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

• Published in: Clinical and experimental allergy Vol. 49; no. 9; pp. 1225 - 1234
• Main Authors: Wang, Alberta L., Gruzieva, Olena, Qiu, Weiliang, Kebede Merid, Simon, Celedón, Juan C., Raby, Benjamin A., Söderhäll, Cilla, DeMeo, Dawn L., Weiss, Scott T., Melén, Erik, Tantisira, Kelan G.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2019
• Subjects: Administration, Inhalation; Adrenal Cortex Hormones - administration & dosage; Allergies; Asthma; Asthma - drug therapy; Asthma - genetics; Asthma - immunology; Asthma - metabolism; Child; Childhood; Children; Corticosteroids; CpG islands; CpG Islands - immunology; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - drug effects; DNA Methylation - immunology; DNA methylation and gene expression; Epidemiology; Epigenome - immunology; Female; Gene expression; Humans; Interleukin 1; Interleukin-12 Subunit p40 - genetics; Interleukin-12 Subunit p40 - immunology; Male; Neuropeptides - genetics; Neuropeptides - immunology; paediatrics; Peripheral blood; pharmacogenetics; Respiratory therapy; paediatrics; DNA methylation and gene expression; asthma; pharmacogenetics
• ISSN: 0954-7894; 1365-2222; 1365-2222
• DOI: 10.1111/cea.13447

Background Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. Objective To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. Methods 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. Results 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. Conclusion and Clinical Relevance 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.