Abstract
Approximately 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. 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.
Abstract
Former asthma patients have epigenetic modifications not present in current asthma which are associated with the activity of genes involved in the resolution of inflammation. Their epigenetic profile also shows them to be different from healthy controls. http://bit.ly/2BGmCPl
Footnotes
This article has supplementary material available from erj.ersjournals.com
Author contributions: C.J. Vermeulen performed differential methylation analysis and drafted and finalised the manuscript, C-J. Xu and J.M. Vonk were involved in data management, data analysis and editing the manuscript, N.H.T. ten Hacken, W. Timens, I.H. Heijink, M.C. Nawijn, A. J. van Oosterhout, K. Affleck and G.H. Koppelman provided guidance and technical knowledge and edited the manuscript, J. Boekhoudt performed eQTM analysis, M. Weckmann contributed expression and methylation data, M. van den Berge, N.H.T. ten Hacken, W. Timens and J.M. Vonk were involved in the design of the study and M. van den Berge drafted parts of the manuscript. All authors approved the final manuscript.
Conflict of interest: C.J. Vermeulen reports grants from GSK, during the conduct of the study.
Conflict of interest: C-J. Xu has nothing to disclose.
Conflict of interest: J.M. Vonk has nothing to disclose.
Conflict of interest: N.H.T. ten Hacken has nothing to disclose.
Conflict of interest: W. Timens reports personal fees from Pfizer, GSK, Chiesi, Roche Diagnostics/Ventana, Biotest, Merck Sharp Dohme, Novartis, Lilly Oncology, Boehringer Ingelheim, AstraZeneca, Bristol-Myers-Squibb and AbbVie, and grants from the Dutch Asthma Fund, outside the submitted work.
Conflict of interest: I.H. Heijink has nothing to disclose.
Conflict of interest: M.C. Nawijn reports grants from GSK and the Lung Foundation of the Netherlands, outside the submitted work.
Conflict of interest: J. Boekhoudt has nothing to disclose.
Conflict of interest: A.J. van Oosterhout reports and holds GSK shares.
Conflict of interest: K. Affleck is an employee of GSK and a member of the company share schemes.
Conflict of interest: M. Weckmann has nothing to disclose.
Conflict of interest: G.H. Koppelman reports grants from the Lung Foundation of the Netherlands, TEVA, GSK, Vertex and Ubbo Emmius Foundation, outside the submitted work; and has served on an international advisory board for GSK (money to institution).
Conflict of interest: M. van den Berge reports grants paid to his university from AstraZeneca, TEVA, GSK and Chiesi, outside the submitted work.
Support statement: Data were generated as part of a Scientific Research Collaboration funded by GSK (COL100037293). The submitted work is co-financed by the Ministry of Economic Affairs and Climate Policy by means of the PPP. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 27, 2019.
- Accepted October 18, 2019.
- Copyright ©ERS 2020
INDIVIDUALS
Log in using your username and password
LIBRARY USERS
Log in through your institution
Purchase access
CONTACT US
If you have any questions about the ERS publications website, please contact journals@ersnet.org