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The 3'UTR VNTR SLC6A3 Genetic Variant and Major Depressive Disorder: A Systematic Review.

ABSTRACT: Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the SLC6A3 gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the SLC6A3 (DAT1) 3'UTR VNTR (rs28363170) gene variant's SS (9R/9R) genotype and S (9R) allele frequency fluctuation and its influence on the modulation of pharmacotherapy in MDD. For this purpose, we searched different databases, and after applying the eligibility criteria, six articles were selected. Studies have shown an association between the SS (9R/9R) genotypic and S (9R) allelic presence with the risk of developing MDD, in addition to influencing the decrease in response to antidepressant therapy. However, despite the findings, disagreements were observed between other studies. For this reason, further studies with the SLC6A3 3'UTR VNTR (rs28363170) variant in different populations are necessary to understand this polymorphism's role in the onset of this disease.

SUBMITTER: Gontijo BR

PROVIDER: S-EPMC10452352 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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The 3'UTR VNTR SLC6A3 Genetic Variant and Major Depressive Disorder: A Systematic Review.

Gontijo Bruna Rodrigues BR Possatti Isabella I Fratelli Caroline Ferreira CF Pereira Alexandre Sampaio Rodrigues ASR Bonasser Larissa Sousa Silva LSS de Souza Silva Calliandra Maria CM Rodrigues da Silva Izabel Cristina IC

Biomedicines 20230815 8

Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the SLC6A3 gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the SLC6A3 (DAT1) 3'UTR VNTR (rs28363170) gene variant's SS (9R/9R) genotyp ...[more]

PMID: 37626766

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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.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:BackgroundAccording to current classification systems, patients with major depressive disorder (MDD) may have very different combinations of symptoms. This symptomatic diversity hinders the progress of research into the causal mechanisms and treatment allocation. Theoretically founded subtypes of depression such as atypical, psychotic, and melancholic depression have limited clinical applicability. Data-driven analyses of symptom dimensions or subtypes of depression are scarce. In this systematic review, we examine the evidence for the existence of data-driven symptomatic subtypes of depression.MethodsWe undertook a systematic literature search of MEDLINE, PsycINFO and Embase in May 2012. We included studies analyzing the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) of adults with MDD in latent variable analyses.ResultsIn total, 1176 articles were retrieved, of which 20 satisfied the inclusion criteria. These reports described a total of 34 latent variable analyses: 6 confirmatory factor analyses, 6 exploratory factor analyses, 12 principal component analyses, and 10 latent class analyses. The latent class techniques distinguished 2 to 5 classes, which mainly reflected subgroups with different overall severity: 62 of 71 significant differences on symptom level were congruent with a latent class solution reflecting severity. The latent class techniques did not consistently identify specific symptom clusters. Latent factor techniques mostly found a factor explaining the variance in the symptoms depressed mood and interest loss (11 of 13 analyses), often complemented by psychomotor retardation or fatigue (8 of 11 analyses). However, differences in found factors and classes were substantial.ConclusionsThe studies performed to date do not provide conclusive evidence for the existence of depressive symptom dimensions or symptomatic subtypes. The wide diversity of identified factors and classes might result either from the absence of patterns to be found, or from the theoretical and modeling choices preceding analysis.

Dataset Information

The 3'UTR VNTR SLC6A3 Genetic Variant and Major Depressive Disorder: A Systematic Review.

Publications

The <i>3'UTR VNTR SLC6A3</i> Genetic Variant and Major Depressive Disorder: A Systematic Review.

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