The development of nicotine dependence requires smoking and results in a sequence of behavioral events that starts with the initiation of cigarette use, the conversion from experimental smoking to the establishment of regular smoking behavior, and then the development of nicotine dependence among smokers [5
]. Nicotine dependence, which is characterized by heavier smoking, early morning smoking, tolerance and withdrawal, predicts difficulty quitting.
Many compounds are present in tobacco, but nicotine is the addictive component that confers the risk of developing dependence. Nicotine binds to nicotinic cholinergic receptors, which are widely distributed in the central and peripheral nervous system. The nicotinic cholinergic receptor is composed of 5 subunit proteins arranged around a central pore, and the receptor is involved in physiologic responses related to smoking. There are 16 different nicotinic receptor subunit genes, α 1–7,9,10, β1–4, δ, ε, γ, and different combinations of these subunit proteins result in receptors that vary in biologic function, distribution throughout the body, and other pharmacologic properties. Binding of nicotine to nicotinic cholinergic receptors forms the basis of the molecular pharmacology that leads to dependence.
Not all smokers are nicotine dependent. Among current smokers, approximately 60% are nicotine dependent based on the Fagerström Test for Nicotine Dependence, a well established scale for assessing nicotine dependence [6
]. Dependence on nicotine has multiple underlying etiologies that include genetic predispositions and environmental risk factors. Evidence for genetic factors contributing to the risk of smoking behaviors and nicotine dependence is shown by the clustering of heavy smoking and nicotine dependence in families and the similarity of smoking behaviors in identical twins [8
]. In contrast to nicotine dependent smokers, light, non-dependent smokers or “chippers” smoke a few cigarettes per day and can easily quit smoking [10
]. These light smokers represent about 15% of the smoking population and can provide a genetic contrast group compared to heavy, nicotine dependent smokers.
It is likely that a large number of genes contribute to nicotine dependence, as well as many environmental factors. This complexity represents a considerable challenge, but it also underscores the potential benefits of genetic studies of nicotine dependence. By understanding genetic factors that contribute to nicotine dependence, we may start to tease apart the different contributions of genes and environments that lead to heavy smoking, which in turn may improve interventions to reduce nicotine dependence and improve smoking cessation treatment.
At this time there are three main pharmacologic approaches to smoking cessation: nicotine replacement therapy (NRT), varenicline, and buproprion. NRT substitutes the nicotine from cigarettes with a sustained nicotine replacement which can then be tapered over several weeks. Varenicline is a partial nicotinic receptor agonist that minimizes nicotine craving and withdrawal. Buproprion acts through a different mechanism via inhibition of catecholamine (noradrenaline and dopamine) reuptake to improve quit rates. It is likely that there are different genetic profiles that identify who will best respond to one pharmacologic treatment or another. A potential promise of the study of the genetics of nicotine dependence is that we may gain insights into these profiles.
Rapid advances in genetic technology now provide a set of tools to identify genetic contributions to common diseases. A map of human genetic variation across major populations and lower cost testing of genetic variants allow large-scale genome-wide association studies (GWAS) that test one million or more genetic variants (single nucleotide polymorphisms or SNPs) in each person. These studies, which include thousands of subjects, test hundreds of thousands of variants across an individual’s complete set of DNA to identify genetic variations associated with a disease. In the last three years this has led to the discovery of new genetic contributions to diabetes, prostate cancer, and many other diseases, including nicotine dependence [11
The aims of this paper are to review the most robust genetic findings for nicotine dependence, lung cancer, and COPD and to place these in the context of smoking cessation.