Meta-analysis reveals significant association of 3'-UTR VNTR in SLC6A3 with smoking cessation in Caucasian populations

Abstract

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.

Figure 1

Forest plot of the first meta-analysis results on pooled effect of 3′-UTR 9-repeat genotypes on smoking cessation. The Z value and P value of each study are presented by rows. The central vertical solid line shows the null hypothesis where the OR is equal to 1. The OR and 95% CI of each study are represented by the square and horizontal bar, respectively. The diamond symbol indicates the estimated pooled OR, which was calculated under the fixed-effects model.

Figure 2

Forest plot of the second meta-analysis results on pooled effect of 3′-UTR 9-repeat genotypes on smoking cessation. The Z value and P value of each study are presented by rows. The central vertical solid line shows the null hypothesis, where the OR is equal to 1. The OR and 95% CI of each study are represented by the square and horizontal bar, respectively. The diamond symbol marks the estimated pooled OR, which was calculated under the fixed-effects model.

Figure 3

Plots of sensitivity analyses results for the last two meta-analyses. The Y axis stands for the pooled OR and the X axis for the individual study that was removed at each time from the included studies. The diamond symbols indicate the pooled OR, and the top and bottom horizontal bars mark the 95% CIs. (A) Plot of sensitivity test for the second meta-analysis. (B) Plot of sensitivity test for the third meta-analysis.