The DRD2 Gene, Smoking, and Lung Cancer
Authors: E. P. Noble
Journal: JNCI Journal of the National Cancer Institute (1998)

Why do some individuals smoke and others do not? Why can some smokers quit, while others cannot? Why do certain smokers develop cancer of the lung, while others, despite prolonged use of cigarettes, do not? These questions have particular relevance during these times when much attention is being focused on the impact of smoking on health throughout the world. It has generally been assumed that environmental factors are primary determinants in the use of cigarettes and other nicotinecontaining products. Indeed, beyond mention that genetics may affect individual differences in vulnerability to tobacco use, human genetics is largely absent from reports on smoking by the U.S. Surgeon General (1) and the Secretary of the U.S. Department of Health and Human Services (2). However, results from adoption, association, family, trait marker, and twin studies indicate that both the acquisition and maintenance of smoking are influenced by heredity [reviewed in (3)]. When systematically compared with prototypic drugs of abuse (e.g., alcohol and cocaine), tobacco is similar along most usual and all critical points of comparison (4). It is also recognized that the use of tobacco is often accompanied by the use of psychoactive agents, particularly alcohol. A close association between smoking and alcohol consumption has been demonstrated in an epidemiologic study (5). In this regard, smoking is found to be as heritable as alcohol consumption, and the magnitude of the genetic effects on smoking is at least as great as that on alcoholism (3). If, in some individuals, a heritable basis exists for nicotine and alcohol dependence, a molecular genetic component should be present in these disorders. However, given the multiple effects that these drugs exert on the central nervous system and on the rest of the body, it is likely that numerous genes are involved in these drug dependencies. On the other hand, if these drugs manifest a common molecular basis, it is possible that one gene or a few genes may be shared in these disorders. An effect that nicotine and various other drugs (alcohol, cocaine, and amphetamine) have in common is the induction of euphoria and pleasurable emotional feelings in users. It has been hypothesized that these positive reinforcement effects are manifested through activation of the mesolimbic dopaminergic reward pathways of the brain (6,7). In support of this hypothesis is a substantial body of evidence indicating that activation of nicotinic receptors by nicotine enhances dopamine release in the brain (8,9), especially in the nucleus accumbens and the ventral tegmental area, regions known to be involved in reward. Inasmuch as there are nicotinic receptors in these regions of the brain (10), these reward areas are believed to be the site of nicotine’s reinforcing effects (11). Enhanced dopamine levels also accrue in the brain following the administration of other drugs, including alcohol, cocaine, amphetamine, and opiates (12). Considered together, the accumulating evidence points to the involvement of the dopaminergic system in the reinforcing actions of nicotine and some other psychoactive agents, actions that have been related to their addictive properties (6,7). Evidence has recently been reported that a molecular genetic diathesis, through the dopaminergic system, might predispose certain individuals to the use of some drugs. As Spitz et al. (13) have indicated in this issue of the Journal, the minor A1 and B1 alleles of the D2 dopamine receptor (DRD2) gene, which are in linkage disequilibrium (i.e., association of these two linked alleles occurs more frequently than would be expected by chance), have been implicated in alcoholism and other conditions involving substance abuse, and the A1 allele has been implicated in smoking behavior. What is unique about the study by Spitz et al. (13) is that these investigators ascertained both TaqIA and TaqIB alleles of the DRD2 gene in lung cancer case subjects and in control subjects who were never smokers, former smokers, or current smokers. Moreover, they determined the relationships between DRD2 polymorphisms and a number of smoking variables. The variables included the following: years of smoking, age smoking started, number of cigarettes smoked per day, duration of smoking cessation, attempts to quit smoking, and nicotine addiction (Fagerstrom Tolerance Questionnaire [FTQ]) scores. The problem of variation in the frequency of DRD2 polymorphisms that may exist among certain racial/ethnic groups was probably minimal in the study conducted by Spitz et al. because they studied a fairly homogeneous group of whites. Another virtue of their study was that the case and control subjects were matched on age, sex, and smoking status. However, this virtue is offset by the small number of never smokers in the case (n 4 15) and matched control (n 4 13) groups. Whereas never smokers may represent only a small fraction of lung cancer patients, the prevalence of the DRD2 alleles in this small group and the matched control subjects may vitiate significant differences when compared with the appropriate smoker groups. Still, in ever-smoker control subjects, the 30.9% prevalence of