title: AHRR(cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality.
abstract: Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the aryl hydrocarbon receptor repressor(AHRR) gene. We tested the hypothesis thatAHRRcg05575921 hypomethylation is associated with risk of smoking-related morbidity and mortality.
  
  
  
  From the Copenhagen City Heart Study representing the Danish general population, we studied 9234 individuals. Using bisulphite treated leucocyte DNA,AHRR(cg05575921) methylation was measured. Rs1051730 (CHRN3A) genotype was used to evaluate smoking heaviness. Participants were followed for up to 22 years for exacerbations of COPD, event of lung cancer and all-cause mortality. Six-year lung cancer risk was calculated according to the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCOM2012).
  
  
  
  AHRR(cg05575921) hypomethylation was associated with former and current smoking status, high daily and cumulative smoking, short time since smoking cessation (all p values <7×10-31), and the smoking-relatedCHRN3Agenotype (-0.48% per T-allele, p=0.002). The multifactorially adjusted HRs for the lowest versus highest methylation quintiles were 4.58 (95% CI 2.83 to 7.42) for COPD exacerbations, 4.87 (2.31 to 10.3) for lung cancer and 1.67 (1.48 to 1.88) for all-cause mortality. Finally, among 2576 high-risk smokers eligible for lung cancer screening by CT, observed cumulative incidences of lung cancer after 6 years for individuals in the lowest and highest methylation quintiles were 3.7% and 0.0% (p=2×10-7), whereas predicted PLCOM20126-year risks were similar (4.3% and 4.4%, p=0.77).
  
  
  
  AHRR(cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality.
authors.affiliation: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Timpson
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Relton
authors.affiliation: MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015415:Biomarkers; D002423:Cause of Death; D019175:DNA Methylation; D003718:Denmark / Q000453:epidemiology; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology*; D011978:Receptors, Nicotinic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D018570:Risk Assessment; D012309:Risk-Taking; D012907:Smoking / Q000009:adverse effects / Q000235:genetics* / Q000401:mortality*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D011978:Receptors, Nicotinic; D012097:Repressor Proteins; C492162:AHRR protein, human; C523021:CHRNA1 protein, human
keywords: COPD epidemiology; Lung Cancer; Tobacco and the lung