The S/S Genotype of the 5-HTTLPR (Serotonin-Transporter-Linked Promoter Region) Variant of the SLC6A4 Gene Decreases the Risk of Pre-Eclampsia.

Pre-eclampsia (PE) is a disorder characterized by hypertension in the second trimester of pregnancy that results from abnormal placentation affecting fetal development and maternal health. Previous studies have shown the role of serotonin (5-HT) that leads to poor placental perfusion, where S/S and S/L polymorphisms promote the solute carrier family 6 member 4 (SLC6A4) gene associated with the risk of developing changes in the microvasculature of the placenta. This study looked at the association between the gene variant 5-HTTLPR (serotonin-transporter-linked promoter region) of the SLC6A4 gene and the occurrence of PE. A total of 200 women were included: 100 cases (pregnant with PE) and 100 controls (pregnant without complications). Genotyping of the 5-HTTLPR variant was performed using polymerase chain reaction (PCR). Associations between the presence of the genetic variant of interest and PE and other clinical features were evaluated statistically. The frequencies of S/S, S/L, and L/L genotypes were 32%, 53%, and 15% for the cases and 55%, 25%, and 20% in the control group. Compared to the controls, the genotype frequencies S/S vs. S/L + L/L (recessive model) in the cases group were different (p = 0.002). The S/S genotype decreased the probability of PE (OR = 0.39, 95% IC: 0.22-0.69, p = 0.002) and PE with severity criteria (OR = 0.39, 95% IC: 0.17-0.91, p = 0.045). The 5-HTTLPR gene variant of the SLC6A4 gene modifies the risk of PE development among the studied population.

Effects of serotonin transporter and receptor polymorphisms on depression.

INTRODUCTION: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. OBJECTIVE: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. METHODS: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). CONCLUSIONS: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.

Efectos de los Polimorfismos del Transportador y de los Receptores de Serotonina en la Depresión

Introducción: La serotonina tiene gran implicación en la regulación del estado emocional y la ejecución de tareas cognitivas, de modo que los genes del transportador de serotonina (5-HTT, SLC6A4) y de los receptores de serotonina (HTR1A, HTR1B, HTR2A) se convierten en candidatos adecuados para estudiar los efectos de estos genes y sus variaciones polimórficas en las características de la depresión. Objetivo: Revisión de reportes de investigación que hayan estudiado los efectos de las variantes de los genes del transportador y de los receptores de serotonina en las diferentes características clínicas de la depresión. Métodos: Se realizó una búsqueda en las bases de datos Scopus, Web of Science y PubMed con las palabras clave "depression", AND "polymorphism". Conclusiones: Según la revisión de 54 artículos, se encontró que el alelo corto del polimorfismo de 5-HTTLPR es el factor de riesgo más reportado en relación con el desarrollo de depresión y su gravedad. Las variantes de los genes estudiados (SLC6A4, HTR1A, HTR1B y HTR2A) pueden generar alteraciones morfológicas de estructuras cerebrales.

Introduction: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. Objective: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. Methods: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). Conclusions: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.

Attachment styles predict personality traits according to a pilot study of patients with anxiety and mood disorders / Los estilos de apego predicen los rasgos de la personalidad según un estudio piloto de pacientes con trastornos de ansiedad y del ánimo

Abstract Introduction The mother and child attachment could have an important and long-lasting impact. An insecure attachment could lead to emotional development difficulties. It has been suggested that maternal care in infants is associated with personality. However, more studies in adults are needed. Objective To determine if attachment styles in subjects with affective or anxiety disorders are associated with the expression of personality traits, and if this effect can be modulated by the presence of the short allele of the 5-HTTLPR polymorphism. Method Our sample included 87 patients with mood or anxiety disorders. The NEO-PI-R questionnaire and the Adult Attachment questionnaire by Melero were used. Results Insecure attachment styles were associated with a higher expression of neuroticism, and a lower expression of extraversion, conscientiousness, and agreeableness, especially in individuals with the most insecure attachment. An interaction was identified between the attachment style and the 5-HTTLPR genotype on the expression of agreeableness. Higher neuroticism, and lower extraversion and conscientiousness tended to be present in carriers of the S allele. Discussion and conclusion There was a significant association between the attachment styles and the expression of neuroticism, extraversion, agreeableness, and conscientiousness-responsibility according to the Big Five Model. The short allele may be associated with the modulation of certain aspects of personality. Prevention strategies should be established to promote adequate attachments between infants and caregivers to avoid a possible risk factor for future maladaptive personality traits.

Resumen Introducción El apego entre la madre y el hijo puede tener un impacto importante. Un apego inseguro podría afectar el desarrollo emocional. Se ha sugerido que los cuidados de la madre en la infancia temprana se asocian a la personalidad. Sin embargo, se requieren más estudios en adultos. Objetivo Determinar si los estilos de apego en personas con trastornos del afecto o ansiedad se asocian a la expresión de rasgos de personalidad y si esta expresión es modulada por la presencia del alelo corto del polimorfismo 5-HTTLPR. Método Se incluyeron 87 pacientes. Se emplearon los cuestionarios NEO-PI-R y el de Apego en el Adulto de Melero. Resultados Los estilos de apego inseguro se asociaron con una expresión mayor de neuroticismo y menor de extroversión, conciencia y amabilidad, especialmente en los individuos con el estilo de apego más inseguro. Se identificó una interacción entre el estilo de apego y el genotipo del 5-HTTLPR en la expresión de amabilidad. En los portadores del alelo corto hubo una tendencia hacia mayores valores de neuroticismo y menores niveles de extroversión y conciencia. Discusión y conclusión Los estilos de apego se asocian con la expresión de neuroticismo, extroversión, amabilidad y conciencia/responsabilidad. El alelo corto del 5-HTTLPR podría asociarse con la modulación de algunos aspectos de la personalidad. Los resultados sugieren la importancia de promover un apego adecuado entre los niños y sus cuidadores primarios para evitar posibles riesgos que se asocien con rasgos desadaptativos de la personalidad.

Effects of Serotonin Transporter and Receptor Polymorphisms on Depression. / Efectos de los Polimorfismos del Transportador y de los Receptores de Serotonina en la Depresión.

INTRODUCTION: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. OBJECTIVE: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. METHODS: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). CONCLUSIONS: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.

5HTTLPR Genetic Variant and Major Depressive Disorder: A Review.

Major Depressive Disorder (MDD) is a disease that involves biological, psychological, and social interactions. Studies have shown the importance of genetics contribution to MDD development. The SCL6A4 protein (5HTTLPR) functions transporting serotonin, a neurotransmitter linked to mood and emotion, to the synaptic cleft. Hence, this study seeks, through a literature review, a better comprehension of the 5HTTLPR genetic variant association with MDD. For this purpose, a search was performed on the Virtual Health Library Portal for articles that related 5HTTLPR to MDD. Most of the articles found were conducted in the American continent, with one (1) study implemented in Brazil. 5HTTLPR associations were found regarding changes in the nervous system, pharmacology, and risk factors seen in MDD patients. When verifying the allelic distribution, the S allele had a higher frequency in most of the studies analyzed. Despite not finding a commonality in the different studies, the tremendous genetic variation found demonstrates the MDD complexity. For this reason, further studies in diverse populations should be conducted to assist in the understanding and treatment of the disease.

Association between resilience and a functional polymorphism in the serotonin transporter (SLC6A4) gene: A meta-analysis.

Resilience is a mechanism used by humans to adapt to adverse situations. It is a protective factor against mental health problems. This process can be influenced by environmental and genetic factors. Several genes have been associated with interindividual differences in resilience levels, but the results are inconclusive. Therefore, the aim of this meta-analysis was to evaluate the effect of a functional polymorphism (5-HTTLPR) in the SLC6A4 gene on resilience levels. A search in PubMed, HugeNavigator and Google Scholar databases was carried out and 16 studies about the association of 5-HTTLPR polymorphism and resilience in humans were identified. The OpenMeta[Analyst] program was employed to perform statistical analysis using a random-effects model. The final analysis included 9 studies, for a total of 4,080 subjects. Significant results were found when the standardized mean differences (SMD) of LL and SL carriers were compared, (SMD: -0.087 (confidence interval: -0.166 to -0.008; I 2 : 0 %); P value: 0.031). A significant result was also found in an analysis comparing SS/SL versus LL genotypes (SMD: -0.231; confidence interval: -0.400 to -0.061, P value: 0.008; I 2 : 0 %). This is the first meta-analysis performed to identify the pooled association of a functional polymorphism in the serotonin transporter gene and resilience. The current results suggest that the L/L genotype is associated with resilience. Further studies are necessary to elucidate the role of genetics on the resilience mechanisms.

SERT and BDNF polymorphisms interplay on neuroticism in borderline personality disorder.

OBJECTIVE: Genetic factors underlying different personality traits are not entirely understood, particularly how genes interact to modulate their effect. We studied 76 patients diagnosed with borderline personality disorder (BPD), characterized by extreme levels of personality traits, especially neuroticism (N), in which we genotyped two polymorphisms, the 5HTTLPR of the Serotonin transporter (SERT) gene, and the Val66Met of the Brain-derived neurotrophic factor (BDNF) gene. RESULTS: We found an association with SERT, where S-allele carriers had significantly higher levels of N than L-homozygous. Furthermore, we found that the protective effect of L-homozygosity is only evident on A-allele carriers of the BDNF Val66Met polymorphism. Genetic constitution in SERT and BDNF seems to be important in neuroticism, the most relevant personality trait on BPD.

Biallelic and triallelic approaches of 5-HTTLPR polymorphism are associated with food intake and nutritional status in childhood.

BACKGROUND: The 5-HTT gene contains polymorphisms in its promoter region, the insertion/deletion (5-HTTLPR) that creates long (L) or short (S) alleles (biallelic approach) and SNP (rs25531) in L allele (triallelic approach). OBJECTIVES: The aim of this study is to investigate the association of the 5-HTTLPR and rs25531 polymorphisms, using bi- and triallelic approach, with dietary intake and anthropometric parameters in children followed until 8 years old. METHODS: The sample were 303 children who were recruited at birth and examined at 1, 3 to 4 and 7 to 8 years old. The polymorphisms were analyzed by polymerase-chain-reaction-based methods. RESULTS: In the biallelic approach, children with the S/S genotype presented a higher body mass index Z-score in the three developmental stages and higher sum of skinfolds at 3 to 4 and 7 to 8 years old than carriers of the L allele. In the triallelic approach, S/S, Lg/S plus Lg/Lg genotypes were associated with higher energy intake daily at 1 year old and with waist circumference at 3 to 4 years old. CONCLUSIONS: In the biallelic approach, the 5-HTTLPR polymorphism is associated with food intake, body mass index Z-score and sum of skinfolds in children, reinforcing the role of the serotonin transporter in childhood obesity. Our data indicate that the biallelic approach is more sensible than the triallelic approach for detected associations with food intake and nutritional status in childhood. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent children to become obese adults.

El papel del gen del transportador de serotonina en los trastornos de la conducta alimentaria / Role of Serotonin Transporter Gene in Eating Disorders

Introducción: Al sistema serotoninérgico se lo ha implicado en la regulación del estado de ánimo y en la conducta alimentaria, por lo que el gen del transportador de serotonina (SLC6A4) es un buen candidato para el desarrollo de los trastornos de la conducta alimentaria (TCA). La mayoría de los estudios genéticos en los TCA se han centrado principalmente en un polimorfismo, el denominado 5-HTTLPR del gen SLC6A4. Objetivo: Realizar una revisión de los estudios de asociación entre el 5-HTTLPR y los TCA, como anorexia nerviosa, bulimia nerviosa y trastornos alimentarios no especificados. Método: Se realizó una búsqueda en MEDLINE, ISI y PubMed de las palabras clave «transportador de serotonina¼ y «TCA¼. Conclusiones: Según la revisión de 37 artículos originales, la variante S del 5-HTTLPR es un factor de riesgo de anorexia nerviosa. Además, se encontró asociación entre el alelo S y el índice de masa corporal, impulsividad, ansiedad, depresión y el tiempo de evolución en TCA. Sin embargo, en bulimia nerviosa no se reporta asociación con las variantes del 5-HTTLPR.

Background: The serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. Objective: We present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). Method: Search of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. Conclusions: From a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients.

The association between 5-HTTLPR gene polymorphism and behavioral inhibition in Chinese toddlers.

As one of the fundamental individual characteristics, behavioral inhibition in early childhood has considerable implications for the development of social, cognitive, and psychological adjustment. The purpose of this study was to examine the relation between the 5-HTTLPR polymorphism and behavioral inhibition in Chinese children using a cross-sectional design. A sample of 263 2-year-old children (134 boys and 129 girls of Han ethnicity; ages ranging from 24 to 26 months) in China participated in the study. Behavioral inhibition was assessed through laboratory observations, and genomic DNA was collected with buccal swabs. The results of analysis of covariance (ANCOVA) indicated that the homozygous short 5-HTTLPR allele was associated with lower levels of behavioral inhibition, which was different from most of the findings based on individuals in Western countries. The results suggest that social and cultural factors may be involved in shaping links between the 5-HTTLPR polymorphism and children's specific behaviors.

[Role of Serotonin Transporter Gene in Eating Disorders]. / El papel del gen del transportador de serotonina en los trastornos de la conducta alimentaria.

BACKGROUND: The serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. OBJECTIVE: We present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). METHOD: Search of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. CONCLUSIONS: From a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients.

Prediction of the time-course pattern of remission in depression by using clinical, neuropsychological, and genetic variables.

BACKGROUND: The prediction of remission in pharmacologically-treated MDD patients has been scarcely studied. The goal of our work is to study the possible effect of clinical variables, neuropsychological performance, and the 5HTTLPR, the rs25531 of the SLC6A4 gene, and the val108/58Met of the COMT gene polymorphisms on the prediction of the speed of remission in MDD patients. METHODS: Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluoxetine treatment. RESULTS: From this original sample 51 patients were considered as remitters at the end of week 12. Thirteen out of those showed a rapid response pattern, 24 showed an oscillating response pattern, and 14 showed a slow response pattern. The following variable combination is capable of showing a statistically significant relationship with the pattern of remission of patients with MDD: initial Hamilton score, age at first depressive episode, AG and GG alleles of the val108/58Met COMT polymorphism, Stroop PC, and SWM Strategy. LIMITATIONS: We have a slightly small sample size, which came to prominence during the data analysis since we were working with 3 subgroups. In this study, the placebo effect has not been controlled. DISCUSSION: Our data suggest that the patients with MDD who remit after a 12-week treatment with fluoxetine show one of the following time-course patterns: a rapid symptomatic improvement, or a slow or oscillating pattern of remission. A combination of clinical, neuropsychological, and genetic variables allows us to predict these response patterns.

Ascending monoaminergic systems alterations in Alzheimer's disease. translating basic science into clinical care.

Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD.

Association of a serotonin transporter gene (SLC6A4) 5-HTTLPR polymorphism with body mass index categories but not type 2 diabetes mellitus in Mexicans.

The serotonergic system has been hypothesized to contribute to the biological susceptibility to type 2 diabetes mellitus (T2DM) and body-mass index (BMI) categories. We investigate a possible association of 5-HTTLPR polymorphism (L and S alleles) in the promoter region of the serotonin transporter gene (SLC6A4) with the development of T2DM and/or higher BMI by analyzing a sample of 138 individuals diagnosed with T2DM and 172 unrelated controls from the Mexican general population. In the total sample genotypes were distributed according to Hardy-Weinberg equilibrium, and S allele frequency was 0.58. There was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in this Mexican population sample (p = 0.12). Nevertheless, logistic regression analysis of the L allele and increased BMI disclosed an association, after adjusting for age, sex and T2DM (p = 0.02, OR 1.74, 95% CI: 1.079-2.808).

Serotonin transporter gene polymorphisms: a case-control study

Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter, are involved in alcoholism and tobacco use and are influenced by polymorphism of the promoter region of 5HTT (5-HTTLPR). As alcohol and tobacco consumption have been implicated in the pathogenesis of oral cancer, the purpose of this study was to investigate 5-HTTLPR polymorphism in patients with oral squamous cell carcinoma (OSCC) compared with a control group in a sample of Brazilian patients. One hundred and three patients affected by OSCC and 103 volunteers without OSCC were genotyped for 5-HTTLPR. Both groups were matched for age, sex and tobacco use. The chi-squared test was used for statistical analysis (α=0.05). There was no statistically significant difference in 5-HTTLPR genotypes between case and control group (p= 0.408). In conclusion, the present investigation demonstrated that serotonin transporter polymorphisms are not implicated in the OSSC development.

Consideráveis evidências indicam que mecanismos serotoninérgicos, particularmente o transportador de serotonina, estão envolvidos no alcoolismo e no uso de fumo e são influenciados pelo polimorfismo da região promotora do 5HTT (5-HTTLPR). Como o consumo de álcool e fumo está implicado na patogênese do câncer, o objetivo deste estudo foi investigar o polimorfismo 5-HTTLPR em pacientes com carcinoma bucal de células escamosas (CBCE) comparado com um grupo controle em uma amostra de pacientes brasileiros. Cento e três pacientes afetados por CBCE e 103 voluntários sem história de CBCE foram genotipados para 5-HTTLPR. Ambos os grupos foram pareados pela idade, gênero e uso de fumo. O teste do qui-quadrado foi usado para análise estatística. Não houve diferença estatística entre os genótipos dos grupos caso e controle (p= 0,408). Concluindo, a presente investigação demonstrou que os polimorfismos do transportador de serotonina não estão implicados no desenvolvimento do CBCE.