Meta-Analysis Reveals Significant Association of the 3′-UTR VNTR inSLC6A3with Alcohol Dependence

Abstract

Background Although many studies have analyzed the association of 3′-untranslated region (UTR) variable number tandem repeat (VNTR) polymorphism in SLC6A3 with alcohol dependence (AD), the results remain controversial. This study aimed to determine whether this variant indeed has any genetic effect on AD by integrating 17 reported studies with 5,929 participants included. Methods The A9-dominant genetic model that considers A9-repeat and non-A9 repeat as two genotypes and compared their frequencies in alcoholics with that in controls was adopted. Considering the potential influence of ethnicity, differences in diagnostic criteria of AD, and alcoholic subgroups, stratified meta-analyses were conducted. There existed no evidence for the presence of heterogeneity among the studied samples, indicating the results under the fixed-effects model are acceptable. Results We found a significant association of VNTR A9 genotypes with AD in all ethnic populations (pooled odds ratio [OR] 1.12; 95% confidence interval [CI] 1.00, 1.25; P=0.045) and the Caucasian population (pooled OR 1.15; 95% CI 1.01, 1.31; P=0.036). We also found VNTR A9 genotypes to be significantly associated with alcoholism as defined by the DSM-IV criteria (pooled OR 1.18; 95% CI 1.03, 1.36; P=0.02). Further, we found a significant association between VNTR A9 genotypes and alcoholism associated with alcohol withdrawal seizure or delirium tremens (pooled OR 1.55; 95% CI 1.24, 1.92; P=1.0×10−4). In all these meta-analyses, no evidence of publication bias was detected. Conclusions We concluded that the VNTR polymorphism has an important role in the etiology of AD, and individuals with at least one A9 allele are more likely to be dependent on alcohol than persons carrying the non-A9 allele.

The SLC6A3 gene possibly affects susceptibility to late-onset alcohol dependence but not specific personality traits in a Han Chinese population

“…Therefore, despite the fact that SLC6A3 promoter variants are excellent candidates for linkage and association studies, we did not find evidence supporting their role in AD in our cohort of Han Chinese population. For the most investigated 3' UTR VNTRs in relation to AD, two meta-analyses showed inconsistent results [ 16 , 17 ]. The contradictory findings might be attributable to differences in study design such as data sampling and statistical methods.…”

“…The contradictory findings might be attributable to differences in study design such as data sampling and statistical methods. In the latter study, for example, Ma et al [ 17 ] concluded that the 9-repeat allele increased the risk for AD in different populations using a dominant genetic model with a larger sample size. However, the authors did not include two studies that considered that the 9-repeat allele was protective for AD in Japanese and Han Chinese populations [ 40 , 41 ].…”

“…Evidence of an association between SLC6A3 and AD was limited using few genetic markers. Meta-analyses that explored whether one of the most frequently tested SLC6A3 polymorphisms, a 40-bp variable number tandem repeat (VNTR) in the 3′ untranslated region, was associated with AD have shown inconsistent results [ 16 , 17 ]. In contrast, other studies found that several single nucleotide polymorphisms (SNPs) located in exons of the SLC6A3 gene may functionally contribute to AD.…”

Significant association of the CHRNB3-CHRNA6 gene cluster with nicotine dependence in the Chinese Han population

“…We searched PubMed and Web of Science for all studies eligible for this meta-analysis according to the PRISMA guidelines 59 , a strategy similar to what we used previously 60 , 61 . The key words used in the search were “ CHRNB3 ” or “ CHRNA6 ” or “cholinergic nicotinic receptor gene” combined with “nicotine dependence” or “ND.” The reports containing the chosen words were checked individually for references that could have been missed by the above-mentioned search protocol.…”

Dopamine Transporter Gene Methylation is Associated with Nucleus Accumbens Activation During Reward Processing in Healthy but not Alcohol‐Dependent Individuals

“…Since striatal dopamine signaling is directly influenced by dopamine transporter (DAT) availability (Shen et al, 2004, e.g., Giros et al, 1996, Heinz et al, 1999), it has been hypothesized that genetic variation in the gene encoding the DAT ( DAT1/SLC6A3 ) contributes to differences in reward processing (Lohoff et al, 2010, Dreher et al, 2009, Hahn et al, 2011). While several studies have indeed found associations of SLC6A3 variation with various alcohol use disorder phenotypes and endophenotypes (Ma et al, 2016, Ray et al, 2014, Wernicke et al, 2002, Le Strat et al, 2008, Gorwood et al, 2003), other studies were unable to replicate results (e.g., Du et al, 2011, Kohnke et al, 2005, Xu and Lin, 2011). Genetic variation is one important factor influencing interindividual differences in reward processing; however, it is likely that other mechanisms affecting DAT expression or function may also contribute.…”