Nicotine dependence and genetic variation in the nicotinic receptors.

Technological advances have led to the discovery of genetic variants that contribute to many illnesses including nicotine dependence. A multi-stage model of the development of nicotine dependence underlies these genetic studies, and it includes a progression through several stages of smoking behavior from never smoking to nicotine dependence. The final step in this model of dependence is the progression from established smoking behavior to the development of nicotine dependence. Contrasting individuals who smoke only a few cigarettes per day, or "chippers", to heavy smoking, nicotine dependent subjects, focuses a genetic study on the transition from smoking to nicotine dependence. This approach has identified distinct genetic variants that contribute to nicotine dependence on chromosome 15 in the region of the alpha5-alpha3-beta4 family of nicotinic receptor genes. This region of association includes an amino acid change in the alpha5 nicotinic receptor protein, which is most likely a biological variant altering the risk of developing dependence. There is also evidence that other variants alter alpha5 nicotinic receptor gene expression and potentially the risk of smoking. The discovery of these genetic variants and their contribution to the development of nicotine dependence highlight some of the many challenges in genetic studies. The first is that the prevalence of risk alleles can vary across populations so that a genetic risk factor can have a larger or small effect in a population depending on its frequency. The second challenge is that the risk that each genetic variant contributes in the development of a disorder is small and so it is many genes along with environmental risk factors that contribute to the development of a disorder. Interestingly, recent genetic studies of lung cancer and chronic obstructive pulmonary disease demonstrate that this same region has an important genetic influence on these disorders. Finally, there are differences in the risk of developing nicotine dependence based on gender and socioeconomic status. As our understanding of the genetic contributions of nicotine dependence increases, we may improve and personalize our treatments for smoking cessation and enhance our knowledge of other smoking related diseases in those who are at high risk for the many adverse consequences of smoking.