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J Allergy Clin Immunol. 2018 Dec 20. pii: S0091-6749(18)32788-X. doi: 10.1016/j.jaci.2018.11.043. [Epub ahead of print]

Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma.

Author information

1
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
2
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
3
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
4
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
5
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
6
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
7
Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
8
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
9
The Curtin/UWA Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, Australia; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia.
10
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
11
Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
12
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
13
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden.
14
Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.
15
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
16
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
17
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
18
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
19
Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.
20
Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland; Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
21
Centre intégré universitaire de santé et de services sociaux du Saguenay, Saguenay, Quebec, Canada; Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
22
Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada.
23
GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
24
Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
25
Telethon Kids Institute, University of Western Australia, Perth, Australia.
26
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
27
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Dental School, University of Bristol, Bristol, UK.
28
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
29
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.
30
Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA; Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
31
Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, INSERM and UPMC Sorbonne Université, Paris, France.
32
Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
33
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
34
Biocenter Oulu, University of Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, London, UK.
35
Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
36
Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
37
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway.
38
Children's Hospital Colorado, Aurora, CO, USA.
39
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden.
40
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
41
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; King's College London, Department of Medical and Molecular Genetics, London, UK.
42
Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA; Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
43
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, Isle of Wight, United Kingdom.
44
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
45
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; Max-Planck-Institute of Psychiatry, Munich, Germany.
46
Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
47
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany.
48
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
49
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK; Biocenter Oulu, University of Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
50
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA; Nicholas School of the Environment, Duke University, Durham, NC, USA.
51
Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
52
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
53
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
54
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden.
55
Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
56
Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
57
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA. Electronic address: london2@niehs.nih.gov.

Abstract

BACKGROUND:

Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.

OBJECTIVE:

To identify differential DNA methylation in newborns and children related to childhood asthma.

METHODS:

Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).

RESULTS:

In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact 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 developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.

KEYWORDS:

asthma; childhood; drug development; epigenetics; methylation; newborn

PMID:
30579849
DOI:
10.1016/j.jaci.2018.11.043
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