The nasal methylome and childhood atopic asthma

Abstract

Background Given strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia may provide insight into allergic asthma. Objective To identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma[N=36] versus healthy controls[N=36]. Results were validated in an independent population of asthmatic children[N=30] using a shared healthy control population[N=36] and in independent population of Caucasian adult atopic asthmatics[N=12] and controls[N=12]. Results We identified 186 genes with significant methylation changes, differentially methylated regions(DMRs) or differentially methylated probes(DMPs), after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy, genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median 9.5%, range:2.6–29.5%). Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10−6 for DMRs and P<7.8x10−10 for DMPs). Quantitative analysis in 53 differentially expressed genes demonstrated that 32(60%) have significant methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. 67/186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult Caucasian asthmatics. Conclusions Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

The Nasal Methylome: A Key to Understanding Allergic Asthma

“…Some of the genes with the most prominent changes in DNA methylation and gene expression are consistent in nasal and airway epithelia (CAPN14, CTSC, and FBXL7, among others), whereas we identified other genes with larger changes in nasal epithelia (POSTN, CCL26, GATA2, HLA genes, to name a few). The majority of the genes with the most pronounced methylation-expression relationships were also identified in our previous nasal epithelial study (5), despite differences in age, ethnicity, and potential exposures between the two cohorts.…”

The environment, epigenome, and asthma

“…109 The magnitude of the methylation changes observed in nasal epithelia of these asthmatic children approaches that reported in malignancies. 110, 111 60% of genes that are differentially expressed in the asthmatic nasal epithelium have significant associations between DNA methylation and gene expression; these include asthma genes ( ALOX15 , CAPN14 , POSTN ), genes involved in inflammation and immunity, cell adhesion, extracellular matrix, obesity and autophagy, and epigenetic regulators, among others.…”

Epigenome-wide association study of asthma and wheeze in childhood and adolescence

“…As is evident from our analyses, adjusting for granulocytes alone does not appear to be sufficient for countering the confounding effects of eosinophils in EWAS using whole blood; however, EWAS based on DNA methylation from PBMC samples may be less affected by cell-type differences. Similarly, a study of asthma using methylation data from nasal epithelium observed associations between asthma and DNA methylation but did not specifically adjust for eosinophil cell counts [24]. However, the authors in this study did attempt to perform cell sorting which may have negated some of the confounding effects of cell mixtures by ensuring a more homogenous cell sample enriched for epithelial cells.…”

“…However, whether these associations are also present for the asthma phenotype has not been assessed. Studies that have examined DNA methylation associations with asthma have not specifically determined whether observed associations are due to cell type confounding between samples [23,24]. Eosinophils, a type of circulating granulocyte, are known to be increased in peripheral blood of some people with allergic conditions, such as certain subtypes of asthma [25,26].…”