• Soyeon Kim, Erick Forno, Rong Zhang, Hyun Jung Park, Zhongli Xu, Qi Yan, Nadia Boutaoui, Edna Acosta-Pérez, Glorisa Canino, Wei Chen, and Juan C Celedón.
• Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA.
• Chest. 2020 Nov 1; 158 (5): 1841-1856.

BackgroundNasal (airway) epithelial methylation profiles have been associated with asthma, but the effects of such profiles on expression of distant cis-genes are largely unknown.Research QuestionTo identify genes whose expression is associated with proximal and distal CpG probes (within 1 Mb), and to assess whether and how such genes are differentially expressed in atopic asthma.Study Design And MethodsGenome-wide expression quantitative trait methylation (eQTM) analysis in nasal epithelium from Puerto Rican subjects (aged 9-20 years) with (n = 219) and without (n = 236) asthma. After the eQTM analysis, a Gene Ontology Enrichment analysis was conducted for the top 500 eQTM genes, and mediation analyses were performed to identify paths from DNA methylation to atopic asthma through gene expression. Asthma was defined as physician-diagnosed asthma and wheeze in the previous year, and atopy was defined as at least one positive IgE to allergens. Atopic asthma was defined as the presence of both atopy and asthma.ResultsWe identified 16,867 significant methylation-gene expression pairs (false-discovery rate-adjusted P < .01) in nasal epithelium from study participants. Most eQTM methylation probes were distant (average distance, ∼378 kb) from their target genes, and also more likely to be located in enhancer regions of their target genes in lung tissue than control probes. The top 500 eQTM genes were enriched in pathways for immune processes and epithelial integrity and were more likely to have been previously identified as differentially expressed in atopic asthma. In a mediation analysis, we identified 5,934 paths through which methylation markers could affect atopic asthma through gene expression in nasal epithelium.InterpretationPrevious epigenome-wide association studies of asthma have estimated the effects of DNA methylation markers on expression of nearby genes in airway epithelium. Our findings suggest that distant epigenetic regulation of gene expression in airway epithelium plays a role in atopic asthma.Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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