Commentary Cell Science Reviews Vol 5 No 2 ISSN 1742-8130

Allelic variation in the α5/α3/β4 nicotinic acetylcholine receptor subunit gene cluster:
The smoking gun in genetic vulnerability to tobacco addiction

Many aspects of the tobacco habit in human cigarette smokers are heritable, but the underlying genetic mechanisms have remained elusive. Nicotinic acetylcholine receptors (nAChRs) are the primary site of action in the brain for nicotine, the major addictive component of tobacco smoke. Nicotinic receptors are comprised of five membrane-spanning subunits (α and β isoforms) that associate in various combinations to generate nAChR isoforms. In a recent report, Berrettini and colleagues provided compelling evidence that allelic variation in the α5/α3/β4 nAChR subunit gene cluster located in chromosome region 15q25 may play a critical role in vulnerability to tobacco addiction. These data are consistent with recent reports suggesting that genetic variation in the same gene cluster may increase the risk of developing lung cancer and peripheral vasculature disease associated with prolonged tobacco consumption, perhaps by increasing vulnerability to nicotine dependence. Similar genetic variation may also predispose individuals to greater risk for developing alcohol dependence but may protect against cocaine dependence. These findings provide important insights into the genetic basis of addiction to tobacco and other drugs of abuse, and suggest that α5/α3/β4-containing nAChRs may be important targets for the development of novel therapeutics to facilitate smoking cessation efforts.

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