title: F2RL3 methylation as a biomarker of current and lifetime smoking exposures.
abstract: BACKGROUND
  Recent genome-wide DNA methylation studies have found a pronounced difference in methylation of the F2RL3 gene (also known as PAR-4) in blood DNA according to smoking exposure. Knowledge on the variation of F2RL3 methylation by various degrees of smoking exposure is still very sparse.
  
  
  OBJECTIVE
  We aimed to assess dose-response relationships of current and lifetime active smoking exposure with F2RL3 methylation.
  
  
  METHODS
  In a large population-based study, we quantified blood DNA methylation at F2RL3 for 3,588 participants using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Associations of smoking exposure with methylation intensity were examined by multiple linear regression, controlling for potential confounding factors and paying particular attention to dose-response patterns with respect to current and lifetime smoking exposure as well as time since cessation of smoking.
  
  
  RESULTS
  F2RL3 methylation intensity showed a strong association with smoking status (p < 0.0001), which persisted after controlling for potential confounding factors. Clear inverse dose-response relationships with F2RL3 methylation intensity were seen for both current intensity and lifetime pack-years of smoking. Among former smokers, F2RL3 methylation intensity increased gradually from levels close to those of current smokers for recent quitters to levels close to never smokers for long-term (> 20 years) quitters.
  
  
  CONCLUSIONS
  F2RL3 methylation is a promising biomarker for both current and long-term past tobacco exposure, and its predictive value for smoking-related diseases warrants further exploration.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rongxi
authors.initials: R
authors.lastname: Yang
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Breitling
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D015331:Cohort Studies; D019175:DNA Methylation; D005858:Germany / Q000453:epidemiology; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000453:epidemiology* / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers; D018179:Receptors, Thrombin; C112908:protease-activated receptor 4