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What Gets You Hooked on Smoking and Nicotine? First complex analysis of the genes that predispose you to addiction	By Stefan Anitei, Science Editor 12th of February 2007, 11:54 GMT Adjust text size:


About 440,000 Americans die of smoking-related illnesses yearly and at global level, the number is about 5 million. People around the world are bombarded with antismoking messages, but despite the evidence that smoking is harmful, just in the US 65 million still continue to smoke. More than half of the smokers consume at least five packs (100 cigarettes) daily in their lives and are clearly nicotine dependent. But about 15 % of the smokers do not develop any symptoms of nicotine dependence. "These people can give up smoking at any time," said Laura Jean Bierut, M.D., associate professor of psychiatry and principal investigator of both studies. "They have no cravings. They smoke socially." That's why genetic factors have been suspected to play an important role in tobacco addiction. Some researches had proven that smoking behaviors tend to gather in families, and large studies of twins revealed that clustering is partly due to genetic factors. Two recent studies were the most complex ones focusing in determining the human's risk of nicotine dependence. The smoking-related genes usually ease signaling between brain's cells, like the alpha-5 nicotinic cholinergic receptor (CHRNA5) gene, a very strong factor of risk for nicotine dependence. A specific mutation in the gene doubled the risk of developing nicotine dependence once exposed to smoking. CHRNA5 receptors are part of neural pathways of the dopamine (the pleasure hormone). The studies also confirmed the hypotheses that genes encoding gamma aminobutyric acid (GABA) receptors are also linked to nicotine dependence. The researches also found a totally new gene involved in nicotine addiction: the Neurexin 1 (NRXN1), that regulates the balance between excitatory mechanisms (that increase neuronal signaling) and inhibitory mechanisms (that slow down signaling). "An imbalance between excitatory and inhibitory activity in the brain may predispose people to addiction, such as alcoholism, drug dependence or nicotine dependence," said Bierut. "The Neurexin gene we've identified is really a key factor in the balance between inhibition and excitatory activity in neurons." The team made two separate researches on almost 2,000 subjects. One American approach investigated the entire human genome for suspicious DNA patches in smokers and "social" smokers, while and Australian approach targeted specific genes. "The combination of these two approaches represents the most powerful and extensive study on nicotine dependence to date and is an important step in a large-scale, genetic examination of nicotine dependence," says Elias A. Zerhouni, M.D., the director of the National Institutes of Health, which funded the studies. Current drug therapies for nicotine dependence have weak results and genetic traits information could make them more effective. "The type of variant you have at this particular receptor - the alpha-5 nicotinic receptor - may actually predict whether or not you will do well on nicotine replacement therapy," she says. Still, further research is needed. These approaches are very important as they compared addicted smokers to non-addicted smokers, not smokers to non-smokers. "You're not at risk for nicotine dependence unless you've smoked," Bierut says. "You have to study smokers to identify the people who are at risk of becoming nicotine dependent versus those who smoke but can give it up at any time."

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