Differential DNA methylation in bronchial biopsies between persistent asthma and asthma in remission
- Cornelis J. Vermeulen1,2⇑,
- Cheng-Jian Xu2,3,4,
- Judith M. Vonk2,5,
- Nick H. T. ten Hacken1,2,
- Wim Timens2,6,
- Irene H. Heijink1,2,6,
- Martijn C. Nawijn2,6,
- Jeunard Boekhoudt6,
- Antoon J. van Oosterhout7,
- Karen Affleck7,
- Markus Weckmann8,
- Gerard H. Koppelman2,3 and
- Maarten van den Berge1,2
- 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, Netherlands
- 2Groningen Research Institute for Asthma and COPD (GRIAC)), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- 3University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, Netherlands
- 4CiiM & TWINCORE, Joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- 5University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands
- 6University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, Netherlands
- 7Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, Hertfordshire, UK
- 8Department of Pediatric Pneumology and Allergology, University Medical Center of Schlesswig-Holstein, Lübeck, Airway Research Centre North, Member of the German Centre of Lung Research, Germany
- Cornelis J. Vermeulen, University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, NL-9700 RB Groningen, Netherlands. E-mail: c.j.vermeulen{at}umcg.nl
Abstract
About 40% of asthmatics experience remission of asthma symptoms. A better understanding of biological pathways leading to asthma remission may provide insight into new therapeutic targets for asthma. As an important mechanism of gene regulation, investigation of DNA methylation provides a promising approach. Our objective was to identify differences in epigenome wide DNA methylation levels in bronchial biopsies between subjects with asthma remission and subjects with persistent asthma or healthy controls.
We analysed differential DNA methylation in bronchial biopsies from 26 subjects with persistent asthma, 39 remission subjects and 70 healthy controls, using the limma package. The comb-p tool was used to identify differentially methylated regions. DNA methylation of CpG-sites was associated to expression of nearby genes from the same biopsies to understand function.
Four CpG-sites and 42 regions were differentially methylated between persistent asthma and remission. DNA methylation at two sites was correlated in cis with gene expression at ACKR2 and DGKQ, respectively. Between remission subjects and healthy controls 1163 CpG-sites and 328 regions were differentially methylated. DNA methylation was associated with expression of a set of genes expressed in ciliated epithelium.
CpGs differentially methylated between remission and persistent asthma identify genetic loci associated with resolution of inflammation and airway responsiveness. Despite the absence of symptoms, remission subjects have a DNA methylation profile that is distinct from that of healthy controls, partly due to changes in cellular composition, with a higher gene expression signal related to ciliated epithelium in remission versus healthy controls.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Vermeulen reports grants from GSK, during the conduct of the study.
Conflict of interest: Dr. Xu has nothing to disclose.
Conflict of interest: Dr. Vonk has nothing to disclose.
Conflict of interest: Dr. ten Hacken has nothing to disclose.
Conflict of interest: Dr. Timens reports personal fees from Pfizer, personal fees from GSK, personal fees from Chiesi, personal fees from Roche Diagnostics / Ventana, grants from Dutch Asthma Fund, personal fees from Biotest, personal fees from Merck Sharp Dohme, personal fees from Novartis, personal fees from Lilly Oncology, personal fees from Boehringer Ingelheim, personal fees from Astra-Zeneca, personal fees from Bristol-Myers-Squibb, personal fees from AbbVie, outside the submitted work.
Conflict of interest: Dr. Heijink has nothing to disclose.
Conflict of interest: Dr. Nawijn reports grants from GSK, grants from Lung Foundation Netherlands, outside the submitted work.
Conflict of interest: J. Boekhoudt has nothing to disclose.
Conflict of interest: Dr. Van Oosterhout reports and holds GSK shares.
Conflict of interest: Dr. Affleck reports and I am an employee of GSK and a member of Company share schemes but have no Conflict of Interest related to this publication.
Conflict of interest: Dr. Weckmann has nothing to disclose.
Conflict of interest: Dr. Koppelman reports grants from Lung Foundation of the Netherlands, TEVA the Netherlands, GSK, Vertex, Ubbo Emmius Foundation, outside the submitted work; and he has served on an international advisory board for GSK (Money to institution).
Conflict of interest: Dr. van den Berge reports grants paid to the University from Astra Zeneca, TEVA, GSK, Chiesi, outside the submitted work.
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- Copyright ©ERS 2019