Smoking leaves ‘footprint’ in DNA

Findings could provide researchers with potential targets for new therapies
September 25, 2016

(credit: American Heart Association)

Smoking leaves its “footprint” on the human genome in the form of DNA methylation, a process that affects what genes are turned on, according to new research in Circulation: Cardiovascular Genetics, an American Heart Association journal.

The new findings could provide researchers with potential targets for new therapies.

“These results are important because methylation, as one of the mechanisms of the regulation of gene expression, affects what genes are turned on, which has implications for the development of smoking-related diseases, said Stephanie J. London, M.D., Dr.P.H., last author and deputy chief of the Epidemiology Branch at the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina. “Even after someone stops smoking, we still see the effects of smoking on their DNA.”

The good news (for some): most DNA methylation sites returned to levels seen in never-smokers within five years of quitting smoking

Smoking remains the leading preventable cause of death worldwide. Even decades after stopping, former smokers are at long-term risk of developing diseases including some cancers, chronic obstructive pulmonary disease, and stroke. While the molecular mechanisms responsible for these long-term effects remain poorly understood, previous studies linking DNA methylation sites to genes involved with coronary heart disease and pulmonary disease suggest it may play an important role.

To find out more, researchers conducted a meta-analysis of DNA methylation sites across the human genome using blood samples taken from nearly 16,000 participants from 16 groups of the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium, including a group of the Framingham Heart Study that has been followed by researchers since 1971.

The researchers compared DNA methylation sites in current and former smokers to those who never smoked. They found:

  • Smoking-associated DNA methylation sites were associated with more than 7,000 genes, or one-third of known human genes.
  • For people who stopped smoking, the majority of DNA methylation sites returned to levels seen in never-smokers within five years of quitting smoking. However, some DNA methylation sites persisted even after 30 years of quitting.
  • The most statistically significant methylation sites were linked to genes enriched for association with numerous diseases caused by cigarette smoking, such as cardiovascular diseases and certain cancers, suggesting that some of these long-lasting methylation sites may be marking genes potentially important for former smokers who are still at increased risk of developing certain diseases.

The discovery of smoking-related DNA methylation sites raises the possibility of developing biomarkers to evaluate a patient’s smoking history, as well as potentially developing new treatments targeted toward these methylation sites. However, the main analysis was not designed to examine effects over long periods of time.


Abstract of Epigenetic Signatures of Cigarette Smoking

Background — DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

Methods and Results — To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p

Conclusions — Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.