title: Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome.
abstract: The impact of cigarette smoking can persist for extended periods following smoking cessation and may involve epigenetic reprogramming. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to the latency between exposure and disease onset. Cross-sectional cohort data from subjects in the International COPD Genetics Network (n = 1085) and the Boston Early-Onset COPD study (n = 369) were analyzed as the discovery and replication cohorts, respectively. Genome-wide methylation data on 27 578 CpG sites in 14 475 genes were obtained on DNA from peripheral blood leukocytes using the Illumina HumanMethylation27K Beadchip in both cohorts. We identified 15 sites significantly associated with current smoking, 2 sites associated with cumulative smoke exposure, and, within the subset of former smokers, 3 sites associated with time since quitting cigarettes. Two loci, factor II receptor-like 3 (F2RL3) and G-protein-coupled receptor 15 (GPR15), were significantly associated in all three analyses and were validated by pyrosequencing. These findings (i) identify a novel locus (GPR15) associated with cigarette smoking and (ii) suggest the existence of dynamic, site-specific methylation changes in response to smoking which may contribute to the extended risks associated with cigarette smoking that persist after cessation.
authors.affiliation: Channing Laboratory and the Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. reesw@channing.harvard.edu
authors.forename: Emily S
authors.initials: ES
authors.lastname: Wan
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Carey
authors.forename: Helene
authors.initials: H
authors.lastname: Bacherman
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Alvar
authors.initials: A
authors.lastname: Agusti
authors.forename: Wayne
authors.initials: W
authors.lastname: Anderson
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
mesh_terms: D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D018179:Receptors, Thrombin / Q000235:genetics; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D016540:Smoking Cessation
chemical_list: C103539:GPR15 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D018179:Receptors, Thrombin; C112908:protease-activated receptor 4