RESUMEN
Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
Asunto(s)
Trastornos de Ansiedad/genética , Proteínas Portadoras/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Trastornos Neuróticos/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Serotonina/metabolismo , Adolescente , Adulto , Alelos , Línea Celular , Femenino , Marcadores Genéticos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Núcleo Familiar , Pruebas de Personalidad , Fenotipo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , TransfecciónRESUMEN
Dopaminergic genes are likely candidates for heritable influences on cigarette smoking. In an accompanying article, Lerman et al. (1999) report associations between allele 9 of a dopamine transporter gene polymorphism (SLC6A3-9) and lack of smoking, late initiation of smoking, and length of quitting attempts. The present investigation extended their study by examining both smoking behavior and personality traits in a diverse population of nonsmokers, current smokers, and former smokers (N = 1,107). A significant association between SLC6A3-9 and smoking status was confirmed and was due to an effect on cessation rather than initiation. The SLC6A3-9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. It is hypothesized that individuals carrying the SLC6A3-9 polymorphism have altered dopamine transmission, which reduces their need for novelty and reward by external stimuli, including cigarettes.
Asunto(s)
Conducta Adictiva/genética , Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad/genética , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Fumar/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Conducta Exploratoria , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite/genética , Polimorfismo Genético , Receptores de Dopamina D2/genética , Fumar/psicología , Estadística como AsuntoRESUMEN
The biosocial model postulates that personality is comprised of two broad domains: temperament, which is largely due to inherited variations in specific monoamine neurotransmitter systems; and character, which arises from socioculturally learned differences in values, goals, and self-concepts and is the strongest predictor of personality disorders. The model also proposes that serotonin modulates the temperament trait of harm avoidance. We analyzed the association of temperament and character traits with the 5-HTTLPR, an inherited variation that modulates serotonin transporter gene expression, in 634 volunteer subjects. Contrary to theory, the 5-HTTLPR was most strongly associated with the character traits of cooperativeness and self-directedness. Associations with the temperament traits of reward dependence and harm avoidance were weaker and could be attributable largely to cross-correlations with the character traits and demographic variables. Psychometric analysis indicated that the serotonin transporter influences two broad areas of personality, negative affect and social disaffiliation, that are consistent across inventories but are more concisely described by the 5-factor model of personality than by the biosocial model. These results suggest that there is no fundamental mechanistic distinction between character and temperament in regard to the serotonin transporter gene, and that a single neurotransmitter can influence multiple personality traits.
Asunto(s)
Proteínas Portadoras/genética , Carácter , Genética Conductual , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Serotonina/genética , Temperamento , Adulto , Anciano , Análisis de Varianza , Femenino , Genotipo , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Modelos Psicológicos , Núcleo Familiar/psicología , Personalidad/genética , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
We describe a new polymorphism upstream of the gene for monoamine oxidase A (MAOA), an important enzyme in human physiology and behavior. The polymorphism, which is located 1.2 kb upstream of the MAOA coding sequences, consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism is in linkage disequilibrium with other MAOA and MAOB gene markers and displays significant variations in allele frequencies across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving three different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2-10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. This promoter region polymorphism may be useful as both a functional and an anonymous genetic marker for MAOA.
Asunto(s)
Monoaminooxidasa/genética , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Adulto , Alelos , Femenino , Ligamiento Genético/genética , Marcadores Genéticos/genética , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite/genéticaRESUMEN
Exochelin is the primary extracellular siderophore of Mycobacterium smegmatis, and the iron-regulated fxbA gene encodes a putative formyltransferase, an essential enzyme in the exochelin biosynthetic pathway (E. H. Fiss, Y. Yu, and W. R. Jacobs, Jr., Mol. Microbiol. 14:557-569, 1994). We investigated the regulation of fxbA by the mycobacterial IdeR, a homolog of the Corynebacterium diphtheriae iron regulator DtxR (M. P. Schmitt, M. Predich, L. Doukhan, I. Smith, and R. K. Holmes, Infect. Immun. 63:4284-4289, 1995). Gel mobility shift experiments showed that IdeR binds to the fxbA regulatory region in the presence of divalent metals. DNase I footprinting assays indicated that IdeR binding protects a 28-bp region containing a palindromic sequence of the fxbA promoter that was identified in primer extension assays. fxbA regulation was measured in M. smegmatis wild-type and ideR mutant strains containing fxbA promoter-lacZ fusions. These experiments confirmed that fxbA expression is negatively regulated by iron and showed that inactivation of ideR results in iron-independent expression of fxbA. However, the levels of its expression in the ideR mutant were approximately 50% lower than those in the wild-type strain under iron limitation, indicating an undefined positive role of IdeR in the regulation of fxbA.
Asunto(s)
Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Hierro/farmacología , Mycobacterium/genética , Proteínas Represoras , Transcripción Genética/genética , Proteínas Bacterianas/genética , Secuencia de Bases , Sitios de Unión , Cationes Bivalentes/farmacología , Huella de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Genes Bacterianos/genética , Genes Reporteros , Transferasas de Hidroximetilo y Formilo/genética , Mutación , Mycobacterium/efectos de los fármacos , Mycobacterium/enzimología , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , ARN Mensajero/análisis , ARN Mensajero/genética , Elementos de Respuesta/genética , Homología de Secuencia de Aminoácido , Transcripción Genética/efectos de los fármacos , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism-a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability-increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs.