MR and GR functional SNPs may modulate tobacco smoking susceptibility.

A number of studies have demonstrated that stress is involved in all aspects of smoking behavior, including initiation, maintenance and relapse. The mineralocorticoid (MR) and glucocorticoid (GR) receptors are expressed in several brain areas and play a key role in negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis. As nicotine increases the activation of the HPA axis, we wondered if functional SNPs (single nucleotide polymorphisms) in MR and GR coding genes (NR3C2 rs5522 and NR3C1 rs6198, respectively) may be involved in smoking susceptibility. The sample included 627 volunteers, of which 514 were never-smokers and 113 lifetime smokers. We report an interaction effect between rs5522 and rs6198 SNPs. The odds ratio (OR) for the presence of the NR3C2 rs5522 Val allele in NR3C1 rs6198 G carriers was 0.18 (P = 0.007), while in rs6198 G noncarriers the OR was 1.83 (P = 0.027). We also found main effects of the NR3C1 rs6198 G allele on number of cigarettes smoked per day (P = 0.027) and in total score of the Fagerström Test for Nicotine Dependence (P = 0.007). These findings are consistent with a possible link between NR3C2 and NR3C1 polymorphisms and smoking behavior and provide a first partial replication for a nominally significant GWAS finding between NR3C2 and tobacco smoking.

Pharmacogenetics of smoking cessation therapy.

Nicotine dependence is a major health problem, with a large amount of smoking-related premature deaths and disabilities. The dependence mechanism of nicotine is especially complex and is under strong genetic influence. Smoking cessation is associated with substantial health benefits. Evidence from animal and human studies suggests that genetic polymorphisms influencing pharmacokinetics and pharmacodynamics of nicotine may have great potential for aiding smoking treatment. There are more than 30 association studies and one genome-wide association study (GWAS) between genetic polymorphisms and smoking cessation following nicotine replacement therapy (NRT) and/or bupropion therapy. However, only a few candidate genes or regions were analyzed more than twice and even these genes require additional investigations in different therapeutic schemes. There are a growing number of new pharmacologic options that have not been pharmacogenetically assessed according to published literature. In addition, molecular genetics studies are needed to assess the functional mechanisms of some putative association results. Taken together, the preliminary findings are promising but raise the need for new studies with adequate sample sizes and adjustment for several potential confounding factors frequently neglected, such as comorbidity and sociodemographic factors. The current state of the art in the field encourages an optimist view that personalized treatment approaches may become possible. However, the current scientific evidence still does not support the use of pharmacogenetic tests in routine smoking cessation therapy.