Abstract
BackgroundGenetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue.MethodsThe association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression.Results15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression.ConclusionThis study is the first to validate a panel of CpG-sites that are associated with cigarette smoking and lung function levels in whole blood in the tissue of interest: lung tissue.
Highlights
Genetic and environmental factors play a role in the development of Chronic Obstructive Pulmonary Disease (COPD)
We aim to identify these CpG-sites by performing an epigenome-wide association study (EWAS) in whole blood in current smokers and validate these smoking-related differences in DNA methylation in lung tissue
Gene function# Repressor of AHR, important in dioxin toxicity and involved in regulation of cell growth and differentiation NA Plays a role in platelet activation and hypomethylation may be associated with human lung cancer NA NA NA NA NA NA NA Transcription repressor essential for hematopoiesis Transcription repressor essential for hematopoiesis Repressor of AHR, important in dioxin toxicity and involved in regulation of cell growth and differentiation Involved in cAMP signaling in cells Transcription repressor essential for hematopoiesis
Summary
Genetic and environmental factors play a role in the development of COPD. The epigenome, and DNA methylation, is recognized as important link between these factors. The development of COPD is known to be associated with both genetic [3,4,5] and environmental factors [6] and their interactions [7]. The epigenome is increasingly recognized as an important link between changes to the inherited genome and environmental exposures such as cigarette smoke [9]. The epigenome comprises several epigenetic mechanisms that affect gene expression without modifying de Vries et al Respiratory Research (2018) 19:212 the DNA sequence. These epigenetic mechanisms are highly dynamic and changes can be induced by environment exposures, diseases and ageing [10]
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