Epigenome-wide meta-analysis of DNA methylation and childhood asthma
Reese, Sarah E.; Xu, Cheng-Jian; den Dekker, Herman T.; Lee, Mi Kyeong; Sikdar, Sinjini; Ruiz-Arenas, Carlos; Merid, Simon K.; Rezwan, Faisal I.; Page, Christian M.; Ullemar, Vilhelmina; Melton, Phillip E.; Oh, Sam S.; Yang, Ivana V.; Burrows, Kimberley; Söderhäll, Cilla; Jima, Dereje D.; Gao, Lu; Arathimos, Ryan; Küpers, Leanne K.; Wielscher, Matthias; Rzehak, Peter; Lahti, Jari; Laprise, Catherine; Madore, Anne-Marie; Ward, James; Bennett, Brian D.; Wang, Tianyuan; Bell, Douglas A.; The BIOS consortium; Vonk, Judith M.; Håberg, Siri E.; Zhao, Shanshan; Karlsson, Robert; Hollams, Elysia; Hu, Donglei; Richards, Adam J.; Bergström, Anna; Sharp, Gemma C.; Felix, Janine F.; Bustamante, Mariona; Gruzieva, Olena; Maguire, Rachel L.; Gilliland, Frank; Baïz, Nour; Nohr, Ellen A.; Corpeleijn, Eva; Sebert, Sylvain; Karmaus, Wilfried; Grote, Veit; Kajantie, Eero; Magnus, Maria C.; Örtqvist, Anne K.; Eng, Celeste; Liu, Andrew H.; Kull, Inger; Jaddoe, Vincent W.V.; Sunyer, Jordi; Kere, Juha; Hoyo, Cathrine; Annesi-Maesano, Isabella; Arshad, Syed Hasan; Koletzko, Berthold; Brunekreef, Bert; Binder, Elisabeth B.; Räikkönen, Katri; Reischl, Eva; Holloway, John W.; Järvelin, Marjo-Riitta; Snieder, Harold; Kazmi, Nabila; Breton, Carrie V.; Murphy, Susan K.; Pershagen, Göran; Anto, Josep Maria; Relton, Caroline L.; Schwartz, David A.; Burchard, Esteban G.; Huang, Rae-Chi; Nystad, Wenche; Almqvist, Catarina; Henderson, A. John; Melén, Erik; Duijts, Liesbeth; Koppelman, Gerard H.; London, Stephanie J. (2018-12-21)
Sarah E. Reese, Cheng-Jian Xu, Herman T. den Dekker, Mi Kyeong Lee, Sinjini Sikdar, Carlos Ruiz-Arenas, Simon K. Merid, Faisal I. Rezwan, Christian M. Page, Vilhelmina Ullemar, Phillip E. Melton, Sam S. Oh, Ivana V. Yang, Kimberley Burrows, Cilla Söderhäll, Dereje D. Jima, Lu Gao, Ryan Arathimos, Leanne K. Küpers, Matthias Wielscher, Peter Rzehak, Jari Lahti, Catherine Laprise, Anne-Marie Madore, James Ward, Brian D. Bennett, Tianyuan Wang, Douglas A. Bell, Judith M. Vonk, Siri E. Håberg, Shanshan Zhao, Robert Karlsson, Elysia Hollams, Donglei Hu, Adam J. Richards, Anna Bergström, Gemma C. Sharp, Janine F. Felix, Mariona Bustamante, Olena Gruzieva, Rachel L. Maguire, Frank Gilliland, Nour Baïz, Ellen A. Nohr, Eva Corpeleijn, Sylvain Sebert, Wilfried Karmaus, Veit Grote, Eero Kajantie, Maria C. Magnus, Anne K. Örtqvist, Celeste Eng, Andrew H. Liu, Inger Kull, Vincent W.V. Jaddoe, Jordi Sunyer, Juha Kere, Cathrine Hoyo, Isabella Annesi-Maesano, Syed Hasan Arshad, Berthold Koletzko, Bert Brunekreef, Elisabeth B. Binder, Katri Räikkönen, Eva Reischl, John W. Holloway, Marjo-Riitta Jarvelin, Harold Snieder, Nabila Kazmi, Carrie V. Breton, Susan K. Murphy, Göran Pershagen, Josep Maria Anto, Caroline L. Relton, David A. Schwartz, Esteban G. Burchard, Rae-Chi Huang, Wenche Nystad, Catarina Almqvist, A. John Henderson, Erik Melén, Liesbeth Duijts, Gerard H. Koppelman, Stephanie J. London, Epigenome-wide meta-analysis of DNA methylation and childhood asthma, ournal of Allergy and Clinical Immunology, Volume 143, Issue 6, 2019, Pages 2062-2074, ISSN 0091-6749, https://doi.org/10.1016/j.jaci.2018.11.043
Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. http://creativecommons.org/licenses/by/4.0/
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi-fe2019050614460
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Abstract
Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.
Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.
Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.
Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.
Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.
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