DNA Methylation Patterns in Nasal Epithelium, Atopy, and Atopic Asthma in Children

Are there specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children?

Comment: This article analyzes DNA methylation patterns in the nasal epithelium of Puerto Rican school-aged children. This population was chosen because Puerto Ricans are disproportionately impacted by asthma and atopy and have exposures to agents linked to both methylation and atopic disease, namely secondhand smoke and air pollution. They found that methylation profiles were markedly different in children with and without atopy. These “findings suggest that DNA methylation may alter airway epithelial integrity and function, leading to antigen penetration of the epithelial barrier, antigen presentation to dendritic cells, altered Th1/Th2 immune responses, and—ultimately—atopy or atopic asthma.” Additionally, they note that the top 30 genes identified are novel and not previously associated with asthma susceptibility. From a clinical standpoint, this study introduces the role of a non-invasive screening mechanism to potentially identify high-risk infants and children, prior to disease development or progression. This timing may also allow for the initiation of measures to mitigate the risk of subsequent disease development or lessen disease severity in these patients.—Jennifer Villwock, MD

Bottom line
The study identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. The findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants.

Background: Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. This study aimed to identify DNA methylation profiles that are associated with—and could accurately classify—atopy and atopic asthma in school-aged children.

Study design: Investigators performed a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9–20 years, recruited using multistage probability sampling.

Synopsis: Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician’s diagnosis plus wheeze in the previous year. Significant methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. The researchers then replicated the top methylation findings in a cohort of 72 predominantly African American children and in 432 children from a European birth cohort. Next, they tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts.

DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, investigators found 8,664 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 atopy based 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 asthma in the Puerto Rico cohort (AUC 0·95–1·00, accuracy 88%) and the replication cohorts (AUC 0·82–0·88, accuracy 86%).

Citation: Forno E, Wang T, Yan Q, et al. DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study. Lancet Respir Med. 2019;7:336–346.