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Lancet Respir Med. 2018 May;6(5):379-388. doi: 10.1016/S2213-2600(18)30052-3. Epub 2018 Feb 26.

DNA methylation in childhood asthma: an epigenome-wide meta-analysis.

Author information

1
Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; GRIAC research institute Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
2
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
3
ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; Centre for Genomic Regulation, the Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
4
Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.
5
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
6
Institute for Risk Assessment Sciences, Utrecht University, the Netherlands.
7
Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
8
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, LA, USA; Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece; Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
9
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Health Research Institute Biodonostia, San Sebastián, Spain; Public Health Department of Gipuzkoa, San Sebastián, Spain.
10
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
11
ib-salut, Area de Salut de Menorca, Menorca, Spain.
12
Department of Epidemiology Lazio Regional Health Service, Rome, Italy.
13
Department of Biomedical and Neuromotor sciences, University of Bologna, Bologna, Italy.
14
Department of Paediatrics, Oslo University Hospital, Oslo, Norway; Department of Paediatric and Adolescent Medicine, University of Oslo, Oslo, Norway.
15
Skin and Allergy Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
16
Department of Human Genetics, McGill University and Genome Quebec, Innovation Centre, Montréal, QC, Canada.
17
GRIAC research institute Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
18
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
19
Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
20
European Institute for Systems Biology and Medicine, Campus Charles Mérieux - Université de Lyon, CIRI CNRS UMR5308, CNRS-ENS-UCBL-ENS, Lyon, France; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
21
Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; GRIAC research institute Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
22
Department of Pediatrics, Erasmus MC - Sophia Children's Hospital University Medical Center, Rotterdam, The Netherlands.
23
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
24
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
25
ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA.
26
ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
27
Faculty of Medicine and Life Sciences and Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
28
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
29
Department of Paediatrics, Oslo University Hospital, Oslo, Norway.
30
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland.
31
European Institute for Systems Biology and Medicine, Campus Charles Mérieux - Université de Lyon, CIRI CNRS UMR5308, CNRS-ENS-UCBL-ENS, Lyon, France; Institute for Advanced Biosciences, UGA-INSERM U1209-CNRS UMR5309, Site Santé, Allée des Alpes, La Tronche, France.
32
European Institute for Systems Biology and Medicine, Campus Charles Mérieux - Université de Lyon, CIRI CNRS UMR5308, CNRS-ENS-UCBL-ENS, Lyon, France.
33
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Research BV, Metslawier, the Netherlands.
34
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
35
National Heart and Lung Institute, Imperial College London, London, UK.
36
ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain.
37
University Hospital, Montpellier, France; Department of Dermatology, Charité, Berlin, Germany.
38
National Institute for Health and Welfare, Helsinki, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
39
Université du Québec à Chicoutimi, Département des sciences fondamentales, Saguenay, QC, Canada; Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean, 305 Saint-Vallier, Saguenay, QC, Canada.
40
Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces Health Research Institute, CIBERDEM, University of the Basque Country UPV-EHU, Leioa-Bizkaia, Spain.
41
ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
42
Institute for Risk Assessment Sciences, Utrecht University, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
43
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Medical and Molecular Genetics, King's College London, London, UK.
44
GRIAC research institute Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
45
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs Children's Hospital, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
46
GRIAC research institute Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: g.h.koppelman@umcg.nl.

Abstract

BACKGROUND:

DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.

METHODS:

We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting.

FINDINGS:

27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10-7) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects.

INTERPRETATION:

Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.

FUNDING:

EU and the Seventh Framework Programme (the MeDALL project).

PMID:
29496485
DOI:
10.1016/S2213-2600(18)30052-3
[Indexed for MEDLINE]
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