title: DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations With Cigarette Smoking and Subclinical Atherosclerosis.
abstract: BACKGROUND
  Tobacco smoke contains numerous agonists of the aryl hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the AhR repressor (AHRR). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis.
  
  
  RESULTS
  DNA methylation profiles of AHRR in monocytes (542 CpG sites ± 150 kb of AHRR, using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated (P=6.1 × 10(-134)) with smoking status (current versus never). Novel associations between cg05575921 methylation and carotid plaque scores (P=3.1 × 10(-10)) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known cardiovascular disease risk factors. This association replicated in an independent cohort using hepatic DNA (n=141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer) and had methylation correlated with AHRR mRNA profiles (P=1.4 × 10(-17)) obtained from RNA sequencing conducted on a subset (n=373) of the samples.
  
  
  CONCLUSIONS
  These findings suggest that AHRR methylation may be functionally related to AHRR expression in monocytes and represents a potential biomarker of subclinical atherosclerosis in smokers.
authors: Lindsay M
authors: LM
authors: Reynolds
authors: Ma
authors: M
authors: Wan
authors: Jingzhong
authors: J
authors: Ding
authors: Jackson R
authors: JR
authors: Taylor
authors: Kurt
authors: K
authors: Lohman
authors: Dan
authors: D
authors: Su
authors: Brian D
authors: BD
authors: Bennett
authors: Devin K
authors: DK
authors: Porter
authors: Ryan
authors: R
authors: Gimple
authors: Gary S
authors: GS
authors: Pittman
authors: Xuting
authors: X
authors: Wang
authors: Timothy D
authors: TD
authors: Howard
authors: David
authors: D
authors: Siscovick
authors: Bruce M
authors: BM
authors: Psaty
authors: Steven
authors: S
authors: Shea
authors: Gregory L
authors: GL
authors: Burke
authors: David R
authors: DR
authors: Jacobs
authors: Stephen S
authors: SS
authors: Rich
authors: James E
authors: JE
authors: Hixson
authors: James H
authors: JH
authors: Stein
authors: Hendrik
authors: H
authors: Stunnenberg
authors: R Graham
authors: RG
authors: Barr
authors: Joel D
authors: JD
authors: Kaufman
authors: Wendy S
authors: WS
authors: Post
authors: Ina
authors: I
authors: Hoeschele
authors: David M
authors: DM
authors: Herrington
authors: Douglas A
authors: DA
authors: Bell
authors: Yongmei
authors: Y
authors: Liu
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000208:ethnology / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D044383:Black People / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D056726:Genetic Association Studies; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008297:Male; D009000:Monocytes / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D012907:Smoking / Q000208:ethnology; D044465:White People / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C492162:AHRR protein, human
keywords: DNA methylation; atherosclerosis; epidemiology; epigenomics; gene expression regulation; smoking