F2RL3 Methylation as a Biomarker of Current and Lifetime Smoking Exposures

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. Objectives: 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. Citation: Zhang Y, Yang R, Burwinkel B, Breitling LP, Brenner H. 2014. F2RL3 methylation as a biomarker of current and lifetime smoking exposures. Environ Health Perspect 122:131–137; http://dx.doi.org/10.1289/ehp.1306937