Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization

Abstract

Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenomewide association meta-analysis and employed pathway and regional analyses of results. Sevenhundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylationtime interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.

Research Progress in Atopic March

“…Multiple methylation site-related genes were enriched to AA pathways, including eosinophil peroxidase ( EPX ), IL4 , interleukin 5 receptor A ( IL5RA ), and proteoglycan 2 ( PRG2 ). Furthermore, Peng et al identified several methylation sites of cord blood to be related to allergic phenotypes in mid-childhood and that some methylation sites of cord blood were also present in mid-childhood ( 89 ), which suggested a longitudinal time trend.…”

Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation

“…6 Recently, epigenome-wide association studies (EWASs) of atopy and total serum IgE level reported that epigenetic regulation of genes involved in asthma, immune responses, and mechanistic target of rapamycin signaling are associated with allergic sensitization. [7][8][9] Nonetheless, limited studies have combined GWAS and EWAS to investigate atopy and allergic diseases. We hypothesized that integrated genetic and epigenetic analyses would help identify novel genes that could not have been identified through GWAS or EWAS alone owing to the moderate magnitudes of their associations.…”

Immunologic and Non-Immunologic Mechanisms Leading to Airway Remodeling in Asthma

“…Assessing the DNA methylation of 1629 children, Wu et al reported hyper-methylation of IL-10 and LIM Domain Only-2 (LMO2) [150]. Interestingly, there is evidence that childhood asthma, as well as COPD (later in life), is linked to a modification of the TGF-β signaling pathway by epigenetic events earlier in life [151]. Hyper-methylation of IL-4, IL-5, and eosinophil peroxidase were reported in two cohorts of children with asthma and were linked to impaired IP3-mTOR signaling [152].…”