Summary: Background: Genetic variation in the β‐2 adrenergic receptor gene (ADRB2) has been implicated in asthma severity and control with conflicting results. Epigenetic variation in the ADRB2 may play an important role in asthma phenotype.Objective: We aimed to evaluate whether DNA methylation of ADRB2 is associated with asthma phenotypes in inner‐city school‐aged children.Methods: Multiple CpG sites in the promoter region of ADRB2 gene were analysed in 177 children enrolled in the School Inner‐City Asthma Study. Blood‐ or saliva‐derived DNA was measured by bisulphite‐polymerase chain reaction pyrosequencing assay. Average percentage DNA methylation across the sites was evaluated for association with asthma severity (report of dyspnoea, night‐time symptoms, rescue medication use, and baseline spirometry) and morbidity (school absences and unscheduled healthcare visits). Three clades composed of highly correlated methylation sites within the methylated segment of ADRB2 were further analysed.Results: Methylation of individual sites generally ranged from 0% to 6% with average percentage methylation across sites of 2.4%. Univariate analyses strongly favoured the association of higher percentage methylation with lower asthma severity measured by report of dyspnoea. Furthermore, there was a non‐significant trend towards less rescue medication use, night‐time symptoms, school absences, activity limitation due to asthma, and improved lung function measurements with increased methylation. Multivariate analysis demonstrated methylation of ADRB2 gene significantly associated with less dyspnoea (odds ratio (OR) 0.2, 95% confidence interval (CI), 0.1–0.6, P = 0.002). Each of the three clades of methylation sites showed a strong, but not statistically significant, effect on decreased dyspnoea.Conclusions and Clinical Relevance: DNA methylation in the ADRB2 gene is associated with decreased asthma symptom severity, suggesting a role for methylation in asthma phenotypes.

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