Abstract
Background: Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung. Aim: To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (DLCO)). Methods: An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) (as DLCO/VA), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the “discovery panel”) and the Framingham Heart Study (FHS, the “replication panel”). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression. Results: We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with DLCO/VA and one (cg05575921) suggestively associated with DLCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with DLCO/VA and DLCO. Conclusions: We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange.
| Original language | English |
|---|---|
| Article number | 00567-2020 |
| Journal | ERJ Open Research |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Jan 2021 |
Bibliographical note
Funding Information:Conflict of interest: N. Terzikhan reports expert consultation for Boehringer Ingelheim GmbH and Novartis. H. Xu has nothing to disclose. A. Edris has nothing to disclose. K.R. Bracke has nothing to disclose. F.M. Verhamme has nothing to disclose. B.H.C. Stricker has nothing to disclose. J. Dupuis reports grants from the National Institutes of Health (NIH) during the conduct of the study. L. Lahousse reports personal fees from AstraZeneca and Chiesi, outside the submitted work and expert consultation for Boehringer Ingelheim GmbH and Novartis. G.T. O’Connor reports grants from the NIH during the conduct of the study. G.G. Brusselle reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, outside the submitted work and is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva.
Funding Information:
The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of the Illumina 450 K methylation array data (the EWAS data) for the Rotterdam Study was by the Human Genotyping Facility of the Genetic Laboratory of the Dept of Internal Medicine, Erasmus Medical Center, The Netherlands. We thank Michael Verbiest, Mila Jhamai, Sarah Higgins, Marijn Verkerk and Lisette Stolk for their help in creating the methylation database. This work was supported by a grant from the Fund for Scientific Research Flanders (FWO) (project G035014N). F.M. Verhame is a post-doctoral fellow of the FWO. The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) in collaboration with Boston University (contract numbers N01-HC-25195, HHSN268201500001I and 75N92019D00031). The Illumina 450 K methylation array data (the EWAS data) was funded by the Genetic Laboratory of the Dept of Internal Medicine, Erasmus Medical Center and by the Netherlands Organization for Scientific Research (project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH (Bethesda, MD, USA) and the NIH Director’s Challenge Award (PI: D. Levy). Funding information for this article has been deposited with the Crossref Funder Registry.
Funding Information:
Support statement: This work was supported by a grant from the Fund for Scientific Research Flanders (FWO) (project G035014N). F.M. Verhame is a post-doctoral fellow of the FWO. The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) in collaboration with Boston University (contract numbers N01-HC-25195, HHSN268201500001I and 75N92019D00031). The Illumina 450 K methylation array data (the EWAS data) was funded by the Genetic Laboratory of the Dept of Internal Medicine, Erasmus Medical Center and by the Netherlands Organization for Scientific Research (project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH (Bethesda, MD, USA) and the NIH Director’s Challenge Award (PI: D. Levy). Funding information for this article has been deposited with the Crossref Funder Registry.
Publisher Copyright:
© ERS 2021.