Epigenome-wide meta-analysis of DNA methylation and childhood asthma - 06/06/19
BIOS consortium
Judith M. Vonk, PhD d, bb, Siri E. Håberg, MD, DrPH ii, Shanshan Zhao, PhD a, Robert Karlsson, PhD o, Elysia Hollams, PhD jj, Donglei Hu, PhD r, Adam J. Richards, PhD s, Anna Bergström, PhD k, kk, Gemma C. Sharp, PhD t, u, ll, Janine F. Felix, MD, PhD e, g, mm, Mariona Bustamante, PhD h, i, j, nn, Olena Gruzieva, PhD k, kk, Rachel L. Maguire, MPH oo, pp, Frank Gilliland, MD, PhD z, Nour Baïz, MSc, PhD qq, Ellen A. Nohr, MHSc, PhD rr, Eva Corpeleijn, PhD bb, Sylvain Sebert, PhD ss, tt, uu, Wilfried Karmaus, MD, DrMed vv, Veit Grote, MD, PhD dd, Eero Kajantie, MD, PhD ww, xx, yy, Maria C. Magnus, PhD t, u, ii, Anne K. Örtqvist, MD, PhD o, Celeste Eng, BS r, Andrew H. Liu, MD zz, Inger Kull, RN, PhD aaa, bbb, Vincent W.V. Jaddoe, MD, PhD e, g, mm, Jordi Sunyer, MD, PhD h, i, j, ccc, Juha Kere, MD, PhD v, ddd, Cathrine Hoyo, MPH, PhD y, oo, Isabella Annesi-Maesano, MD, PhD, DSc qq, Syed Hasan Arshad, MBBS, DM, FRCP eee, fff, Berthold Koletzko, MD, PhD dd, Bert Brunekreef, PhD ggg, hhh, Elisabeth B. Binder, MD, PhD iii, jjj, Katri Räikkönen, PhD ee, Eva Reischl, PhD kkk, John W. Holloway, PhD l, eee, Marjo-Riitta Jarvelin, MD, PhD cc, ss, tt, Harold Snieder, PhD bb, Nabila Kazmi, PhD u, aa, Carrie V. Breton, DSc z, Susan K. Murphy, PhD lll, mmm, Göran Pershagen, MD, PhD k, kk, Josep Maria Anto, MD, PhD h, i, j, ccc, Caroline L. Relton, PhD t, u, David A. Schwartz, MD s, Esteban G. Burchard, MD, MPH r, nnn, Rae-Chi Huang, FRCP, PhD jj, Wenche Nystad, PhD ii, Catarina Almqvist, MD, PhD o, ooo, A. John Henderson, MD t, Erik Melén, MD, PhD k, bbb, ‡ , Liesbeth Duijts, MD, PhD f, ppp, ‡ , Gerard H. Koppelman, MD, PhD c, d, ‡ , Stephanie J. London, MD, DrPH a, ⁎, ‡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.
Le texte complet de cet article est disponible en PDF.Key words : Epigenetics, methylation, asthma, childhood, newborn, drug development
Abbreviations used : ALSPAC, BAMSE, BIOS, CHOP, CHS, DMR, EDEN, EWAS, FDR, GALA II, GOYA, GWAS, ICAC, IoW, INMA, MoBa, NEST, NFBC, PACE, PIAMA, SNP, STOPPA, UCSC
Plan
Supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. See supplemental materials in this article's Online Repository at www.jacionline.org for complete funding information for individual studies. |
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Disclosure of potential conflict of interest: C. Ruiz-Arenas receives grant support from Agència de Gestió d’Ajuts Universitaris i de Recerca. S. S. Oh, C. Eng, and E. G. Burchard receive grant support from the NIH and the Tobacco-Related Disease Research Program. I. V. Yang and C. V. Breton receive grant support from the National Institutes of Health (NIH). C. Söderhäll receives grant support from several competitive grants from public and private sources and receives royalties from book chapters in study material. R. Arathimos and G. C. Sharp receive support from the Medical Research Council. E. Kajantie receives grant support from the European Commission, Academy of Finland, Foundation for Pediatric Research, Sigrid Jusélius Foundation, Signe and Ane Gyllenberg Foundation, and Juho Vainio Foundation. G. Pershagen receives grant support from the Swedish Research Council. C. L. Relton receives grant support from Wellcome Trust. C. Almqvist receives grant support from the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework, Stockholm County Council (ALF-projects), Swedish Heart-Lung Foundation, and Swedish Asthma and Allergy Association's Research Foundation. A. J. Henderson receives grant support from the Medical Research Council and Wellcome Trust. E. Melén received grant support from the European Research Council during conduct of the study and lecture fees from Thermo Fisher Scientific and Meda outside the submitted work. G. H. Koppelman receives grant support from the Lung Foundation of the Netherlands, MEDALL EU FP7, the UBBO EMMIUS Foundation, TEVA The Netherlands, Vertex, GlaxoSmithKline, and the TETRI Foundation. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2062-2074 - juin 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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