Alberta L Wang1,2, Olena Gruzieva3,4, Weiliang Qiu1, Simon Kebede Merid3,4, Juan C Celedón5, Benjamin A Raby1,6,7, Cilla Söderhäll8,9, Dawn L DeMeo1,6, Scott T Weiss1, Erik Melén3,4,10, Kelan G Tantisira1,6. 1. Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 4. Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden. 5. Division of Pediatric Pulmonary Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 6. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7. Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 8. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. 9. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 10. Sachs' Children's Hospital, Stockholm, Sweden.
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.
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.
Authors: Anna Gref; Simon K Merid; Olena Gruzieva; Stéphane Ballereau; Allan Becker; Tom Bellander; Anna Bergström; Yohan Bossé; Matteo Bottai; Moira Chan-Yeung; Elaine Fuertes; Despo Ierodiakonou; Ruiwei Jiang; Stéphane Joly; Meaghan Jones; Michael S Kobor; Michal Korek; Anita L Kozyrskyj; Ashish Kumar; Nathanaël Lemonnier; Elaina MacIntyre; Camille Ménard; David Nickle; Ma'en Obeidat; Johann Pellet; Marie Standl; Annika Sääf; Cilla Söderhäll; Carla M T Tiesler; Maarten van den Berge; Judith M Vonk; Hita Vora; Cheng-Jian Xu; Josep M Antó; Charles Auffray; Michael Brauer; Jean Bousquet; Bert Brunekreef; W James Gauderman; Joachim Heinrich; Juha Kere; Gerard H Koppelman; Dirkje Postma; Christopher Carlsten; Göran Pershagen; Erik Melén Journal: Am J Respir Crit Care Med Date: 2017-05-15 Impact factor: 21.405
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Authors: Erick Forno; Jessica Lasky-Su; Blanca Himes; Judie Howrylak; Clare Ramsey; John Brehm; Barbara Klanderman; John Ziniti; Erik Melén; Goran Pershagen; Magnus Wickman; Fernando Martinez; Dave Mauger; Christine Sorkness; Kelan Tantisira; Benjamin A Raby; Scott T Weiss; Juan C Celedón Journal: J Allergy Clin Immunol Date: 2012-05-02 Impact factor: 10.793
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