Genetic influence of dopamine receptor, dopamine transporter, and nicotine metabolism on smoking cessation and nicotine dependence in a Japanese population.

BACKGROUND: This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects' smoking history on the association. RESULTS: Genotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence. CONCLUSIONS: This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.

Effects of moderating factors including serotonin transporter polymorphisms on smoking behavior: a systematic review and meta-analysis update.

INTRODUCTION: The aim of this review was to report an update of a previous meta-analysis (by another group) of a possible relationship between serotonin transporter (5-HTTLPR) genotype and smoking behavior, and extend previous work by factoring in some demographic parameters (age, gender, and ethnicity) in a multiple regression model to examine the relationship between these demographic factors and the effect of 5-HTTLPR polymorphism on smoking behavior. METHODS: Effect sizes were calculated for each study selected for meta-analysis and were pooled using the random-effects model, which assumes within-study sampling and between-study variance and provides wider confidence intervals. Effect sizes calculated in each study were used to evaluate the correlations with participant data for age, gender, and ethnicity (moderating variable) by multiple regression analysis. RESULTS: Meta-analysis indicated a relationship between smoking rate and the 5-HTTLPR genotype, but not smoking initiation and persistence, which was consistent with that of the previous review. Publication bias was not indicated for smoking initiation or persistence. Multiple regression analysis revealed that mean participant age significantly affected effect sizes for smoking initiation and persistence of each study. The proportion of Caucasians may have been partially influenced by the difference in effect sizes for smoking persistence among the studies. CONCLUSION: A significant relationship stratified by ancestry was observed between the 5-HTTLPR genotype and smoking rate, but not between the 5-HTTLPR genotype and smoking initiation and persistence. Regression analysis detected effects of age and/or ethnicity as moderating factors on smoking initiation and persistence.

Association between dopamine receptor 2 TaqIA polymorphisms and smoking behavior with an influence of ethnicity: a systematic review and meta-analysis update.

INTRODUCTION: The relationship between dopamine receptor D2 (DRD2) gene TaqIA polymorphisms and smoking behavior remains controversial. The aim of this review was to update a previous meta-analysis on the effect of DRD2 polymorphisms on smoking behavior by considering the influence of ethnicity. METHODS: This review presents analyses stratified by ancestry, as the samples included individuals of different ethnicities. Pooled effect sizes were calculated using fixed- and random-effects models to verify heterogeneity. We investigated the association for the proportion of men and Caucasians by regression analysis using the effect sizes calculated by each meta-analysis. RESULTS: Analysis of smoking cessation revealed a significant effect, which suggested that ethnic differences between Caucasians and Asians moderate the effect of DRD2 polymorphisms. Smoking initiation and rate exhibited no relationship with DRD2 polymorphisms; furthermore, we detected heterogeneity. Although the analysis of smoking persistence indicated significant effects, heterogeneity was detected. The finding of heterogeneity for smoking persistence and rate suggests the possibility of gene-gene interactions arising from ethnic differences between the samples. We found a significant inverse relationship between the proportion of men and effect sizes among Caucasians for smoking persistence and rate. Gender differences between Caucasian samples may moderate the effect of DRD2 polymorphisms on smoking persistence and rate. CONCLUSIONS: Our findings indicate that the ethnicity of the participants alters the effect of DRD2 polymorphisms on smoking behavior. The observed heterogeneity may be associated with participant gender as a moderating factor, and the association may be specific to Caucasians.

Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling.

Stress-induced overactivation of glucocorticoid signaling may contribute to mental illness by inducing neuronal death and dysfunction. We previously reported that pretreatment with the plant flavonoid butein inhibits corticosterone (CORT)-induced apoptosis of Neuro2A (N2A) cells. In the current study, we examined whether MEK-ERK and PI3K-AKT signaling pathways are involved in neuroprotection by butein. N2A cells were pre-incubated with serum-free DMEM containing 0.5 µM butein for 30 min, and then incubated with serum-free DMEM containing 0.5 µM butein, 50 µM CORT, 50 µM LY294002, or 50 µM PD98059 as indicated for 24 h. We subsequently performed the MTT assay and the western blot analysis. As expected, CORT considerably reduced N2A cell viability and increased relative expression of the apoptosis effector cleaved caspase-3, whereas pretreatment with butein blocked these cytotoxic effects. Treatment with CORT alone also decreased both AKT and ERK protein phosphorylation. Butein pretreatment had no effect on AKT phosphorylation, and only partially reversed the reduction in phosphorylated ERK. However, cotreatment with butein and the PI3K inhibitor LY294002 during CORT exposure enhanced ERK phosphorylation, whereas cotreatment with butein and the ERK phosphorylation/activation inhibitor PD98059 enhanced AKT phosphorylation, suggesting that MEK-ERK negatively regulates AKT phosphorylation. Moreover, the protective efficacy of butein was blocked by PD98059 cotreatment but not LY294002 cotreatment. These findings suggest that butein protects neurons against glucocorticoid-induced apoptosis by sustaining ERK phosphorylation and downstream signaling.

Protective effects of butein on corticosterone-induced cytotoxicity in Neuro2A cells.

A functional understanding of the relationship between glucocorticoids and neuronal apoptosis induced by the production of reactive oxygen species (ROS) may lead to a novel strategy for the treatment or prevention of depression. Previous reports suggest that butein, a type of flavonoids, may be a potent candidate against depression-related neuronal cell apoptosis caused by oxidative stress; however, the protective effects of butein on damaged corticosterone (CORT)-treated neuronal cells has not been elucidated. In the present study, we examined the protective effect of butein on CORT-induced cytotoxicity and neurite growth during cell differentiation of mouse neuroblastoma Neuro2A (N2A) cells. Moreover, the effect on cultured cells by high concentrations of butein was confirmed. Our results demonstrate that CORT treatment significantly decreases cell viability and induces cell death. CORT was suggested to induce apoptosis via mitochondrial dysfunction and caspase-3 activation; this apoptosis may be attributed to DNA damage by ROS generation, found in this study to be significantly inhibited by pretreatment with butein. We found that CORT produced significant growth suppression of retinoic acid-induced neurite outgrowth in N2A cells; however, butein significantly increased neurite length and induced dose-dependent apoptotic cytotoxicity in N2A cells. This study suggests that low concentration of butein can prevent CORT-induced cytotoxicity in N2A cells, and provides preliminary results supporting some of the beneficial roles of butein in neuroprotection.

Effect of genetic polymorphism of brain-derived neurotrophic factor and serotonin transporter on smoking phenotypes: A pilot study of Japanese participants.

PURPOSE: This study investigated whether a gene polymorphism causing a Val66Met substitution (rs6265) in brain-derived neurotrophic factor (BDNF) is associated with smoking initiation, smoking cessation, nicotine dependence and age of smoking initiation, in Japanese participants. Additionally, this study examined whether the S allele of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with the BDNF Val66Met polymorphism on smoking phenotypes. PATIENTS AND METHODS: The genotypic proportion of the polymorphism responsible for BDNF Val66Met was determined in 148 participants including 88 current smokers, 21 former smokers, and 39 never smokers, and Fisher's exact test was used to investigate the relationship between this polymorphism and smoking cessation and initiation as well as the association between the genotypes of current smokers with a heavy smoking index (HSI) and the age of smoking initiation. In addition to the BDNF Val66Met polymorphism, the 5-HTTLPR polymorphism has also been evaluated in a specific subset of participants. RESULTS: We found statistically significant correlations between the BDNF Val66Met polymorphism and the HSI, both in the whole study sample (P = 0.017) and in the male subgroup (P = 0.049). Moreover, the 5-HTTLPR polymorphism was associated with the age of smoking initiation in current smokers carrying the BDNF Met allele, in both the whole study sample (P = 0.041) and the male subgroup (P = 0.041). On the other hand, no association was observed between the BDNF Val66Met polymorphism, either alone or in combination with the 5-HTTLPR polymorphism, and the age of smoking cessation. Finally, no independent effects of the BDNF Val66Met genotype on the age of smoking initiation were detected. CONCLUSION: This pilot study provides preliminary findings regarding the influence of BDNF Val66Met on smoking phenotypes and the interacting effect of 5-HTTLPR on the association between BDNF Val66Met and smoking phenotypes in Japanese participants.