Epigenome-wide meta-analysis of DNA methylation and childhood asthma - 06/06/19

Doi : 10.1016/j.jaci.2018.11.043

Sarah E. Reese, PhD ^a,^{∗
These authors contributed equally to this work as first authors.}, Cheng-Jian Xu, PhD ^b,^c,^d,^{∗
These authors contributed equally to this work as first authors.}, Herman T. den Dekker, MD, PhD ^e,^f,^g,^{∗
These authors contributed equally to this work as first authors.}, Mi Kyeong Lee, PhD ^a,^{∗
These authors contributed equally to this work as first authors.}, Sinjini Sikdar, PhD ^a,^{∗
These authors contributed equally to this work as first authors.}, Carlos Ruiz-Arenas, MSc ^h,^i,^j, Simon K. Merid, BSc ^k, Faisal I. Rezwan, PhD ^l, Christian M. Page, PhD ^m,ⁿ, Vilhelmina Ullemar, PhD ^o, Phillip E. Melton, PhD ^p,^q, Sam S. Oh, PhD ^r, Ivana V. Yang, PhD ^s, Kimberley Burrows, PhD ^t,^u, Cilla Söderhäll, PhD ^v,^w, Dereje D. Jima, MSc ^x,^y, Lu Gao, BS ^z, Ryan Arathimos, BSc ^u,^aa, Leanne K. Küpers, PhD ^t,^u,^bb, Matthias Wielscher, PhD ^cc, Peter Rzehak, PhD ^dd, Jari Lahti, PhD ^ee,^ff, Catherine Laprise, PhD ^gg,^hh, Anne-Marie Madore, PhD ^hh, James Ward, PhD ^a, Brian D. Bennett, PhD ^a, Tianyuan Wang, PhD ^a, Douglas A. Bell, PhD ^a, the
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,^{‡
These authors contributed equally to this work as senior authors.}, Liesbeth Duijts, MD, PhD ^f,^ppp,^{‡
These authors contributed equally to this work as senior authors.}, Gerard H. Koppelman, MD, PhD ^c,^d,^{‡
These authors contributed equally to this work as senior authors.}, Stephanie J. London, MD, DrPH ^a,^⁎,^{‡
These authors contributed equally to this work as senior authors.}
^a Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC
^b Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
^c Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
^d GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
^bb Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
^e Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
^f Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
^g Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
^mm Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
^ppp Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
^h CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
ⁱ ISGlobal, Barcelona, Spain
^j Universitat Pompeu Fabra (UPF), Barcelona, Spain
^k Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
^o Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^w Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
^aaa Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
^l Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
^eee Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
^m Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
ⁿ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
^p Curtin/UWA Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia
^q School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia
^r Department of Medicine, University of California San Francisco, San Francisco, Calif
ⁿⁿⁿ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, Calif
^s Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
^t Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
^u Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
^aa School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
^ll Bristol Dental School, University of Bristol, Bristol, United Kingdom
^v Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
^x Bioinformatics Research Center, North Carolina State University, Raleigh, NC
^y Center for Human Health and the Environment, North Carolina State University, Raleigh, NC
^oo Department of Biological Sciences, North Carolina State University, Raleigh, NC
^z Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Calif
^cc Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, United Kingdom
^uu Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, London, United Kingdom
^dd Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany
^ee Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
^ff Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland
^gg Centre intégré universitaire de santé et de services sociaux du Saguenay, Saguenay, Quebec, Canada
^hh Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada
ⁱⁱ Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway
^jj Telethon Kids Institute, University of Western Australia, Perth, Australia
^kk Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden
ⁿⁿ Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain
^pp Department of Community and Family Medicine, Duke University Medical Center, Durham, NC
^lll Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC
^qq Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, INSERM and UPMC Sorbonne Université, Paris, France
^rr Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
^ss Biocenter Oulu, University of Oulu, Oulu, Finland
^tt Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
^vv Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, Tenn
^ww Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
^xx Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
^yy Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
^zz Children's Hospital Colorado, Aurora, Colo
^bbb Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden
^ccc Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
^ddd Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
^fff David Hide Asthma and Allergy Research Centre, Isle of Wight, United Kingdom
^ggg Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
^hhh Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
ⁱⁱⁱ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga
^jjj Max-Planck-Institute of Psychiatry, Munich, Germany
^kkk Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany
^mmm Nicholas School of the Environment, Duke University, Durham, NC
^ooo Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden

^∗Corresponding author: Stephanie J. London, MD, DrPH, NIEHS, PO Box 12233, MD A3-05, Research Triangle Park, NC 27709.NIEHSPO Box 12233, MD A3-05Research Triangle ParkNC27709

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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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.

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.

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Vol 143 - N° 6

P. 2062-2074 - juin 2019 Retour au numéro

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Epigenome-wide meta-analysis of DNA methylation and childhood asthma - 06/06/19

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