Síndrome de Down e polimorfismos em genes envolvidos no metabolismo do folato

• Ano de defesa: 2011
• Autor(a) principal: Marucci, Gustavo Henrique
• Orientador(a): Pavarino-bertelli, érika Cristina
• Banca de defesa: Machado, Ricardo Luiz Dantas , Cintra, Mariangela Torreglosa Ruiz , Santos, Izaura dos
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Faculdade de Medicina de São José do Rio Preto
• Programa de Pós-Graduação: Programa de Pós-Graduação em Ciências da Saúde::123123::600
• Departamento: Medicina Interna; Medicina e Ciências Correlatas::123123::600
• País: BR
• Palavras-chave em Português: Síndrome de Down; Trissomia do 21; Polimorfismo genético; Homocisteína; Ciências da Saúde
• Palavras-chave em Inglês: Down Syndrome; Trisomy of 21; genetic polymorphism; homocystein; folate; Health Sciences; Polymorphism, Genetic; Homocysteine
• Palavras-chave em Espanhol: Ciencias de la Salud
• Área do conhecimento CNPq: CNPQ::CIENCIAS DA SAUDE::123123::600
• Link de acesso: http://bdtd.famerp.br/handle/tede/108

Down syndrome (DS) is a complex genetic disease resulting mainly from the presence of three copies of chromosome 21. It is the most frequent human chromosomal abnormality and, in most cases (about 95%) results from maternal chromosome nondisjunction, which occurs during meiosis I. Recent studies suggest that the etiology of maternal risk for DS in young mothers is associated with polymorphisms in genes of folate/homocysteine metabolism. The proper function of folate metabolism is essential for the synthesis of methyl groups necessary for DNA methylation. The deficiency of this metabolite has resulted in DNA hypomethylation, chromosomal breakage and aneuploidies. Objectives: Evaluate the influence of the C1420T polymorphism in serine hidroximetiltransferase (SHMT) gene on the maternal risk for DS, and investigate the association between this polymorphism and variation in the concentration of serum folate, plasma Hcy and methylmalonic acid (MMA); investigate the impact of 19 base pairs (pb) deletion polymorphism of the dihydrofolate reductase (DHFR) gene and the C1420T polymorphism of the SHMT gene on serum folate concentrations, plasma Hcy and MMA in individuals with DS. Material and methods: 105 mothers of individuals with free trisomy of chromosome 21 and 185 mothers of individuals without the syndrome (no history of miscarriage), and 85 individuals with free trisomy of 21 chromosome were included in this study. The polymorphism of DHFR gene was evaluated by Polymerase Chain Reaction (PCR) by fragment size difference, and the polymorphism of SHMT gene was analyzed by real-time PCR allelic discrimination. Results: The SHMT CC and CT genotypes were associated with decreased maternal risk for DS (CC: P= 0.0002; 95% CI: 0.20 0.60; OR: 0.35. CT: P < 0.0001; 95% IC: 0.11 - 0.39; OR: 0.21). The different genotypes did not influence the concentrations of metabolites studied. In individuals with DS, the combined genotypes DHFR II/ SHMT TT and DHFR DD/ SHMT TT were associated, respectively, with increased concentrations of Hcy (P<0.001) and folate (P<0.001). Moreover, individuals with DHFR II/ SHMT CT genotypes presented a reduction of folate concentration (P= 0.01). Conclusion: The CC and CT genotypes of SHMT C1020T polymorphism has a protector effect for maternal risk for DS. This polymorphism does not seem to influence the folate, Hcy and MMA concentrations. The del 19pb DHFR and SHMT C1420T polymorphisms present a synergic effect in modulating folate and Hcy concentrations in individuals with DS.