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.

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response

“…Remarkably, in recent years, the number of pharmacogenomic, epigenomic, and metabolomic studies that included ethnically diverse minority populations such as African Americans and Hispanic/Latinos have increased compared to the past [25][26][27]38,63,82,83]. However, studies in populations of Asian ancestry remain still scarce [51].…”

“…Further validation should also be sought by ex-vivo studies and directed to the development of panels of biomarkers with clinical applicability. Moreover, many studies have investigated whole tissues with a heterogeneous composition of multiple cell types [38,39,49,51,63], but more initiatives to refine specific cell-type patterns in disease-relevant tissues are required. Besides, while replication attempts are a common practice among pharmacogenomic studies, this strategy should expand to other omics, especially when sample sizes are limited.…”

“…During the reviewed period, two epigenome-wide association studies (EWAS) conducted by Wang et al analyzed the association of CpG sites methylation status with treatment response in childhood asthma ( Table 2, Table S3). Both evaluated the effects of ICS response on DNA methylation patterns in peripheral blood cells (PBCs) [38,39]. In the first study [38], treatment response was measured by the following two outcomes: (1) the absence of severe asthma exacerbations defined by ER visits or hospitalizations and (2) the absence of OCS use, both of them related to asthma symptoms in the last year despite ICS therapy.…”

“…Both evaluated the effects of ICS response on DNA methylation patterns in peripheral blood cells (PBCs) [38,39]. In the first study [38], treatment response was measured by the following two outcomes: (1) the absence of severe asthma exacerbations defined by ER visits or hospitalizations and (2) the absence of OCS use, both of them related to asthma symptoms in the last year despite ICS therapy. A relative hypomethylation of the CpG site cg00066816 near IL12B showed a protective effect for severe exacerbations after false discovery rate (FDR) adjustment (q-value = 0.028) in a meta-analysis across non-Hispanic whites from the Childhood Asthma Management Program (CAMP, n = 154), Europeans from the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE, n = 72), and Hispanic/Latinos from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS, n = 168).…”

Call for papers for special issue in 2020

“…Wang et al. have looked at the relationship between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma . They question whether this explains the differences between responses to corticosteroid between individuals.…”