VCU researchers link gene to nicotine dependence

By Lorraine Cichowski, Kenneth Kendler and Xiangning Chen

RICHMOND, Va. – People who carry a mutation of the gene known as Epac are more likely to start smoking and become addicted to nicotine than people without the mutation, according to preliminary findings released today (March 25) by researchers at Virginia Commonwealth University.

Kenneth S. Kendler, M.D., the Rachel Brown Banks Distinguished Professor of Psychiatry and Professor of Human Genetics and director of the Virginia Institute for Psychiatric and Behavioral Genetics at VCU, said a study of 688 twins who are registered with VCU’s Mid-Atlantic Twin Registry linked variants in Epac with a tendency in the twins to start smoking and become nicotine dependent.  

“Although these findings are preliminary, it’s important that we have been able to point to variations in one gene that apparently make some people more susceptible to nicotine dependence than other people,” Kendler told the Virginia Forum on Youth Tobacco Use, a two-day meeting sponsored by the Virginia Youth Tobacco Project.  “The earlier that we can identify those at risk for smoking, the earlier we can intervene to prevent young people from developing the smoking habit.”

Previous studies have showed that smoking is highly heritable. However, various genes as well as environmental factors – such as parents smoking at home – are believed to play a role, and researchers so far have been unable to identify one specific gene responsible for an increased tendency to smoke.

Epac (exchange protein directly activated by cAMP) is a gene located on Chromosome 12.  The gene has been shown to increase its expression in a rat’s brain after the rat has been given nicotine. The VCU study, which is expected to be published later this year, sought to test the potential role that Epac plays in influencing risk in humans for starting to smoke and becoming dependent on nicotine.  

VCU researcher Dr. Xiangning Chen, assistant professor of psychiatry, typed five single nucleotide polymorphisms, or SNPs, in the 688 twins studied -- 244 of them life-long nonsmokers, 215 moderate smokers and 299 heavy smokers. Two of the SNPs, which are DNA sequence variations, were shown to have a modest association with a progression to nicotine dependence, and one SNP was shown to have a weak association with starting to smoke. Scientists are interested in SNPs, which make up about 90% of all human genetic variation, because they believe some SNPs could predispose people to disease or other conditions and influence their response to drugs.

Chen and Kendler, working in collaboration with researchers from VCU’s Department of Pharmacology and Toxicology, will be following up this work by looking at more candidate genes in the twin sample whose expression levels also are altered in a rodent’s brain by administration of nicotine.

The work was supported by grants from the National Institute of Health and the Virginia Tobacco Settlement Foundation through the Virginia Youth Tobacco Project to VCU.

The Virginia Youth Tobacco Project, coordinated by VCU, is a coalition of Virginia universities originated by the Virginia Tobacco Settlement Foundation to study why young people begin to smoke and why some become addicted to nicotine in tobacco products. The team, which also includes researchers from the University of Virginia, James Madison University, Virginia Tech, the College of William and Mary and George Mason University, also is evaluating which anti-tobacco programs work most effectively. The project is funded by the Virginia Tobacco Settlement Foundation, which was created by the General Assembly in 1999 to distribute part of the money Virginia will receive over 25 years from tobacco product manufacturers under a national Master Settlement Agreement with 47 states.