Epigenetic landscape links upper airway microbiota in infancy with allergic rhinitis at 6 years of age

Abstract

Background: The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR). Objective: We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children. Methods: We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Results: We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P 5 .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module's eigenvector (r 5 20.25; P 5 3.3 3 10 25). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module. Conclusions: Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells. (J Allergy Clin Immunol 2020;nnn:nnn-nnn.)

Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus

“…While we did not observe an enrichment of adult onset asthma GWAS SNPs among AEC eQTLs, SNPs were enriched among AEC molecular QTLs when we considered meQTLs. This suggests that DNA methylation may be a relatively more important contributor to adult onset compared to childhood onset asthma, consistent with both the greater environmental contributions to adult onset asthma [6] and the more stable nature of DNA methylation compared to gene expression across treatments in our study and possibly throughout life (e.g., [15]).…”

“…For example, GWASs do not generally consider tissue-or environment-specific effects, or gene by environment interactions. Moreover, most genome-wide epigenetic studies of exposures (e.g., [14][15][16][17][18]) or of asthma-related traits (e.g., [19][20][21][22][23][24]) have not integrated their findings with GWAS. Only a few studies have formally integrated asthma GWAS and epigenetic studies in airway tissues (e.g., [25][26][27]), but none have considered genotype effects on genome-wide epigenetic and transcriptional responses to RV infection with asthma GWASs.…”

Interaction between early-life pet exposure and methylation pattern of ADAM33 on allergic rhinitis among children aged 3-6 years in China

“…Recent studies have supported a relationship between external exposome in the prenatal and early-life risk factors and their effects on the development of allergic diseases later in life (11). The association of these risk factors and the subsequent development of AR focuses on maternal allergic history (12), mode of delivery (13), microbial exposure (14,15), indoor allergens (furred pet exposure, for example) (16), and environmental air pollutants (17) during early-life have been previously reported. One mechanism underlying the effect of air pollutants on AR using mice model has been reported recently showing that PM2.5 exposure exacerbates AR by increasing DNA methylation in the IFN-gamma gene promoter in T cells (18).…”

Interaction between early-life pet exposure and methylation pattern of ADAM33 on allergic rhinitis among children aged 3–6 years in China

“…Recent studies have supported a relationship between external exposome in the prenatal and earlylife risk factors and their effects on the development of allergic diseases later in life [11]. The association of these risk factors and the subsequent development of AR focuses on maternal allergic history [12], mode of delivery [13], microbial exposure [14,15], indoor allergens (furred pet exposure, for example) [16], and environmental air pollutants [17] during early-life have been previously reported. One mechanism underlying the effect of air pollutants on AR using mice model has been reported recently showing that PM2.5 exposure exacerbates AR by increasing DNA methylation in the IFN-gamma gene promoter in T cells [18].…”