Made available in DSpace on 2016-03-15T19:40:37Z (GMT). No. of bitstreams: 1 Aline Helen Correa Garcia.pdf: 980441 bytes, checksum: 43fff507ceb0e88ebcf821770349257e (MD5) Previous issue date: 2008-11-06 / Fundo Mackenzie de Pesquisa / Pervasive Developmental Disorders are characterized by deficiency in three areas: communication, social interaction, repetitive and stereotypical behavior from causes not yet fully known. Evidences have suggested that autism possesses a significant genetic component from a complex multifaceted heredity with a multiloci model of interaction. Several experimental techniques and models have been utilized in order to assess the activity, expression and the alelo association of theTIDs as illnesses with a genetic component. The role of the 5HTT serotonin renders the genes of the serotonin-energetic system of interest for the study of the pathology of autism. Our work obtained and analyzed the DNA from periferic blood samples of 50 subjects diagnosed with PDD for the polymorphism T102C of the 2ª receptor of serotonin (HTR2A) comparing the results to a control population of 206 individuals, separated by both sex and racial background. The cases were analyzed through the ASQ and ABC instruments according to a greater susceptibility to repetitive and stereotyped behaviors. RESULTS: There was no significant statistical evidence for the distribution of the genotypes either in the cases (qui-quadrado=2,967/2GL/p= 0,2268) or in the control. However, it was observed a large prevalence of the heterozygote genotype among the cases (64%) while in the control this genotype was present in 50% of the individuals. Also the genotypical occurrences did not demonstrate any difference when the subjects, cases and control, were divided by sex and racial background as white and non-white. Regarding the number of stereotypes, in the ASQ as well as in the ABC, there was no difference in the genotype distribution. The sample was in accordance to the Hardy-Weiberg equilibrium. / Os Transtornos Invasivos do Desenvolvimento têm como características deficiência em três domínios: comunicação, interação social e comportamentos repetitivos e estereotipados de causas ainda não bem conhecidas. Evidências têm sugerido que o autismo tem um grande componente genético de herança multifatorial complexa com modelo de interação multiloci. Várias técnicas experimentais e modelos para avaliar a atividade, expressão e alelo associação dos TIDs, enquanto doenças com algum componente genético, têm sido usados. As funções da serotonina 5HTT, tornam os genes do sistema serotoninérgico como de interesse para estudo da patologia do autismo. O nosso trabalho extraiu e analisou o DNA do sangue periférico de 50 portadores de transtornos invasivos do desenvolvimento para o polimorfismo T102C do receptor 2A da serotonina (HTR2A) comparando os resultados com uma população controle de 206 indivíduos, ambos separados por sexo e antecedentes raciais. Os casos foram analisados pelos instrumentos ASQ e ABC quanto a maior susceptibilidade para comportamentos repetitivos e estereotipados. Resultados: Não houve evidência estatística significativa para a distribuição dos genótipos, tanto nos casos (qui-quadrado=2,967; 2GL; p=0,2268) como nos controles. Contudo foi observada a grande predominância do genótipo heterozigoto entre os casos (64%) enquanto que nos controles este genótipo foi evidenciado em 50% dos indivíduos. Não houve evidência estatística significativa para a distribuição dos genótipos, tanto nos casos (qui-quadrado=2,967; 2GL; p=0,2268) como nos controles. As freqüências genotípicas também não mostraram diferença quando os sujeitos caso e controle foram estratificados por sexo e antecedentes raciais branco e não branco. Quanto ao número de estereotipias, tanto no ASQ quanto no ABC, não houve diferença na distribuição do genótipo. A amostra estava em equilíbrio de Hardy-Weiberg.

Doenças e comportamentos de risco relacionados ao polimorfismo T102C do gene 5- HT2A, como esquizofrenia, suicídio, impulsividade, alcoolismo, tabagismo, entre outros, podem encurtar o tempo de vida médio. Uma amostra de 687 indivíduos residentes na região metropolitana da Grande Porto Alegre foi genotipada e categorizada de acordo com suas respectivas idades e gêneros. Foram observadas diferenças significativas entre a distribuição dos genótipos do polimorfismo T102C do gene 5-HT2A e idade média da amostra (p=0,026) e também entre os genótipos e grupos etários (p=0,012). Estes resultados sugerem que o polimorfismo T102C do gene 5-HT2A possa desempenhar algum papel no tempo de vida médio dos seres humanos. / Diseases and risk behaviors related to the T102C polymorphism of the 5-HT2A gene such as schizophrenia, suicide, impulsivity, alcoholism, smoking addiction, among others, may potentially shorten mean life span. A sample of 687 individuals residents in Porto Alegre metropolitan region was genotyped and categorized according to their respective age and gender. Significant differences were found between the distribution of genotypes of T102C polymorphism of gene 5-HT2A and the mean age of the sample (p=0.026) as well as distribution of genotypes and age groups (p=0.012). The present results suggest that T102C polymorphism of gene 5-HT2A may play a role in mean life span of human beings.

Doenças e comportamentos de risco relacionados ao polimorfismo T102C do gene 5- HT2A, como esquizofrenia, suicídio, impulsividade, alcoolismo, tabagismo, entre outros, podem encurtar o tempo de vida médio. Uma amostra de 687 indivíduos residentes na região metropolitana da Grande Porto Alegre foi genotipada e categorizada de acordo com suas respectivas idades e gêneros. Foram observadas diferenças significativas entre a distribuição dos genótipos do polimorfismo T102C do gene 5-HT2A e idade média da amostra (p=0,026) e também entre os genótipos e grupos etários (p=0,012). Estes resultados sugerem que o polimorfismo T102C do gene 5-HT2A possa desempenhar algum papel no tempo de vida médio dos seres humanos. / Diseases and risk behaviors related to the T102C polymorphism of the 5-HT2A gene such as schizophrenia, suicide, impulsivity, alcoholism, smoking addiction, among others, may potentially shorten mean life span. A sample of 687 individuals residents in Porto Alegre metropolitan region was genotyped and categorized according to their respective age and gender. Significant differences were found between the distribution of genotypes of T102C polymorphism of gene 5-HT2A and the mean age of the sample (p=0.026) as well as distribution of genotypes and age groups (p=0.012). The present results suggest that T102C polymorphism of gene 5-HT2A may play a role in mean life span of human beings.

Doenças e comportamentos de risco relacionados ao polimorfismo T102C do gene 5- HT2A, como esquizofrenia, suicídio, impulsividade, alcoolismo, tabagismo, entre outros, podem encurtar o tempo de vida médio. Uma amostra de 687 indivíduos residentes na região metropolitana da Grande Porto Alegre foi genotipada e categorizada de acordo com suas respectivas idades e gêneros. Foram observadas diferenças significativas entre a distribuição dos genótipos do polimorfismo T102C do gene 5-HT2A e idade média da amostra (p=0,026) e também entre os genótipos e grupos etários (p=0,012). Estes resultados sugerem que o polimorfismo T102C do gene 5-HT2A possa desempenhar algum papel no tempo de vida médio dos seres humanos. / Diseases and risk behaviors related to the T102C polymorphism of the 5-HT2A gene such as schizophrenia, suicide, impulsivity, alcoholism, smoking addiction, among others, may potentially shorten mean life span. A sample of 687 individuals residents in Porto Alegre metropolitan region was genotyped and categorized according to their respective age and gender. Significant differences were found between the distribution of genotypes of T102C polymorphism of gene 5-HT2A and the mean age of the sample (p=0.026) as well as distribution of genotypes and age groups (p=0.012). The present results suggest that T102C polymorphism of gene 5-HT2A may play a role in mean life span of human beings.

Features of impulsivity underlie multiple psychological disorders. The body of work examining impulsivity has largely focussed on self-report measurement and has incorporated psychological constructs without reference to the broader biological factors that may influence impulsive behaviour. Two studies were conducted to examine whether environmental stress and genetic status associated with dopaminergic and serotonergic function (DRD2, ANKK1 and 5HT2AR genotypes) were predictive of dimensions of impulsivity and risky behaviour (alcohol use). The two studies used a multi-method approach in a non-clinical community sample of young adults (aged 17-25 years). Dopamine is integral to the two leading theories of impulsive personality, Gray's Reinforcement Sensitivity Theory and Cloninger's Psychobiological model of personality. Dopamine plays a crucial role in reward reinforcement circuits in the brain. The A1 allele of the ANKK1 gene (also referred to as TaqIA of the DRD2 gene region) and the CC genotype of the C957T polymorphism of the DRD2 gene have both been associated with reduced D2 dopamine receptor density in key structures linked to brain reward. In addition, a strong body of evidence implicates their involvement in a number of clinical disorders associated with impulsivity. Serotonin function has also been associated with impulsivity in Cloninger's theory and there is also evidence of associations of two polymorphisms of the 2A serotonin receptor gene (5HT2AR T102C and -1438A/G SNPs) with impulsivity. Acute and chronic forms of stress are also important correlates of impulsive behaviour and the two studies directly examined the relationship between genotype, stress and impulsivity. Study 1 (N=180) utilised a cross-sectional design and examined interactions between these polymorphisms and chronic stress exposure on key impulsivity dimensions of reward sensitivity, Novelty Seeking and rash impulsiveness. Participants completed psychological questionnaires measuring chronic stress, dimensions of impulsivity, mood and substance use and provided mouth swab samples of buccal mucosal cells for DNA analysis. The study confirmed the association between A1 and CC allelic status and chronic stress being associated with harm avoidance and sensitivity to punishment. This suggests a role for both dopamine and background stress in impulsive behaviour. Study 2 (N=73) built upon this questionnaire research in the laboratory by utilising experimental psychological paradigms of impulsive behaviour and experimentally manipulating acute stress. Study 2 employed a mixed experimental design with a sub-sample of those studied in the cross-sectional sample. These behavioural paradigms included pre- and post- stress induction administration of the Card Arranging Reward Responsiveness Objective Test (capturing behavioural approach in the presence of reward cues, presumed to reflect reward sensitivity) and post-induction delay discounting and response inhibition measures. Study 2 confirmed the role of one of the two dopamine-related polymorphisms, with those with A1+ allelic status demonstrating lower reward responsiveness prior to rest or stress induction, which was overcome in the second administration of this task, independent of environment. A1+ allelic individuals also demonstrated significantly poorer response inhibition independent of stress, further confirming the association between A1+ allelic status and impulsivity. Those with CC allelic status showed an increase in reward responsiveness only in the stress induction condition. Together, results from the two studies inform the development of a multidimensional model of impulsivity that captures gene-environment influences on discrete aspects of impulsive personality and behaviour. Further refinement of this model may lead to the development of more effective customised prevention and treatment interventions for clinically disordered impulsivity. The implications of dopaminergic systems and stress in understanding disorders such as ADHD and substance dependence are discussed.