Abstract
BACKGROUND: Expression quantitative trait methylation (eQTM) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 megabase). OBJECTIVES: This study sought to identify cis- and trans-methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma. METHODS: In this study, the investigators conducted both cis- and trans-eQTM analyses in nasal (airway) epithelial samples from 158 Puerto Rican youth with atopic asthma and 100 control subjects without atopy or asthma. The investigators then attempted to replicate their findings in nasal epithelial samples from 2 studies of children, while also examining whether their results in nasal epithelium overlap with those from an eQTM analysis in white blood cells from the Puerto Rican subjects. RESULTS: This study identified 9,108 cis-eQTM pairs and 2,131,500 trans-eQTM pairs. Trans-associations were significantly enriched for transcription factor and microRNA target genes. Furthermore, significant cytosine-phosphate-guanine sites (CpGs) were differentially methylated in atopic asthma and significant genes were enriched for genes differentially expressed in atopic asthma. In this study, 50.7% to 62.6% of cis- and trans-eQTM pairs identified in Puerto Rican youth were replicated in 2 smaller cohorts at false discovery rate-adjusted P < .1. Replicated genes in the trans-eQTM analysis included biologically plausible asthma-susceptibility genes (eg, HDC, NLRP3, ITGAE, CDH26, and CST1) and are enriched in immune pathways. CONCLUSIONS: Studying both cis- and trans-epigenetic regulation of airway epithelial gene expression can identify potential causal and regulatory pathways or networks for childhood asthma. Trans-eQTM CpGs may regulate gene expression in airway epithelium through effects on transcription factor and microRNA target genes.