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Eur Respir J. 2019 May 9. pii: 1900457. doi: 10.1183/13993003.00457-2019. [Epub ahead of print]

Epigenome-wide association study of lung function level and its change.

Author information

1
Swiss Tropical and Public Health Institute, Basel, Switzerland medea.imboden@swisstph.ch nicole.probst@swisstph.ch.
2
University of Basel, Switzerland.
3
MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
4
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
5
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
6
Population Health and Occupational Disease, NHLI, Imperial College London, London, UK.
7
Swiss Tropical and Public Health Institute, Basel, Switzerland.
8
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
9
Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
10
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
11
Department of Psychology, University of Edinburgh, Edinburgh, UK.
12
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
13
Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
14
Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL).
15
Department of Mathematical Sciences, University of Memphis, Memphis, TN, USA.
16
Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
17
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
18
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
19
Department of Population Health Sciences, Bristol Medical School, University of Bristol, UK.
20
Bristol Dental School, University of Bristol, Bristol, UK.
21
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
22
Unit of Clinical Physiology, HUS Medical Imaging Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
23
Obesity Research Unit, Reserch Programs Unit, University of Helsinki, Helsinki, Finland.
24
Abdominal Center, Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
25
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
26
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands.
27
Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
28
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals, Nottingham, UK.
29
Department of Health Sciences, University of Leicester, Leicester, UK.
30
National Institute of Health Research Biomedical Research Centre, University of Leicester, Leicester, UK.
31
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Finland.
32
Biocenter Oulu, University of Oulu, Oulu, Finland.
33
Unit of Primary Health Care, Oulu University Hospital, Finland.
34
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, UK.

Abstract

Previous reports link differential DNA methylation (DNAme) to environmental exposures which are associated with lung function. Direct evidence on lung function DNAme is however limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, six-to-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical-bias adjusted residuals of a regression of the normalised absolute beta-values on control-probe-derived principle components were regressed on level and change of FEV1, FEV1/FVC and FVC in covariate-adjusted discovery EWAS. Inverse-variance weighted meta-analyses were performed on results from discovery and replication samples in all participants and never smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: Pdiscovery=3.96×10-21 and Pcombined=7.22×10-50). A score combining ten DNAme markers previously reported to mediate the smoking effect on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function associated methylation signals in adults are predominantly smoking-related and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time points are needed to identify lung function DNAme in never smokers and in children.

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