excellent ...prediction of exacerbation. We hypothesized that a panel of circulating microRNAs in a pediatric asthma cohort combined with an exacerbation clinical score might predict exacerbation better than the latter alone.
Serum samples from 153 children at randomization in the Childhood Asthma Management Program were profiled for 754 microRNAs. Data dichotomized for asthma exacerbation one year after randomization to inhaled corticosteroid treatment were used for binary logistic regression with miRNA expressions and exacerbation clinical score.
12 of 125 well-detected circulating microRNAs had significant odd ratios for exacerbation with miR-206 being most significant. Each doubling of expression of the 12 microRNA corresponded to a 25-67% increase in exacerbation risk. Stepwise logistic regression yielded a 3-microRNA model (miR-146b, miR-206 and miR-720) that, combined with the exacerbation clinical score, had excellent predictive power with a 0.81 AUROC. These 3 microRNAs were involved in NF-kβ and GSK3/AKT pathways.
This combined circulating microRNA-clinical score model predicted exacerbation in asthmatic subjects on inhaled corticosteroids better than each constituent feature alone.
ClinicalTrials.gov Identifier: NCT00000575 .
MicroRNAs are key transcriptional and network regulators previously associated with asthma susceptibility. However, their role in relation to asthma severity has not been delineated.
We hypothesized ...that circulating microRNAs could serve as biomarkers of changes in lung function in asthma patients.
We isolated microRNAs from serum samples obtained at randomization for 160 participants of the Childhood Asthma Management Program. Using a TaqMan microRNA array containing 754 microRNA primers, we tested for the presence of known asthma microRNAs, and assessed the association of the individual microRNAs with lung function as measured by FEV1/FVC, FEV1% and FVC%. We further tested the subset of FEV1/FVC microRNAs for sex-specific and lung developmental associations.
Of the 108 well-detected circulating microRNAs, 74 (68.5%) had previously been linked to asthma susceptibility. We found 22 (20.3%), 4 (3.7%) and 8 (7.4%) microRNAs to be associated with FEV1/FVC, FEV1% and FVC%, respectively. 8 (of 22) FEV1/FVC, 3 (of 4) FEV1% and 1 (of 8) FVC% microRNAs had functionally validated target genes that have been linked via genome wide association studies to asthma and FEV1 change. Among the 22 FEV1/FVC microRNAs, 9 (40.9%) remain associated with FEV1/FVC in boys alone in a sex-stratified analysis (compared with 3 FEV1/FVC microRNAs in girls alone), 7 (31.8%) were associated with fetal lung development, and 3 (13.6%) in both. Ontology analyses revealed enrichment for pathways integral to asthma, including PPAR signaling, G-protein coupled signaling, actin and myosin binding, and respiratory system development.
Circulating microRNAs reflect asthma biology and are associated with lung function differences in asthmatics. They may represent biomarkers of asthma severity.
The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association ...study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids.
We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects.
We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P=0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P=0.0007 for pooled data). Overall, the mean (±SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2±1.6% vs. 9.4±1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.
A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma.
Circulating microRNAs (miRNA) are promising biomarkers for human diseases. Our study hypothesizes that circulating miRNA would reveal candidate biomarkers related to airway hyperresponsiveness (AHR) ...and provide biologic insights into asthma epigenetic influences.
Serum samples obtained at randomization for 160 children in the Childhood Asthma Management Program were profiled using a TaqMan miRNA array set. The association of the isolated miRNA with methacholine PC20 was assessed. Network and pathway analyses were performed. Functional validation of two significant miRNAs was performed in human airway smooth muscle cells (HASMs).
Of 155 well-detected circulating miRNAs, eight were significantly associated with PC20 with the strongest association with miR-296-5p. Pathway analysis revealed miR-16-5p as a network hub, and involvement of multiple miRNAs interacting with genes in the FoxO and Hippo signaling pathways by KEGG analysis. Functional validation of two miRNA in HASM showed effects on cell growth and diameter.
Reduced circulatory miRNA expression at baseline is associated with an increase in PC20. These miRNA provide biologic insights into, and may serve as biomarkers of, asthma severity. miR-16-5p and -30d-5p regulate airway smooth muscle phenotypes critically involved in asthma pathogenesis, supporting a mechanistic link to these findings. Functional ASM phenotypes may be directly relevant to AHR.
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.
Globally, asthma is a chronic inflammatory respiratory disease affecting over 300 million people. Some asthma patients remain poorly controlled by conventional therapies and experience more ...life-threatening exacerbations. Vitamin D, as an adjunct therapy, may improve disease control in severe asthma patients since vitamin D enhances glucocorticoid responsiveness and mitigates airway smooth muscle (ASM) hyperplasia. We sought to characterize differences in transcriptome responsiveness to vitamin D between fatal asthma- and non-asthma-derived ASM by using RNA-Seq to measure ASM transcript expression in five donors with fatal asthma and ten non-asthma-derived donors at baseline and with vitamin D treatment. Based on a Benjamini-Hochberg corrected p-value <0.05, 838 genes were differentially expressed in fatal asthma vs. non-asthma-derived ASM at baseline, and vitamin D treatment compared to baseline conditions induced differential expression of 711 and 867 genes in fatal asthma- and non-asthma-derived ASM, respectively. Functional gene categories that were highly represented in all groups included extracellular matrix, and responses to steroid hormone stimuli and wounding. Genes differentially expressed by vitamin D also included cytokine and chemokine activity categories. Follow-up qPCR and individual analyte ELISA experiments were conducted for four cytokines (i.e. CCL2, CCL13, CXCL12, IL8) to measure TNFα-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNFα-induced IL8 protein secretion levels to a comparable degree in fatal asthma- and non-asthma-derived ASM even though IL8 had significantly higher baseline levels in fatal asthma-derived ASM. Our findings identify vitamin D-specific gene targets and provide transcriptomic data to explore differences in the ASM of fatal asthma- and non-asthma-derived donors.
Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological ...mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA-mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA-mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in
= 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value < 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3,
) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA-mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (
, LBH regulator of WNT signaling (
) and sex hormone signaling (Coactivator associated methyltransferase 1(
). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.
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