Global hypomethylation in childhood asthma identified by genome‐wide DNA‐methylation sequencing preferentially affects enhancer regions

Background Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA‐methylation profiles of asthmatic children compared to healthy controls. Methods Peripheral blood samples of 40 asthmatic and 42 control children aged 5–15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype‐associated, cell‐type‐dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR‐associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level. Results In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure. Conclusion This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma. Whole‐genome bisulfite sequencing in whole blood identifies 158 DMRs related to childhood‐asthma predominantly affecting enhancer regions, including an enhancer for IL‐4. Global DNA‐hypomethylation in the asthma‐phenotype affects key immune genes such as IL5RA or EPX. 35% of the aberrant DNA‐methylation in asthma is already present in cord blood, which is partially related to adverse prenatal influences such as tobacco smoke exposure.Abbreviations: DMR, differentially methylated region, EPX, eosinophil peroxidase; IL5RA, interleukin 5 receptor subunit alpha; LINA, Lifestyle and environmental factors and their influence on newborns allergy risk; LISA, Lifestyle‐related factors on the immune system a