Smoking has a very broad, long-lasting impact on the human genome

The new findings suggest that DNA methylation could be an important sign that reveals an individual's smoking history, and 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. "Equally important is our finding that even after someone stops smoking, we still see the effects of smoking on their DNA."

Smoking remains the leading preventable cause of death worldwide, despite a decline in smoking in many countries as a result of smoking cessation campaigns and legislative action. 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.

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.

The researchers suggest 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.

The main analysis was not designed to examine effects over long periods of time. The researchers note, that this is the largest examination of the effects of smoking on DNA methylation.

"Our study has found compelling evidence that smoking has a long-lasting impact on our molecular machinery, an impact that can last more than 30 years," said Roby Joehanes Ph.D. of Hebrew SeniorLife, first author and an instructor at Harvard Medical School in Boston, Massachusetts. "The encouraging news is that once you stop smoking, the majority of DNA methylation signals return to never smoker levels after five years, which means your body is trying to heal itself of the harmful impacts of tobacco smoking."