Physicians may some day have a new tool for tailoring smoking cessation treatments to a patient's individual genetic makeup. Researchers from Duke University Medical Center and the National Institute on Drug Abuse scanned the entire genetic makeup, or genome, of smokers and found that variants in 221 genes distinguished smokers who were successful in quitting from those who were not. "The long-term hope is that identifying these genetic variables in smokers will help us determine which type of treatment would be most effective," said Jed Rose, Ph.D., director of Duke's Center for Nicotine and Smoking Cessation Research. "Knowing a smoker's genetic makeup could indicate how intensely they need to be treated. People who are having trouble quitting because of their genes might need more treatment to overcome their addiction." The results of the research were published online April 2, 2007, in the journal BMC Genetics. The study was supported by the National Institutes of Health and Philip Morris USA Inc. "We now have further evidence that there is a biological basis not only for addiction, but for a smoker's ability to successfully beat the addiction," said George Uhl, Ph.D., a neurologist and neuroscientist in the Molecular Neurobiology Branch of the National Institute on Drug Abuse. Uhl's laboratory performed the genetic screening. "It is becoming clear that there is both a biological and an environmental basis to addiction and the ability to quit. Those involved in getting smokers to quit must pay attention to both factors." The researchers screened 520,000 individual genes taken from blood samples of smokers and nonsmokers. When they compared the genes of smokers with those who had successfully given up the habit, they found clusters of positive results in 221 gene variants present only in the successful quitters. Uhl said that researchers know the function of 187 of the 221 genes they identified, while the functions of the remaining variants are still to be determined. "We also found that at least 30 of the genes that we had previously identified as playing roles in dependence to other drugs also contribute to nicotine dependence," Uhl said. "These findings lend further support to the idea that nicotine dependence shares some common genetic vulnerabilities with addictions to other legal and illegal substances." Some of the specific genes identified might provide insights into why some people appear to have a susceptibility to addiction and why others are more successful in their attempts to quit. "For example, one of the genes identified controls the production of adhesion molecules, which are crucial in guiding connections between individual nerve cells," Rose said. "Smokers whose nerve cell connections aren't working properly may be more vulnerable to addiction and may face a tougher time quitting. These findings open up new possibilities in finding specific targets for treatment." Other identified genes play a role in controlling how people respond to stress. Uhl pointed out that one of the genes controls the production of a protein that is important in guiding learning processes in the brain. The researchers are planning additional studies to try to correlate this new genetic information with how smokers actually respond to the many forms of cessation treatments. ### Other members of the team, all from the National Institute on Drug Abuse, were Qing-Roong Liu, Tomas Drgon, Catherine Johnson and Donna Walther. Contact: Richard Merritt

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