DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study

Summary Background Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopicdiseases such as asthma. We aimed to identify DNA methylation profiles that are associated with—and could accurately classify— atopyand atopic asthmain school-aged children. Methods We did a genome-wide study of DNA methylation in nasal epithelium and atopyor atopic asthmain 483 Puerto Rican children aged 9–20 years, recruited using multistage probability sampling. Atopywas defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheezein the previous year. Significant ( false discovery ratep Findings DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopyin the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10 −17 to 2·18 × 10 −22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26 , and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1 , and SLC9A3 . Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopybased on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93–0·94 and accuracy 85–88%) and in both replication cohorts (AUC 0·74–0·92, accuracy 68–82%). The models also performed well for atopic asthmain the Puerto Rico cohort (AUC 0·95–1·00, accuracy 88%) and the replication cohorts (AUC 0·82–0·88, accuracy 86%). Interpretation We identified specific methylation profiles in airway epithelium that are associated with atopyand atopic asthmain children, and a nasal methylation panel that could classify children by atopyor atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezinginfants. Funding US National Institutes of Health.