Tobacco smoking leads to extensive genome-wide changes in DNA methylation

PLoS One. 2013 May 17;8(5):e63812. doi: 10.1371/journal.pone.0063812. Print 2013.


Environmental factors such as tobacco smoking may have long-lasting effects on DNA methylation patterns, which might lead to changes in gene expression and in a broader context to the development or progression of various diseases. We conducted an epigenome-wide association study (EWAs) comparing current, former and never smokers from 1793 participants of the population-based KORA F4 panel, with replication in 479 participants from the KORA F3 panel, carried out by the 450K BeadChip with genomic DNA obtained from whole blood. We observed wide-spread differences in the degree of site-specific methylation (with p-values ranging from 9.31E-08 to 2.54E-182) as a function of tobacco smoking in each of the 22 autosomes, with the percent of variance explained by smoking ranging from 1.31 to 41.02. Depending on cessation time and pack-years, methylation levels in former smokers were found to be close to the ones seen in never smokers. In addition, methylation-specific protein binding patterns were observed for cg05575921 within AHRR, which had the highest level of detectable changes in DNA methylation associated with tobacco smoking (-24.40% methylation; p = 2.54E-182), suggesting a regulatory role for gene expression. The results of our study confirm the broad effect of tobacco smoking on the human organism, but also show that quitting tobacco smoking presumably allows regaining the DNA methylation state of never smokers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alkaline Phosphatase / genetics
  • Analysis of Variance
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • CpG Islands / genetics
  • DNA Methylation / drug effects*
  • Electrophoretic Mobility Shift Assay
  • Epigenomics / methods
  • Female
  • GPI-Linked Proteins / genetics
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Genome, Human / drug effects
  • Genome, Human / genetics*
  • Humans
  • Isoenzymes / genetics
  • Linear Models
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Thrombin / genetics
  • Repressor Proteins / genetics
  • Sex Factors
  • Smoking / adverse effects*
  • Smoking Cessation / statistics & numerical data
  • Time Factors


  • AHRR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • GPI-Linked Proteins
  • Isoenzymes
  • Receptors, Thrombin
  • Repressor Proteins
  • ALPG protein, human
  • Alkaline Phosphatase
  • alkaline phosphatase, placental
  • protease-activated receptor 4

Grants and funding

The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. This work was supported by the DFG/Tr22-Z03 and the Graduate School of Information Science in Health, Technische Universität München. The funders had no role in study design, data collection and analysis, decision to publish, or preperation of the manuscript.