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

机译：DNA甲基化与持续儿童哮喘患者的吸入皮质类固醇反应有关

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摘要

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.
机译：摘要吸入皮质类固醇的背景响应是高度变化的，并且不知道DNA甲基化和治疗反应之间的关联。目的探讨患有持续性哮喘儿童外周血DNA甲基化和吸入皮质类固醇反应的关联。方法在吸入皮质类固体中的三个独立和种族多样的队列儿童哮喘管理计划（营地）中分析外膜内甲醚的DNA甲基化;儿童，过敏，Milieu，斯德哥尔摩，流行病学（BAMSE）;哥斯达黎加研究哮喘遗传流行病学（GACRS）。使用两个定义评估治疗响应，缺乏急诊部门访问和/或住院，以及在吸入皮质类固醇治疗时使用的缺乏口服皮质类固醇。 CpG位点会满足每个结果的标称意义（p≤0.05），在三队的荟萃分析中组合，调整多次测试。使用Pearson和部分相关性与基因表达相关的DNA甲基化。结果154个受试者从BAMSE的营地，72个受试者，来自GACRS的168个，CG00066816的相对低甲基化（IL12B上游的171个碱基）与缺乏急诊部门访问和/或住院（Q？= 0.03）相关联和较低的IL12B表达（ρ？=？0.34，p？= 0.01）。 CG04256470的相对高甲基化（在Cort上游的688碱基）与所有群组和更高的Cort表达中的口腔皮质类固醇使用（Q？= 0.04）有关（Q？= 0.04）相关（ρα= 0.20，P？0.045）。结论及临床相关性DNA甲基化IL12B和CORT与持续儿童哮喘患者中吸入的皮质类固醇治疗反应有关。药物 - 甲基化可以识别哮喘中治疗敏感性的新型标记。

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    Wang Alberta L.; Gruzieva Olena; Qiu Weiliang; Kebede Merid Simon; Celedón Juan C.; Raby Benjamin A.; S?derh?ll Cilla; DeMeo Dawn L.; Weiss Scott T.; Melén Erik; Tantisira Kelan G.;

  • 作者单位

    Channing Division of Network Medicine Brigham and Women’s HospitalHarvard Medical SchoolBoston;

    Institute of Environmental MedicineKarolinska InstitutetStockholm Sweden;

    Channing Division of Network Medicine Brigham and Women’s HospitalHarvard Medical SchoolBoston;

    Institute of Environmental MedicineKarolinska InstitutetStockholm Sweden;

    Division of Pediatric Pulmonary Medicine Children’s Hospital of Pittsburgh of UPMCUniversity of;

    Channing Division of Network Medicine Brigham and Women’s HospitalHarvard Medical SchoolBoston;

    Department of Women’s and Children’s HealthKarolinska InstitutetStockholm Sweden;

    Channing Division of Network Medicine Brigham and Women’s HospitalHarvard Medical SchoolBoston;

    Channing Division of Network Medicine Brigham and Women’s HospitalHarvard Medical SchoolBoston;

    Institute of Environmental MedicineKarolinska InstitutetStockholm Sweden;

    Channing Division of Network Medicine Brigham and Women’s HospitalHarvard Medical SchoolBoston;

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  • 正文语种 eng
  • 中图分类 医学免疫学;
  • 关键词

    asthma; DNA methylation and gene expression; paediatrics; pharmacogenetics;

    机译：哮喘;DNA甲基化和基因表达;儿科;药物发生;

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