title: Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation.
abstract: Smoking is a major risk factor in many diseases. Genome wide association studies have linked genes for nicotine dependence and smoking behavior to increased risk of cardiovascular, pulmonary, and malignant diseases. We conducted an epigenome wide association study in peripheral-blood DNA in 464 individuals (22 current smokers and 263 ex-smokers), using the Human Methylation 450 K array. Upon replication in an independent sample of 356 twins (41 current and 104 ex-smokers), we identified 30 probes in 15 distinct loci, all of which reached genome-wide significance in the combined analysis P < 5 × 10(-8). All but one probe (cg17024919) remained significant after adjusting for blood cell counts. We replicated all 9 known loci and found an independent signal at CPOX near GPR15. In addition, we found 6 new loci at PRSS23, AVPR1B, PSEN2, LINC00299, RPS6KA2, and KIAA0087. Most of the lead probes (13 out of 15) associated with cigarette smoking, overlapped regions of open chromatin (FAIRE and DNaseI hypersensitive sites) or/and H3K27Ac peaks (ENCODE data set), which mark regulatory elements. The effect of smoking on DNA methylation was partially reversible upon smoking cessation for longer than 3 months. We report the first statistically significant interaction between a SNP (rs2697768) and cigarette smoking on DNA methylation (cg03329539). We provide evidence that the metSNP for cg03329539 regulates expression of the CHRND gene located circa 95 Kb downstream of the methylation site. Our findings suggest the existence of dynamic, reversible site-specific methylation changes in response to cigarette smoking , which may contribute to the extended health risks associated with cigarette smoking.
authors.affiliation: a Wellcome Trust Sanger Institute ; Hinxton , Cambridge , UK.
authors.forename: Loukia G
authors.initials: LG
authors.lastname: Tsaprouni
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.forename: Jordana
authors.initials: J
authors.lastname: Bell
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Dick
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kanoni
authors.forename: James
authors.initials: J
authors.lastname: Nisbet
authors.forename: Ana
authors.initials: A
authors.lastname: Viñuela
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Eshwar
authors.initials: E
authors.lastname: Meduri
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Francois
authors.initials: F
authors.lastname: Cambien
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Dermitzakis
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017423:Sequence Analysis, RNA; D012907:Smoking / Q000009:adverse effects*
keywords: AHRR, aryl-hydrocarbon receptor repressor; ALPP, alkaline phosphatase, placental; AVPR1B, arginine vasopressin; CHRND; CHRND, cholinergic nicotinic receptor; COPD, chronic obstructive pulmonary disease; CPOX; CPOX, coproporphyrinogen oxidase; DNA methylation; DNMT, DNA methyltransferase; EWAS, epigenome wide association study; FDR, false discovery rate; GWAS, genome-wide association studies; PRSS23, serine protease 23; PSEN2, presenilin-2 gene; RPS6KA2, ribosomal protein S6 kinase; epigenome-wide screen; gene network; metQTL, methylation quantitative trait loci; metQTLs; rs2697768; smoking