Applying genetic approaches to the treatment of nicotine dependence

Abstract

To advance the science of tobacco control, an enhanced understanding of the bio-behavioral basis of nicotine addiction is needed. In this study, we provide an overview of data from investigations of genetic factors in smoking behavior, discuss potential bio-behavioral mechanisms and effect modifiers, and suggest avenues for pharmacogenetics research in the area of smoking cessation treatment. The evidence to date is very consistent with respect to the significance of genetic contributions to smoking behavior. However, attempts to elucidate the role of specific genetic variants have met with mixed success. Explanations for the lack of consistency in the results of genetic association studies include biases in ascertainment, ethnic admixture, lack of attention to covariates or modifiers of genetic risk, and the need for more refined phenotypes. As the field of genetics and smoking research progresses, increasing attention is being devoted to gene -environment interactions, with particular attention to the identification of genetic variants that may modify the effects of pharmacological treatment for smoking. With advances in molecular biology and genomics technology, individualized tailoring of smoking cessation therapy to genotype is within our grasp. Such research has the potential to improve treatment outcome, thereby reducing morbidity and mortality from smoking-related disease.

Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch

“…We therefore sought to examine the influence of these functional polymorphisms in the DRD4 gene on smoking cessation outcomes, and to evaluate whether or not the DRD4 VNTR or C-521T polymorphisms would moderate NRT efficacy for smoking cessation in a placebo-controlled, randomised clinical trial of the NRT for smoking cessation. Consistent with the hypothesis that reduced dopaminergic tone represents a risk factor for substance use and dependence, 50 and published pharmacogenetic studies of NRT patch [15][16][17] and bupropion, 7,16,[18][19][20] we hypothesised that genetic variants resulting in decreased D4 receptor availability (DRD4 VNTR long and À521T alleles) would be associated with reduced likelihood of smoking cessation. Furthermore, we also hypothesised that participants with reduced activity DRD4 alleles would be more responsive to NRT.…”

“…14 Three polymorphisms (C957T, À141Cins/del and Taq1A or C32806T) in the dopamine D2 receptor gene (DRD2) appear to influence treatment response to NRT patch [15][16][17] and/or bupropion for smoking cessation, 7,16,[18][19][20] although recent evidence indicates that the Taq1A polymorphism is, in fact, present in a protein kinase gene (ANKK1) located downstream of the DRD2 gene. 21 However, to date, there are no published pharmacogenetic smoking cessation studies evaluating dopamine D4 receptor gene (DRD4) polymorphisms.…”

“…[3][4][5][6] Thus, the quest for more efficacious smoking cessation therapies has been augmented in recent years by the exploration of how variation in the human genome might influence treatment response to the two first-line pharmacotherapies for smoking cessation currently in widespread use, namely nicotine replacement therapy (NRT) and sustained-release bupropion. 7 Converging evidence from animal and human studies indicates that nicotine dependence is under the influence of dopamine-dependent mesolimbic and mesocortical brain systems, 8 and that nicotine stimulates burst firing of dopaminergic neurones when binding to nicotinic acetylcholine receptors in the midbrain tegmentum, 9 which in turn results in enhanced release of dopamine in the outer shell of the nucleus accumbens and prefrontal cortex. 10,11 This cascade of events, including changes in post-synaptic signalling, is theorised to be positively reinforcing with hedonic and appetitive motivational properties.…”

Associação entre polimorfismo SLC6A3 3’UTR VNTR e a resposta ao tratamento da dependência de nicotina

“…Nesse sentido, evidências em modelos humanos e animais sugerem a importância da dopamina como substrato do circuito de recompensa na dependência de nicotina. O foco atual das pesquisas tem se voltado para a influência da variação individual na transmissão dopaminérgica na resposta aos tratamentos farmacológicos para tabagismo 12 .…”

A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation

“…The basic premise of this approach is that inherited differences in drug metabolism and drug targets have important effects on treatment toxicity and efficacy (Evans & Relling, 1999;Poolsup, Li Wan Po, & Knight, 2000). Advantages of a pharmacogenetic approach to the study of smoking cessation treatment include the use of more refined phenotypes for genetic analysis (e.g., prospectively assessed abstinence symptoms, side effects, measures of the rewarding valence of nicotine, and smoking cessation under different treatment conditions) and the use of experimental designs that control the dosing and timing of therapy (Lerman & Niaura, 2002).…”