Shared DNA methylation signatures in childhood allergy:The MeDALL study

BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into shared or unique etiology of asthma, rhinitis and eczema.OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy.METHODS: Within the European Mechanisms of the Development of ALLergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation using a cross-sectional design. Allergy is defined as having symptoms from at least one allergic disease (asthma/rhinitis/eczema) and positive serum specific IgE to common aeroallergens. The discovery study included 219 cases and 417 controls at age 4 and 228 cases and 593 controls at age 8 from three birth cohorts, with replication analyses in 325 cases and 1,111 controls. We performed additional analyses on 21 replicated sites in 785 cases and 2,124 controls by allergic symptoms only from eight cohorts, three not previously included in analyses.RESULTS: We identified 80 differentially methylated CpG sites (CpGs) which showed 1-3% methylation difference in the discovery phase, of which 21, including five novel CpGs, passed genome-wide significance after meta-analysis. All 21 CpGs were also significantly differentially methylated with allergic symptoms, and shared between asthma, rhinitis and eczema. The 21 CpGs mapped to relevant genes, including ACOT7, LMAN3 and CLDN23. All 21 CpGs were differently methylated in asthma in isolated eosinophils, and ten were replicated in respiratory epithelium.CONCLUSION: Reduced whole blood DNA methylation at 21 CpGs was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis and eczema.