Epigenome-wide association study identifies epigenetic markers for asthma and rhinitis in nasal epithelial cells in the PIAMA study
Overig (Epigenetics)Rationale: Epigenetic changes in allergic disease have recently attracted considerable interest because they might mediate genetic and environmental effects and lead to allergic disease1. Epigenetic patterns in nasal epithelium, may be a good and accessible proxy for the bronchial epithelium2, and provide insights into the cellular mechanisms of asthma and rhinitis. We aimed to identify methylation signatures in nasal epithelial brushes related to rhinitis and asthma and relate those to environmental factors.
Methods: DNA methylation was assessed using the Illumina Methylation 450k BeadChip in 455 nasal brush samples collected from 16-years-old participants within the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort of Dutch children born in 1996-1997. CpG sites (CpGs) related to asthma, rhinitis and respiratory allergic disease (ARD, defined as asthma or rhinitis) were identified using logistic regression, and replicated in two independent cohorts (72 predominantly African American children, and 487 Puerto Rican children). Results were stratified by asthma / rhinitis patients with and without IgE sensitization. Significant CpGs were related to environmental exposures, and correlated to gene expression by RNA-sequencing (n=244).
Results: The prevalence of asthma, rhinitis and ARD was 8.13%, 45.05% and 46.37% respectively, and 6.81% of total population have both asthma and rhinitis. After replication, one out of 95 CpGs associated with asthma, 62 out of 81 CpGs associated with rhinitis and 60 out of 75 CpGs associated with ARD. The results of rhinitis and ARD were highly overlapping. Top replicated CpGs were near genes relevant to inflammatory response, including NTRK1, GJA4 and CYP27B1. Methylation levels of top CpGs associated with gene-expression levels of nearby genes, and these cis-eQTM (expression quantitative trait DNA methylation) genes were enriched in immune-related pathways. The IgE stratified analysis indicated that the nasal DNA methylation signals associated with ARD were driven by IgE positive subjects. CpG (cg03565274) showed positive association with pet exposure (P = 7.57×10-4), negative correlation with allergic respiratory disease, and positive correlation with expression level of ZMYND10 which is highly expressed in ciliated cells.
Conclusion: We identified methylation profiles across the genome in relation to asthma and rhinitis in nasal epithelium. Our study indicates that nasal epithelial epigenetic research on asthma should take the strong effect of rhinitis into consideration. Early-life pet exposure may have long lasting effects on nasal epithelial methylation in allergic respiratory disease.
1. Xu, C.-J. et al. DNA methylation in childhood asthma: an epigenome-wide meta-analysis. The Lancet Respiratory Medicine 6, 379–388 (2018).
2. Bergougnoux, A., Claustres, M. & De Sario, A. Nasal epithelial cells: a tool to study DNA methylation in airway diseases. Epigenomics 7, 119–126 (2015).