Fatemeh Hosseini,1,*
1. P.HD Student In Physiology Tehran Shomal Azad University Tehran Iran
Introduction: One of the most prevalent types of psychiatric disease is depression (DD). The World Health Organization estimates that a DD affects roughly 350 million individuals. In most nations, the prevalence of DDs is between 8 and 12%, ranging from 3% in Japan to 16.9% in the USA. According to predictions, DDs will overtake ischemic heart disease as the second-leading global cause of disability by the year 2020. The serotonin transporter SLC6A4 (formerly known as SERT), which is responsible for the absorption of serotonin (5-HTT) from the synaptic cleft to the presynaptic neuron and hence plays a role in maintaining the serotonin level in the presynaptic area, has been the focus of the majority of investigations. Interest in this transporter also arises from the observation that inhibitors of neural serotonin reuptake are used widely in psychiatry for the treatment of depression, anxiety, and other conditions. The aim of this study was to investigate genetic factors in Major Depression Disease.
Methods: this review has been written from scientific databases such as Science Direct, Springer, Google Scholar, and PubMed.
Results: The structure of SLC6A4 may be far more complicated. Recent publications have reported that the expression of this gene is modulated by microRNA mir-16 binding sites in the 3′-nontranslated region of the gene. Therefore, polymorphisms localized within or near microRNA binding sites may be able to exert a strong effect on SLC6A4 expression and, consequently, on 5-HTT functions. It is possible that the abovementioned complexity of SLC5A4 organization may be one reason for the conflicting results obtained by analyses of the association of this gene's polymorphic variants (primarily in the analysis of the L/S polymorphism of the 5-HTTLPR repeat) with the onset of depression. Meta-analyses of these studies allow no final conclusion to be drawn about the role of this polymorphism in the development of depression. For instance, the meta-analysis conducted by Lopez-Leon et al. disclosed an elevated risk of DDs in S allele carriers, whereas no similar association was found in carriers of other alleles. The latest meta-analysis of the results of 23 original studies has shown that the S allele raises the risk of DDs; the risk of depression in S allele carriers is increased 1.14-fold (CI: 1.05–1.24). Nevertheless, the high level of heterogeneity of the data included in this meta-analysis should be noted. In all analyzed models, the association p-value does not reach 0.05. This may be due to the inclusion in the meta-analysis of studies of different size samples, including samples comprising fewer than 50 people. In the context of the monoamine theory of DD development, analysis of a large number of candidate genes has been performed. They are, in particular, receptor genes for dopamine (DRD3, DRD4) and serotonin (HTR1A, HTR2A, HTR1B, HTR2C); genes for noradrenalin (SLC6A2) and dopamine (SLC6A3); genes for the enzymes monoamine oxidase A (MAOA), tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), catechol-o-methyl transferase (COMT); and the piccolo presynaptic cytomatrix protein (PCLO). For each of these genes, polymorphic variants were identified that were associated with point mutations or tandem repeat polymorphisms. These polymorphisms were analyzed in samples from patients of different ethnicities with DD. As for SLC6A4, different studies have produced conflicting results, and it seems reasonable not to analyze the results of individual studies but to consider only the meta-analyses that have shown the existence of associations between definite variants of the genes and DD development. One of the first large-scale meta-analyses of the genetic case–control research on DDs was conducted in 2008 by Lopez-Leon and coauthors. The final analysis focused on 20 polymorphisms in 18 genes. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Among the genes of the monoaminergic system, statistically reliable associations were found for SLC6A4 and SLC6A3.
Conclusion: Despite the drawbacks of such models, a three-pronged strategy that combines gene-association studies with assessments of the epigenetic status of DD patients and examination of the alterations in animal models of depression will allow researchers to pinpoint the contributions of genetic, epigenetic, and environmental factors to various forms of DDs and to create strategies for lowering the risk of depression and for providing adequate treatment.