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Universidade Estadual De Campinas 1 UNIVERSIDADE ESTADUAL DE CAMPINAS INSTITUTO DE BIOLOGIA BRUNO BATISTA DE SOUZA ASPECTOS GENÉTICOS DO GLAUCOMA PRIMÁRIO DE ÂNGULO FECHADO CAMPINAS 2017 2 BRUNO BATISTA DE SOUZA ASPECTOS GENÉTICOS DO GLAUCOMA PRIMÁRIO DE ÂNGULO FECHADO Tese apresentada ao Instituto de Biologia da Universidade Estadual de Campinas como parte dos requisitos exigidos para a obtenção do título de Doutor em Genética e Biologia Molecular, na área de Genética Animal e Evolução. Orientadora: Profa Dra Mônica Barbosa de Melo ESTE ARQUIVO DIGITAL CORRESPONDE À VERSÃO FINAL DA TESE DEFENDIDA PELO ALUNO BRUNO BATISTA DE SOUZA E ORIENTADA PELA MÔNICA BARBOSA DE MELO. Campinas 2017 3 FICHA CATALOGRÁFICA 4 Campinas, 30 de Agosto de 2017. COMISSÃO EXAMINADORA Prof.(a) Dr.(a). Mônica Barbosa de Melo (orientadora) Prof.(a). Dr.(a) Mônica Alves Prof.(a) Dr(a). Cláudia Vianna Maurer-Morelli Prof. Dr. Marcelo de Lima Ribeiro Prof. Dr. Niro Kasahara Os membros da Comissão Examinadora acima assinaram a Ata de Defesa, que se encontra no processo de vida acadêmica do aluno. 5 DEDICATÓRIA “Nenhum trabalho de qualidade pode ser feito sem concentração e auto- sacrifício, esforço e dúvida” (Max Beerbohm) Dedicado à minha esposa Erika e meu filho Davi 6 AGRADECIMENTOS Agradeço à minha orientadora Profa. Mônica pela minha formação científica, por sua paciência e inestimável contribuição durante todos esses seis anos de trabalhos. Agradeço ao meu coorientador Prof. Dr. José Paulo por todos os ensinamentos e contribuição para minha formação científica. Agradeço à Daniela Stancato pelas várias ajudas concedidas. Agradeço aos colegas e amigos do laboratório de genética humana, pelo companheirismo e momentos de descontração. Obrigado Ana Maria, Ana Luiza, Gislene, Galina, Milena, Paulo, Pedro, Gabriela, Mirta e Sueli pela companhia, amizade e paciência. Agradeço à todos os amigos do CBMEG, em especial Letícia pelo companheirismo durante esses anos Agradeço aos meus pais, que me deram todo apoio quando decidi seguir carreira acadêmica. Agradeço à minha esposa Erika pela paciência nessa caminhada e ao meu filho Davi, peças fundamentais em minha vida e razões do meu esforço. Por fim, agradeço ao CNPq pela bolsa e financiamento imprescindíveis para a realização deste projeto 7 RESUMO O glaucoma é a principal causa de cegueira irreversível no mundo, acometendo cerca de 70 milhões de indivíduos, com pelo menos 6,8 milhões de pessoas apresentando cegueira bilateral. As formas mais comuns são o glaucoma primário de ângulo aberto (GPAA), seguido pelo glaucoma primário de ângulo fechado (GPAF). O GPAF é caracterizado por uma alteração anatômica na íris periférica, a qual leva ao bloqueio do fluxo do humor aquoso com consequente elevação da pressão intraocular (PIO). Suas formas clínicas incluem a crise aguda, processo tipicamente unilateral, mais agressivo e sintomático, levando a fortes dores oculares, dores de cabeça, visão borrada, náuseas e vômitos, e fechamento angular crônico, processo geralmente indolor e assintomático. Existe uma série de fatores predisponentes que foram extensivamente estudados na tentativa de explicar as variações populacionais e raciais na prevalência do GPAF. Além de fatores como sexo, idade e etnia, fatores anatômicos como 1) posição basal da íris, 2) medida da pressão diferencial e 3) resistência do canal íris-lente podem também contribuir para o desenvolvimento da doença. As predisposições étnicas e gênero- específicas e também o histórico familiar sugerem uma base genética para o desenvolvimento do GPAF. Dois Genome Wide Association Studies (GWAS) confirmaram a associação entre os loci rs11024102, rs3753841 e rs1015213 e o desenvolvimento do GPAF. O presente estudo propôs o estudo de características genéticas do GPAF em uma amostra de nossa população por meio da replicação dos loci previamente associados ao desenvolvimento da doença e o sequenciamento de exomas em duas famílias informativas para o GPAF. O estudo dos SNPs rs11024102, rs3753841 e rs1015213 não evidenciou associação entre os SNPs e o desenvolvimento do GPAF ou suas formas clínicas em nossa população. O estudo de exomas não evidenciou qual gene poderia estar causando a doença em ambas as famílias. 8 ABSTRACT Glaucoma is the leading cause of irreversible blindness worldwide, affecting approximately 70 million individuals, with at least 6.8 million people presenting bilateral blindness. The most common forms are primary open-angle glaucoma (POAG), followed by primary angle-closure glaucoma (PACG). Primary angle-closure glaucoma is characterized by an anatomical alteration in the peripheral iris, which leads to blockage of the aqueous humor outflow and consequent elevation of intraocular pressure (IOP). Its clinical forms include acute attacks, typically unilateral, more aggressive and symptomatic process, leading to severe eye pain, headaches, blurred vision, nausea and vomiting, and chronic angle closure, a process that is painless and asymptomatic. A number of predisposing factors are extensively studied in an attempt to explain geographic and racial variations in the prevalence of PACG. In addition to factors such as sex, age and ethnicity, anatomical factors such as 1) basal iris position, 2) differential pressure measurement, and 3) iris-lens resistance may also contribute to the development of the disease. Ethnical and gender-specific predispositions as well as family history suggest a genetic basis for the development of PACG. In an attempt to better comprehend the genetic aspects of PACG in a sample of the Brazilian population, two strategies have been used. A replication study was conducted in order to verify the frequency of rs11024102, rs3753841 and rs1015213 in PACG cases and controls as well as to determine their association with the disease and its clinical characteristics. These loci have been associated with the disease in two previous studies. Simultaneously, the evaluation of two informative families harboring PACG has been performed through exome sequencing. Our results showed no association between rs11024102, rs3753841 and rs1015213 with PACG development, as well as with its clinical forms. The exome study could not detect which gene might be responsible for the development of the disease in both studied families. 9 LISTA DE SÍMBOLOS E ABREVIATURAS C1QTNF8 C1q And Tumor Necrosis Factor Related Protein 8 CHX10 retinal homeobox 10 CIP Conteúdo Informativo do Polimorfismo COL11A1 Collagen Type XI Alpha 1 Chain CQ Controle de qualidade CTBP2 C-Terminal Binding Protein 2 DHR Doenças hereditárias da retina DNA ácido desoxirribonucléico dNTP didesoxinucleotídeos EDTA ácido etilenodiaminotetracético FALS Esclerose lateral amiotrófica familial FKBP15 FK506 binding protein 15 FREM2 FRAS1-related extracellular matrix protein 2 GPAA Glaucoma primário de ângulo aberto GPAA-J Glaucoma primário de ângulo aberto juvenil GPAF Glaucoma primário de ângulo fechado GCP Glaucoma congênito primário GPN Glaucoma de pressão normal GPR137 G Protein-Coupled Receptor 137 GWAS Genome-wide association study HGF Hepatocyte growth factor HSDL2 Hydroxysteroid Dehydrogenase Like 2 HWE Hardy-Weinberg Equilibrium IC Intervalo de confiança ITGAE Integrin Subunit Alpha E LIMS2 LIM Zinc Finger Domain Containing 2 LRRN2 Leucine Rich Repeat Neuronal 2 MFRP Membrane Frizzled-Related Protein mmHg milímetros de mercúrio MMP9 Matrix metallopeptidase 9 MTHFR Methylenetetrahydrofolate reductase ng nanogramas NID2 Nidogen 2 NNO1 Nanophthalmos 1 OCT Optic Coherence Tomography OR Odds ratio PCA análise de componente principal PCR reação em cadeia da polimerase RNA ácido ribonucléico PCMTD1 Protein-L-Isoaspartate (D-Aspartate) O-Methyltransferase Domain Containing 1 PIO Pressão intra-ocular PLEKHA7 Pleckstrin Homology Domain Containing A7 SNP Polimorfismo de base única SPA sinéquias periféricas anteriores ST18 suppression of tumorigenicity 18 TMF1 TATA Element Modulatory Factor 1 10 SUMÁRIO RESUMO ......................................................................................................................................... 7 ABSTRACT ....................................................................................................................................... 8 INTRODUÇÃO ................................................................................................................................ 12 Glaucoma .................................................................................................................................. 12 GPAF: Definição, etiologia e critérios de classificação .................................................................. 13 Fatores de risco ......................................................................................................................... 16 Epidemiologia ............................................................................................................................ 19 Genética envolvida no GPAF ...................................................................................................... 22 JUSTIFICATIVA ............................................................................................................................... 31 OBJETIVOS GERAIS ........................................................................................................................ 32 CAPÍTULO I .................................................................................................................................... 33 OBJETIVOS GERAIS ....................................................................................................................
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