DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics.

Abstract

Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P<0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q=0.03) in all cohorts and lower IL12B expression (ρ=0.34, P=0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q=0.04) in all cohorts and higher CORT expression (ρ=0.20, P=0.045) in CAMP. Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.