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Contributo para o estudo dos determinantes genéticos na suscetiblidade e resposta à terapêutica na asma
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Resumo(s)
A asma é uma doença inflamatória crónica das vias respiratórias caracterizada por uma obstrução brônquica reversível e que desencadeia episódios recorrentes de sibilância, dispneia, aperto torácico e tosse. A patogénese da asma associa-se a mecanismos moleculares e celulares da inflamação característicos de uma resposta de linfócitos auxiliares do tipo Th2. Esta é uma doença que afeta cerca de 300 milhões de pessoas em todo o mundo de todas as idades e etnias. Em Portugal estima-se que a asma afete 10% da população. A asma é uma doença heterogénea, com uma forte relação entre fatores ambientais e fatores genéticos. Os estudos genéticos são importantes pois permitem associar polimorfismos genéticos ao desenvolvimento da doença e à variabilidade interpessoal na resposta à terapêutica. Estima-se que cerca de 80% da variabilidade na resposta a terapêutica tem uma base genética. Neste âmbito estudou-se o polimorfismo de repetição de 27 pb no intrão 4 do gene da sintase do óxido nítrico endotelial (eNOS), uma enzima envolvida na formação do óxido nítrico, e os polimorfismos de uma única base no codão 16 e 27 do gene do recetor β2-adrenérgico (ADRβ2) que está envolvido no relaxamento do músculo liso das vias aéreas e é o alvo de alguns dos medicamentos usados no tratamento da doença. Existem diferenças significativas na distribuição genotípica da eNOS entre asmáticos e o grupo controlo (p=0,016) e um dos genótipos (aa) representa-se como um fator de proteção para a doença (OR=0,095; IC=0,012 a 0,727). Não foi encontrada nenhuma associação entre os polimorfismos da eNOS e do ADRβ2 e a resposta à terapêutica Os resultados sugerem que existe uma associação entre o polimorfismo de repetição do gene eNOS e a suscetibilidade para asma, embora este resultado esteja condicionado pela escolha do grupo controlo, e que os polimorfismos estudados não têm influência no controlo da doença.
Asthma is a chronic inflammatory disease of the airways, characterized by a reversible bronchial constriction and that triggers recurring episodes of wheezing, dyspnea, thoracic constriction and cough. The pathogenesis of asthma is associated to molecular and cellular mechanisms of inflammation typical of a Th2 cell response. It’s a disease that affects around 300 million people worldwide, of all ages and ethnicities. In Portugal it is estimated to affect 10% of the population. Asthma is a heterogeneous disease, with a strong relation between environmental and genetic factors. Genetic studies are important to associate polymorphisms with the development of the disease and deficiencies in the response to therapeutics. It is estimated that about 80% of the variability in response to therapeutics has e genetic basis. In this context, the repetition polymorphism of intron 4 of the nitric oxide synthase gene (eNOS), an enzyme involved in the production of nitric oxide, and the single nucleotide polymorphisms of codons 16 and 27 of the β2-adrenergic receptor gene (ADRβ2), involved in the relaxation of the airways’ smooth muscle and target of some of the medications used in the treatment of the disease, were studied. There are significant differences in the genotypic distribution of eNOS between asthmatics and control (p=0,016), and the aa genotype represents a protective factor for the disease (OR=0,095 CI=0,012-0,727). No association was found between eNOS or ADRβ2 polymorphisms and response to therapeutics. The results suggest that there is an association between repetition polymorphism of the eNOS gene and asthma susceptibility, but this result is biased by the choice of control group, and that the polymorphisms studied don’t influence the response to therapeutics.
Asthma is a chronic inflammatory disease of the airways, characterized by a reversible bronchial constriction and that triggers recurring episodes of wheezing, dyspnea, thoracic constriction and cough. The pathogenesis of asthma is associated to molecular and cellular mechanisms of inflammation typical of a Th2 cell response. It’s a disease that affects around 300 million people worldwide, of all ages and ethnicities. In Portugal it is estimated to affect 10% of the population. Asthma is a heterogeneous disease, with a strong relation between environmental and genetic factors. Genetic studies are important to associate polymorphisms with the development of the disease and deficiencies in the response to therapeutics. It is estimated that about 80% of the variability in response to therapeutics has e genetic basis. In this context, the repetition polymorphism of intron 4 of the nitric oxide synthase gene (eNOS), an enzyme involved in the production of nitric oxide, and the single nucleotide polymorphisms of codons 16 and 27 of the β2-adrenergic receptor gene (ADRβ2), involved in the relaxation of the airways’ smooth muscle and target of some of the medications used in the treatment of the disease, were studied. There are significant differences in the genotypic distribution of eNOS between asthmatics and control (p=0,016), and the aa genotype represents a protective factor for the disease (OR=0,095 CI=0,012-0,727). No association was found between eNOS or ADRβ2 polymorphisms and response to therapeutics. The results suggest that there is an association between repetition polymorphism of the eNOS gene and asthma susceptibility, but this result is biased by the choice of control group, and that the polymorphisms studied don’t influence the response to therapeutics.
Descrição
Tese de mestrado. Biologia (Biologia Molecular e Genética). Universidade de Lisboa, Faculdade de Ciências, 2012
Palavras-chave
Biologia molecular Asma Polimorfismo genético Farmacogenética Teses de mestrado - 2012