From blood to lung tissue: effect of cigarette smoke on DNA methylation and lung function

• Published in: Respiratory research Vol. 19; no. 1; p. 212
• Main Authors: de Vries, Maaike, van der Plaat, Diana A, Nedeljkovic, Ivana, Verkaik-Schakel, Rikst Nynke, Kooistra, Wierd, Amin, Najaf, van Duijn, Cornelia M, Brandsma, Corry-Anke, van Diemen, Cleo C, Vonk, Judith M, Marike Boezen, H
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.11.2018; BioMed Central; BMC
• Subjects: Adult; Aged; Blood; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarette smoking; Cigarette Smoking - adverse effects; Cigarette Smoking - blood; Cigarette Smoking - genetics; CpG islands; CpG Islands - physiology; Deoxyribonucleic acid; Development and progression; DNA; DNA methylation; DNA Methylation - physiology; Environmental factors; Epigenetics; EWAS; Female; Gene expression; Genetic aspects; Genome-Wide Association Study - methods; Genomes; Health aspects; Health risk assessment; Humans; Influence; Lung - pathology; Lung - physiology; Lung function; Lung tissue; Lungs; Male; Middle Aged; Regression analysis; Respiratory function; Robustness (mathematics); Smoke; Smokers; Smoking; Studies; Young Adult; DNA methylation; Lung function; EWAS; Cigarette smoking; Lung tissue
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-018-0904-y

Genetic 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. The 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. 15 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. This 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.