title: Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation.
abstract: Several studies have recently identified strong epigenetic signals related to tobacco smoking. However, an aspect that did not receive much attention is the evolution of epigenetic changes with time since smoking cessation. We conducted a series of epigenome-wide association studies to capture the dynamics of smoking-induced epigenetic changes after smoking cessation, using genome-wide methylation profiles obtained from blood samples in 745 women from 2 European populations. Two distinct classes of CpG sites were identified: sites whose methylation reverts to levels typical of never smokers within decades after smoking cessation, and sites remaining differentially methylated, even more than 35 years after smoking cessation. Our results suggest that the dynamics of methylation changes following smoking cessation are driven by a differential and site-specific magnitude of the smoking-induced alterations (with persistent sites being most affected) irrespective of the intensity and duration of smoking. Analyses of the link between methylation and expression levels revealed that methylation predominantly and remotely down-regulates gene expression. Among genes whose expression was associated with our candidate CpG sites, LRRN3 appeared to be particularly interesting as it was one of the few genes whose methylation and expression were directly associated, and the only gene in which both methylation and gene expression were found associated with smoking. Our study highlights persistent epigenetic markers of smoking, which can potentially be detected decades after cessation. Such historical signatures are promising biomarkers to refine individual risk profiling of smoking-induced chronic disease such as lung cancer.
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Florence
authors.initials: F
authors.lastname: Guida
authors.affiliation: Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Torkjel M
authors.initials: TM
authors.lastname: Sandanger
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Raphaële
authors.initials: R
authors.lastname: Castagné
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Campanella
authors.affiliation: HuGeF, Human Genetics Foundation, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Krogh
authors.affiliation: Ragusa Cancer Registry Azienda Ospedaliera "Civile M.P. Arezzo," Ragusa, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.affiliation: HuGeF, Human Genetics Foundation, Torino, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.affiliation: HuGeF, Human Genetics Foundation, Torino, Italy, Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Australia.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Soterios A
authors.initials: SA
authors.lastname: Kyrtopoulos
authors.affiliation: Institute of Biology, Pharmaceutical Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Georgiadis
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel C H
authors.initials: RC
authors.lastname: Vermeulen
authors.affiliation: Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK, HuGeF, Human Genetics Foundation, Torino, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands and m.chadeau@imperial.ac.uk.
authors.forename: Marc
authors.initials: M
authors.lastname: Chadeau-Hyam
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D016540:Smoking Cessation; D013997:Time Factors