Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

BACKGROUND: Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.OBJECTIVE: To identify differential DNA methylation in newborns and children related to childhood asthma.METHODS: Within the Pregnancy And Childhood Epigenetics (PACE) consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally, in school-age children. We also identified differentially methylated regions (DMRs).RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports regulatory impact on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.