Dataset Information

The role of the SLC6A3 3' UTR VNTR in nicotine effects on cognitive, affective, and motor function.

ABSTRACT:

Rationale

Nicotine has been widely studied for its pro-dopaminergic effects. However, at the behavioural level, past investigations have yielded heterogeneous results concerning effects on cognitive, affective, and motor outcomes, possibly linked to individual differences at the level of genetics. A candidate polymorphism is the 40-base-pair variable number of tandem repeats polymorphism (rs28363170) in the SLC6A3 gene coding for the dopamine transporter (DAT). The polymorphism has been associated with striatal DAT availability (9R-carriers > 10R-homozygotes), and 9R-carriers have been shown to react more strongly to dopamine agonistic pharmacological challenges than 10R-homozygotes.

Objectives

In this preregistered study, we hypothesized that 9R-carriers would be more responsive to nicotine due to genotype-related differences in DAT availability and resulting dopamine activity.

Methods

N=194 non-smokers were grouped according to their genotype (9R-carriers, 10R-homozygotes) and received either 2-mg nicotine or placebo gum in a between-subject design. Spontaneous blink rate (SBR) was obtained as an indirect measure of striatal dopamine activity and smooth pursuit, stop signal, simple choice and affective processing tasks were carried out in randomized order.

Results

Reaction times were decreased under nicotine compared to placebo in the simple choice and stop signal tasks, but nicotine and genotype had no effects on any of the other task outcomes. Conditional process analyses testing the mediating effect of SBR on performance and how this is affected by genotype yielded no significant results.

Conclusions

Overall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype.

SUBMITTER: Schroder R

PROVIDER: S-EPMC8638222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Many studies have examined the association between SLC6A3 3'-untranslated region (UTR) variable number tandem repeat (VNTR) polymorphism and smoking cessation; however, the results are inconclusive, primarily because of the small-to-moderate size samples. The primary goal of this study was to determine whether this polymorphism has any effect on smoking cessation by a meta-analysis of all reported studies. We adopted a 9-repeat dominant model that considers 9-repeat and non-9-repeat as two genotypes and compared their frequencies in former vs current smokers. Eleven studies with 5480 participants were included. Considering the presence of study heterogeneity and differences in the availability of information from each study, three separate meta-analyses were performed with the Comprehensive Meta-Analysis statistical software (version 2.0). The first meta-analysis provided evidence of association between the 9-repeat genotype and smoking cessation under the fixed-effects model (pooled odds ratio (OR)=1.13; 95% confidence interval (CI)=1.01, 1.27; P=0.037) but not in the random-effects model (pooled OR=1.11; 95% CI=0.96, 1.29; P=0.159). Given the marginal evidence of heterogeneity among studies (P=0.10; I2=35.9%), which likely was caused by inclusion of an Asian population treatment study with an opposite effect of the polymorphism on smoking cessation, we excluded the data of this study, revealing a significant association between the 9-repeat genotype and smoking cessation under both the fixed- and random-effects models (pooled OR=1.15; 95% CI=1.02, 1.29; P=0.02 for both models). By analyzing adjusted and unadjusted results, we performed the third meta-analysis, which showed consistently that the 9-repeat genotype was significantly associated with smoking cessation under both the fixed- and random-effects models (pooled OR=1.17; 95% CI=1.04, 1.31; P=0.009 for both models). We conclude that the 3'-UTR VNTR polymorphism is significantly associated with smoking cessation, and smokers with one or more 9-repeat alleles have a 17% higher probability of smoking cessation than smokers carrying no such allele.