Nasal DNA methylation differentiates severe from non‐severe asthma in African‐American children

Abstract

Background: Asthma is highly heterogeneous, and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis.This study aimed to identify nasal epithelial DNAm differences between severe and nonsevere asthmatic children and evaluate the impact of environmental exposures.Methods: Thirty-three nonsevere and 22 severe asthmatic African American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. Twenty-seven DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs was altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched.Conclusions: Significant differences in nasal epithelial DNAm were observed between nonsevere and severe asthma in African American children, a subset of which may be useful to predict disease severity. These CpG sites are subjected to the influences of environmental exposures and may regulate gene expression. | 1837 ZHU et al.

DNA methylation biomarkers in asthma and rhinitis: Are we there yet?

“…DNAm levels of 39 DMPs significantly correlated with mRNA levels in children with RNA-seq data available. Moreover, enrichment was observed for three regulatory histone marks associated with functional gene regulatory elements around CpG sites associated with asthma severity, 49 confirming the hypothesis that histone modifications are essential for the pathogenesis and progression of asthma, which regulates gene function together with, or independent, of DNAm. 63,64 Regarding AR, data indicating its association with the methylation of nasal epithelial cells is scarce.…”

“…Several of the annotated genes, play a critical role in asthma 57–62 . Six DMPS, which revealed to be associated with asthma severity, annotated to TMEM51 , WDR25 , HIPK3 , and KLF11 , 49 were associated with clinical features of asthma in Project VIVA, 13 supporting the involvement of these identified CpGs in regulation of asthma severity. DNAm levels of 39 DMPs significantly correlated with mRNA levels in children with RNA‐seq data available.…”

“…identified 48 DMRs that are significantly associated with environmental tobacco smoke (ETS). Furthermore, Zhu et al 49 . 2019 showed that DMPs which are associated to asthma severity are also associated to second‐hand smoking.…”

“…Furthermore, Zhu et al. 49 2019 showed that DMPs which are associated to asthma severity are also associated to second‐hand smoking.…”

Single-cell RNA-seq analysis reveals lung epithelial cell-specific contributions of Tet1 to allergic inflammation

“…Using RNA-sequencing, previous studies have noted significant transcriptomic differences in both asthmatic patients and animals with allergic lung inflammation [2][3][4] . Recent studies, including ours 2,[5][6][7] , have also linked DNA methylation-associated transcriptomic changes to the pathogenesis and progression of asthma. Other studies have linked enzymes involved in DNA methylation maintenance to asthma pathogenesis 8 .…”