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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00000575.

Keywords: DNA methylation and gene expression; asthma; paediatrics; pharmacogenetics.

Conflict of interest statement

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.

© 2019 John Wiley & Sons Ltd.

Figures

FIGURE 1

DNA methylation analysis of inhaled corticosteroid response in the CAMPa, BAMSEb, and GACRSc. aChildhood Asthma Management Program. bSwedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology. cGenetic Epidemiology of Asthma in Costa Rica Study. §The number of differentially methylated CpG sites for each outcome that met nominal P < 0.05 are shown. ||Oral corticosteroid. **The absence of oral corticosteroid use outcome was not measured in BAMSE. ††False discovery rate

FIGURE 2

DNA methylation is a pharmaco-epigenetic marker of inhaled corticosteroid treatment responseab. A, Cg00066816 hypomethylation was associated with the absence of severe exacerbations only in subjects on inhaled corticosteroid treatment compared to placebo (standardized coefficient −3.051, P = 0.002). B, Cg04256470 hypermethylation was associated with the absence of oral corticosteroid only in subjects on inhaled corticosteroid treatment compared to placebo (standardized coefficient 2.322,P = 0.02). aThe analyses were performed using DNA methylation M values. β values are displayed for easier biologic interpretability. bInteraction analyses were performed only in CAMP because BAMSE and GACRS did not have DNA methylation data available on subjects on inhaled corticosteroids and placebo

FIGURE 3

DNA methylation is associated with gene expression in the BAMSE and CAMP cohorts. A, Partial correlation between DNA methylation and gene expression controlling for emergency department visits and/or hospitalizations in the prior year while on inhaled corticosteroid therapy, in addition to age, sex, batch effect, and cell type composition, in BAMSE (ρ = 0.34,P = 0.01). B, Partial correlation between DNA methylation and gene expression controlling for oral corticosteroid use in the prior year while on inhaled corticosteroid therapy, in addition to age, sex, and batch effect, in CAMP (ρ = 0.20, P = 0.045)