These results suggest that a single exposure of IL-13 may selectively induce long-lasting DNA methylation changes in asthmatic airways that alter specific AEC pathways and contribute to asthma phenotypes.

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Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had racedependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that raceassociated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life.

Background Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma. Methods Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci. Results Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. Conclusions This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.

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.)