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Machado Renatoassis M.Pdf RENATO ASSIS MACHADO “ASSOCIAÇÃO DOS POLIMORFISMOS NOS GENES HOXD1, TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3 E TIMP3 COM FISSURAS DE LÁBIO E/OU PALATO NÃO-SINDRÔMICA EM UMA POPULAÇÃO BRASILEIRA” PIRACICABA 2015 i ii UNIVERSIDADE ESTADUAL DE CAMPINAS FACULDADE DE ODONTOLOGIA DE PIRACICABA RENATO ASSIS MACHADO “ASSOCIAÇÃO DOS POLIMORFISMOS NOS GENES HOXD1, TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3 E TIMP3 COM FISSURAS DE LÁBIO E/OU PALATO NÃO-SINDRÔMICA EM UMA POPULAÇÃO BRASILEIRA” Dissertação apresentada à Faculdade de Odontologia de Piracicaba da Universidade Estadual de Campinas para a obtenção do título de Mestre em Estomatopatologia, na Área de Patologia. Orientador: Prof. Dr. Ricardo Della Coletta Coorientador: Prof. Dr. Hercilio Martelli Junior Este exemplar corresponde a versão final da dissertação defendida por Renato Assis Machado e orientada pelo Prof. Dr. Ricardo Della Coletta. ____________________________________ Assinatura do orientador PIRACICABA 2015 iii Ficha catalográfica Universidade Estadual de Campinas Biblioteca da Faculdade de Odontologia de Piracicaba Marilene Girello - CRB 8/6159 Machado, Renato Assis, 1989- M18a MacAssociação dos polimorfismos nos genes HOXD1, TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3 e TIMP3 com fissuras de lábio e/ou palato não- sindrômica em uma população brasileira / Renato Assis Machado. – Piracicaba, SP : [s.n.], 2015. MacOrientador: Ricardo Della Coletta. MacCoorientador: Hercilio Martelli Junior. MacDissertação (mestrado) – Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba. Mac1. Fenda labial. 2. Polimorfismo genético. I. Della Coletta, Ricardo,1972-. II. Martelli Junior, Hercilio. III. Universidade Estadual de Campinas. Faculdade de Odontologia de Piracicaba. IV. Título. Informações para Biblioteca Digital Título em outro idioma: Association of polymorphisms in genes HOXD1, TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3 and TIMP3 with nonsyndromic cleft lip and/or palate in a Brazilian population Palavras-chave em inglês: Cleft lip Polymorphism, genetic Área de concentração: Patologia Titulação: Mestre em Estomatopatologia Banca examinadora: Ricardo Della Coletta [Orientador] Mário Sérgio Oliveira Swerts Edgard Graner Data de defesa: 26-02-2015 Programa de Pós-Graduação: Estomatopatologia iv Powered by TCPDF (www.tcpdf.org) v vi RESUMO O desenvolvimento craniofacial envolve uma série de eventos altamente coordenados e variações polimórficas nos genes que controlam estes eventos podem afetar a morfogênese labial e palatina, resultando nas fissuras do lábio e/ou palato não-sindrômicas (FL/PNS). O objetivo do presente estudo foi verificar a associação dos polimorfismos em genes relacionados ao desenvolvimento craniofacial, HOXD1 (rs1374326), TNP1 (rs748044), MSX1 (rs1106514), TCOF1 (rs28372960, rs15251, rs2569062), FGFR1 (rs7829058), COL2A1 (rs1793949), WNT3 (rs11653738) e TIMP3 (rs242082), na susceptibilidade das FL/PNS em uma população brasileira. Para verificar a associação destes polimorfismos, este estudo associou o teste de desequilíbrio de transmissão (TDT) com a análise caso-controle com correção de variações genéticas de ancestralidade em uma amostra composta de 189 trios com fissura labial com ou sem fissura palatina não-sindrômica (FL±PNS), 107 trios com fissura palatina não-sindrômica (FPNS), 318 amostras isoladas de pacientes com FL±PNS, 189 amostras isoladas de pacientes com FPNS e 599 controles. Todos os polimorfismos foram inicialmente analisados por TDT e as associações significantes foram confirmadas na análise caso-controle. Os polimorfismos rs28372960 e rs7829058 foram transmitidos de maneira significante dos genitores para os pacientes com FL±PNS (p=0,04), assim como os polimorfismos rs1374326 e rs11653738 nos trios com FPNS (p=0,04). Contudo, o estudo caso-controle não confirmou tais associações. O haplótipo T-C-C formado pelos polimorfismos rs28372960, rs15251 e rs2569062 no gene TCOF1 foi significantemente mais comum nos pacientes com FL±PNS em comparação com o grupo controle (p=0,01). Frente as modestas associações, nossos resultados não suportam a hipótese de que variantes estudadas nos genes HOXD1, TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3 e TIMP3 são fatores de risco para FL/PNS em uma população brasileira. Palavras chaves: fissura de lábio e/ou palato não-sindrômica, genes do desenvolvimento craniofacial, polimorfismo genético. vii viii ABSTRACT The craniofacial development involves a series of highly coordinated events, and polymorphic variations in genes that control these events can affect the morphogenesis of the lip and palate, resulting in the non-syndromic cleft lip and/or palate (NSCL/P). The aim of present study was to verify the association of polymorphisms in genes related to craniofacial development, HOXD1 (rs1374326), TNP1 (rs748044), MSX1 (rs1106514), TCOF1 (rs28372960, rs15251, rs2569062), FGFR1 (rs7829058), COL2A1 (rs1793949), WNT3 (rs11653738) and TIMP3 (rs242082), in the susceptibility of NSCL/P in a Brazilian population. To verify the association of those polymorphisms, the study associated the transmission disequilibrium test (TDT) and a structured case-control analysis based on the individual ancestry proportions in a sample composed of 189 case-parent trios of non-syndromic cleft lip with or without cleft palate (NSCL±P), 107 case-parent trios of non-syndromic cleft palate (NSCP), 318 isolated samples of NSCL±P, 189 isolated samples of NSCP and 599 healthy controls. All polymorphisms were initially evaluated by TDT, and significant associations were valitaded in a case-control analysis. A significant overtransmission of rs28372960 and rs7829058 polymorphisms in NSCL±P trios was observed (p=0.04), as well as the rs1374326 and rs11653738 polymorphisms in NSCP trios (p=0.04). However, the structured case-control analysis did not confirm those associations. The haplotype T-C-C formed by rs28372960, rs15251 and rs2569062 polymorphisms in TCOF1 gene was significantly more frequent in patients with NSCL±P in comparison with the control group (p=0.01). With the modest associations, our results do not support the hypothesis that HOXD1, TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3 and TIMP3 variants are risk factors for NSCL/P in a Brazilian population. Keywords: nonsyndromic cleft lip and/or palate, craniofacial development genes, genetic polymorphism. ix x SUMÁRIO DEDICATÓRIA xiii AGRADECIMENTOS xv LISTA DE FIGURAS xix LISTA DE TABELAS xxi LISTA DE ABREVIATURAS E SIGLAS xxiii 1 INTRODUÇÃO 1 2 REVISÃO DE LITERATURA 5 2.1 Fissuras do lábio e/ou palato não-sindrômicas (FL/PNS) 5 2.2 Embriologia do lábio e palato e a associação com FL/PNS 6 2.3 Epidemiologia das FL/PNS 11 2.4 Etiologia das FL/PNS 12 2.4.1 Fatores ambientais 12 2.4.2 Fatores genéticos 17 2.4.2.1 HOXD1 19 2.4.2.2 TNP1 20 2.4.2.3 MSX1 21 2.4.2.4 TCOF1 23 2.4.2.5 FGFR1 24 2.4.2.6 COL2A1 25 xi 2.4.2.7 WNT3 26 2.4.2.8 TIMP3 27 2.5 Delineamento experimental 28 3 PROPOSIÇÃO 31 4 MATERIAL E MÉTODOS 32 4.1 Aprovação do Comitê de Ética em Pesquisa 32 4.2 Desenho do estudo 32 4.3 Amostra 32 4.4 Coleta das amostras de células bucais 33 4.5 Isolamento do DNA 33 4.6 Seleção dos polimorfismos genéticos 34 4.7 Genotipagem pelo método de discriminação alélica com sondas fluorescentes 34 4.8 Análises estatísticas 35 5 RESULTADOS 37 6 DISCUSSÃO 45 7 CONCLUSÃO 51 REFERÊNCIAS 52 ANEXO 76 xii DEDICATÓRIA Aos pacientes com FL/PNS e suas famílias, razão de nosso estudo, que gentilmente colaboraram, confiaram e se prontificaram em participar desta pesquisa. Pacientes que nos ensinaram o valor do nosso trabalho e depositaram em nós suas esperanças em busca de uma melhor qualidade de vida. Que este estudo, em sua pequena contribuição e buscando reduzir o universo de desconhecimento sobre o assunto, possa ajudar-nos a oferecer-lhes uma melhor qualidade em suas jornadas diárias. xiii xiv AGRADECIMENTOS Agradeço primeiramente a Deus, por me dar força para superar as dificuldades e mostrar os caminhos certos nas horas difíceis. À Faculdade de Odontologia de Piracicaba da Universidade Estadual de Campinas, na pessoa de seu diretor, Professor Doutor Guilherme Elias Pessanha Henriques. Ao Professor Doutor Alan Roger dos Santos Silva, coordenador do Programa de Pós-Graduação em Estomatopatologia da Faculdade de Odontologia de Piracicaba da Universidade Estadual de Campinas. Ao meu orientador Professor Doutor Ricardo Della Coletta, pela transmissão de ensinamentos diários, mostrou sempre importante na minha formação pessoal e profissional, pelo exemplo de seriedade, paciência, persistência e bondade em tudo que se envolve. Registro aqui minha profunda admiração pela sua capacidade de construir novos caminhos e por me ensinar principalmente pelo exemplo. Ao meu coorientador Professor Doutor Hercílio Martelli Júnior, pelo incentivo aos trabalhos científicos desde a graduação e por compartilhar seus conhecimentos com tranquilidade e sabedoria. Aos Professores Doutores do Departamento de Diagnóstico Oral, áreas de Patologia e Semiologia da Faculdade de Odontologia de Piracicaba, Ricardo Della Coletta, Alan Roger dos Santos Silva, Jacks Jorge Júnior, Pablo Vargas, Márcio Ajudarte Lopes, Edgard Graner e Oslei Paes de Almeida. Obrigado pelos ensinamentos repassados durante a realização dos créditos. xv À coordenadora do comitê de ética da FOP Lívia Maria Andaló Tenuta pelo auxílio prestado durante o processo de submissão do trabalho, pela sua disposição, solidariedade e auxílio mostrando em tudo dedicação e responsabilidade. Aos funcionários da FOP-UNICAMP Geovania Almeida, Emílio Salles, João Carlos Gomes, Adriano
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