University of Oulu

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, Journal of Allergy and Clinical Immunology, 2018, ISSN 0091-6749, https://doi.org/10.1016/j.jaci.2018.11.043

Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Saved in:
Author: Reese, Sarah E.1; Xu, Cheng-Jian2,3,4; den Dekker, Herman T.5,6,7;
Lee, Mi Kyeong1; Sikdar, Sinjini1; Ruiz-Arenas, Carlos8,9,10; Merid, Simon K.11; Rezwan, Faisal I.12; Page, Christian M.13,14; Ullemar, Vilhelmina15; Melton, Phillip E.16,17; Oh, Sam S.18; Yang, Ivana V.19; Burrows, Kimberley20,21; Söderhäll, Cilla22,23; Jima, Dereje D.24,25; Gao, Lu26; Arathimos, Ryan21,27; Küpers, Leanne K.20,21,28; Wielscher, Matthias29; Rzehak, Peter30; Lahti, Jari31,32; Laprise, Catherine33,34; Madore, Anne-Marie34; Ward, James1; Bennett, Brian D.1; Wang, Tianyuan1; Bell, Douglas A.1; The BIOS consortium; Vonk, Judith M.4,28; Håberg, Siri E.35; Zhao, Shanshan1; Karlsson, Robert15; Hollams, Elysia36; Hu, Donglei18; Richards, Adam J.19; Bergström, Anna11,37; Sharp, Gemma C.20,21,38; Felix, Janine F.5,7,39; Bustamante, Mariona8,9,10,40; Gruzieva, Olena11,37; Maguire, Rachel L.41,42; Gilliland, Frank26; Baïz, Nour43; Nohr, Ellen A.44; Corpeleijn, Eva28; Sebert, Sylvain45,46,47; Karmaus, Wilfried48; Grote, Veit30; Kajantie, Eero49,50,51; Magnus, Maria C.20,21,35; Örtqvist, Anne K.15; Eng, Celeste18; Liu, Andrew H.52; Kull, Inger53,54; Jaddoe, Vincent W.V.5,7,39; Sunyer, Jordi8,9,10,55; Kere, Juha22,56; Hoyo, Cathrine25,41; Annesi-Maesano, Isabella43; Arshad, Syed Hasan57,58; Koletzko, Berthold30; Brunekreef, Bert59,60; Binder, Elisabeth B.61,62; Räikkönen, Katri31; Reischl, Eva63; Holloway, John W.12,57; Järvelin, Marjo-Riitta29,45,46; Snieder, Harold28; Kazmi, Nabila21,27; Breton, Carrie V.26; Murphy, Susan K.64,65; Pershagen, Göran11,37; Anto, Josep Maria8,9,10,55; Relton, Caroline L.20,21; Schwartz, David A.19; Burchard, Esteban G.18,66; Huang, Rae-Chi36; Nystad, Wenche35; Almqvist, Catarina15,67; Henderson, A. John20; Melén, Erik11,54; Duijts, Liesbeth6,68; Koppelman, Gerard H.3,4; London, Stephanie J.1,69
Organizations: 1Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC
2Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
3Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
4GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
5Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
6Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
7Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
8CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
9ISGlobal, Barcelona, Spain
10Universitat Pompeu Fabra (UPF), Barcelona, Spain
11Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
12Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
13Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
14Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
15Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
16Curtin/UWA Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia
17School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia
18Department of Medicine, University of California San Francisco, San Francisco, Calif
19Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
20Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
21Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
22Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
23Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
24Bioinformatics Research Center, North Carolina State University, Raleigh, NC
25Center for Human Health and the Environment, North Carolina State University, Raleigh, NC
26Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Calif
27School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
28Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
29Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, United Kingdom
30Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany
31Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
32Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland
33Centre intégré universitaire de santé et de services sociaux du Saguenay, Saguenay, Quebec, Canada
34Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada
35Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway
36Telethon Kids Institute, University of Western Australia, Perth, Australia
37Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden
38Bristol Dental School, University of Bristol, Bristol, United Kingdom
39Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
40Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain
41Department of Biological Sciences, North Carolina State University, Raleigh, NC
42Department of Community and Family Medicine, Duke University Medical Center, Durham, NC
43Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, INSERM and UPMC Sorbonne Université, Paris, France
44Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
45Biocenter Oulu, University of Oulu, Oulu, Finland
46Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
47Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, London, United Kingdom
48Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, Tenn
49Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
50Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
51Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
52Children's Hospital Colorado, Aurora, Colo
53Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
54Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden
55Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
56Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
57Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
58David Hide Asthma and Allergy Research Centre, Isle of Wight, United Kingdom
59Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
60Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
61Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga
62Max-Planck-Institute of Psychiatry, Munich, Germany
63Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany
64Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC
65Nicholas School of the Environment, Duke University, Durham, NC
66Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, Calif
67Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
68Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
69Corresponding author: Stephanie J. London, MD, DrPH, NIEHS, PO Box 12233, MD A3-05, Research Triangle Park, NC 27709
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019050614460
Language: English
Published: Elsevier, 2019
Publish Date: 2019-05-06
Description:

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.

see all

Series: Journal of allergy and clinical immunology
ISSN: 0091-6749
ISSN-E: 1085-8725
ISSN-L: 0091-6749
Volume: In press
DOI: 10.1016/j.jaci.2018.11.043
OADOI: https://oadoi.org/10.1016/j.jaci.2018.11.043
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: [...] The research of the CHOP study reported herein was partially supported by the Commission of the European Community, specific RTD Programme “Quality of Life and Management of Living Resources,” within the 5th Framework Programme (research grant nos. QLRT-2001-00389 and QLK1-CT-2002-30582); the 6th Framework Programme contract no. 007036 (FP6-007036); the European Union’s Seventh Framework Programme Project EarlyNutrition under grant agreement no. 289346 (FP7-289346), the Horizon 2020 research and innovation programme DYNAHEALTH (no. 633595) and the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG – no. 322605). Additional support from the German Ministry of Education and Research, Berlin (Grant Nr. 01 GI 0825) and the University of Munich Innovative Research Priority Project MC-Health is gratefully acknowledged. This manuscript does not necessarily reflect the views of the Commission and in no way anticipates the future policy in this area. The funders of this study had no role in study design, data collection, data analysis, data interpretation, decision to publish, or preparation of the manuscript. [...]
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
Copyright information: 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/