Abstract
BackgroundTreatment response to systemic corticosteroid in asthmatic children is heterogeneous and may be mediated by epigenetic mechanism(s). We aim to identify DNA methylation (DNAm) changes responsive to steroid, and DNAm biomarkers that distinguish treatment response.Materials and methodsWe followed 33 children (ages 5–18) presenting to the Emergency Department (ED) for asthma exacerbation. Based on whether they met discharge criteria in ≤24 hours, participants were grouped into good and poor responders to steroid treatment. Nasal samples were collected upon presentation to the ED (T0) and 18–24 hours later (T1). Genome-wide DNAm was measured for both time points in 20 subjects, and compared between T0 and T1 in good and poor responders respectively. DNAm at T1 was also compared between two responder groups. DNAm of selected CpGs was verified in the complete cohort, and expression of associated genes was examined. Interactions between DNAm, common single nucleotide polymorphism (SNP) located at the CpG sites and treatment responses were assessed.ResultsThree CpGs located in the OTX2 promoter showed responder-specific DNAm changes from T0 to T1, in which DNAm decreased in good but not in poor responders. Good and poor responders showed differential DNAm at T1 in 127 CpGs without and 182 CpGs with common SNP co-localization. Negative correlations between DNAm and gene expression were observed at CpGs located within the LDHC promoter, suggesting an impact of DNAm on gene regulation. Interactions between SNPs, DNAm and treatment response were detected.ConclusionAcute systemic steroid treatment modifies nasal DNAm in good responders. Nasal DNAm, dependent or independent of SNPs, can differentiate response to treatment in acute asthmatic children.
Highlights
Asthma is the leading cause of emergency care and hospitalization in children
Three CpGs located in the OTX2 promoter showed responder-specific DNA methylation (DNAm) changes from T0 to T1, in which DNAm decreased in good but not in poor responders
We examined genome-wide DNAm using nasal epithelial cells to comprehensively search for CpG sites that undergo differential methylation changes in response to systemic corticosteroid treatment in good and poor steroid responder groups, as well as to identify biomarkers for treatment response
Summary
Asthma is the leading cause of emergency care and hospitalization in children. The current standard and most effective treatment for treating asthma exacerbation is systemic corticosteroid treatment. Due to heterogeneity in asthma phenotypes and natural history [1, 2], 40–70% of asthma treatment showed absent or incomplete efficacy [3]. Heterogeneous responses to current standard treatment regimens have been observed in children hospitalized for acute asthma exacerbations, and nearly two thirds of children who currently have asthma reported at least one attack in the previous 12 months. Care practices other than the standard treatments may improve asthma management; effective predictions of responses to standard treatments are needed in prior. Treatment response to systemic corticosteroid in asthmatic children is heterogeneous and may be mediated by epigenetic mechanism(s). We aim to identify DNA methylation (DNAm) changes responsive to steroid, and DNAm biomarkers that distinguish treatment response
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