| Name: | Description: | Size: | Format: | |
|---|---|---|---|---|
| 2.88 MB | Adobe PDF |
Advisor(s)
Abstract(s)
Introdução: As doenças cardiovasculares são uma importante causa de mortalidade e morbilidade em Portugal e no mundo. Os factores que causam as mesmas são múltiplos. Sabe-se que o perfil lipídico da população em muito influencia o seu risco cardiovascular. A hipercolesterolémia familiar (HF) e a hiperlipidémia familiar combinada (HFC) são duas doenças genéticas de origens monogénica e poligénica respectivamente. Estas entidades patológicas potenciam grandemente o risco cardiovascular e estão sub-diagnosticadas em Portugal. A frequência da HF é de 1/500 nos países Europeus, sendo que em Portugal estima-se que existam cerca de 20.000 casos. A frequência de HFC em Portugal não é conhecida. Torna-se imperativo o estudo mais aprofundado, nomeadamente a nível molecular, dos doentes que apresentem valores de lípidos séricos elevados e/ou risco de doença vascular aterosclerótica. O objectivo deste trabalho foi caracterizar clínica e molecularmente uma caso de HF.
Metodologia: Foi identificada uma família em que nas últimas 3 gerações, vários membros apresentavam características clínicas sugestivas de HF. Foram feitas análises sanguíneas para estudo bioquímico e molecular. Os genes estudados foram os associados à HF (LDLR, APOB, PCSK9, APOE) e HFC (LPL, APOA4, APOA5, APOC2, APOC3, USF1). Estudou-se ainda o gene da APOE em todos os participantes do estudo por estar associado ao perfil lipídico. O estudo incluiu reacção de PCR (polymerase chain reaction) e sequenciação automática do ácido desoxirribonucleico (DNA) tendo sido ainda estudado, através de técnica de amplificação dependente de múltiplas sondas (MLPA), grandes rearranjos ou deleções no gene LDLR.
Resultados: Não foi identificada qualquer mutação patogénica nos genes estudados. No entanto, foram encontrados vários polimorfismos no caso-index incluindo os polimorfismos rs688, rs3737787 e rs2073658 que estão relacionados com níveis elevados de colesterol e associados ao risco aumentado de desenvolvimento de aterosclerose.
Discussão e Conclusão: A família em estudo apresenta critérios clínicos de HF embora a presença de triglicerídeos elevados em alguns membros da família possa sugerir que se trata de uma HFC. Não foram no entanto, encontradas alterações patogénicas nos genes estudados. Ainda assim, a presença de certos polimorfismos predispõe a mesma para níveis elevados de lípidos no sangue. A confirmação de valores elevados nos vários elementos da família permite concluir que a carga genética em consonância com a carga ambiental devem ser tidas em conta no tratamento da família em estudo, pelo risco cardiovascular acrescido.
Background: Cardiovascular diseases are a major source of mortality and morbidity in Portugal and worldwide. The factors that cause them are multiple, but it is known that the lipid profile of the population influences their cardiovascular risk. Familial hypercholesterolemia and combined dyslipidemia are two pathological entities that greatly potentiate the cardiovascular risk and are under-diagnosed in Portugal. The frequency of familial hypercholesterolemia is 1/500 in European countries, and in Portugal it is estimated that there are about 20.000 cases. Frequency of familial combined hypercholesterolemia in Portugal is not known. Further studies are needed, particularly at the molecular level, of patients showing high serum lipid values and / or risk of atherosclerotic vascular disease. The aim of this study was to characterise the molecular and clinical features of a family with familial hypercholesterolemia. Methods: A three-generation family was identified with several members with clinical characteristics suggestive of familial hypercholesterolemia. Blood tests for biochemical and molecular studies were performed. The genes studied were the ones associated with familial hypercholesterolemia (LDLR, APOB, PCSK9), and familial combined hyperlipidemia (LPL, APOC4, APOA5, APOC2, APOC3, USF1). APOE gene was study in all participants of the study because it is related with the lipid profile in blood. The study included polymerase chain reaction (PCR), DNA automated sequencing and MLPA was used to detect large genetic rearrangements or deletions in the LDLR gene. Results: No pathogenic mutation was identified in the studied genes. However, there were various polymorphisms found in the index-case, including the rs688, rs3737787 and rs2073658 polymorphisms which are associated with high levels of cholesterol and increased risk of developing atherosclerosis. Discussion and Conclusion: The studied family presents familial hypercholesterolemia although the presence of high triglycerides in some family members suggests that it could be a familial combined hyperlipidemia. However, no mutations were found in the known genes. Nevertheless, the presence of certain polymorphisms may predispose them to high levels of lipids in blood. The genetic load should be taken into consideration in the treatment in line with the environmental load because of the increased cardiovascular risk of this family.
Background: Cardiovascular diseases are a major source of mortality and morbidity in Portugal and worldwide. The factors that cause them are multiple, but it is known that the lipid profile of the population influences their cardiovascular risk. Familial hypercholesterolemia and combined dyslipidemia are two pathological entities that greatly potentiate the cardiovascular risk and are under-diagnosed in Portugal. The frequency of familial hypercholesterolemia is 1/500 in European countries, and in Portugal it is estimated that there are about 20.000 cases. Frequency of familial combined hypercholesterolemia in Portugal is not known. Further studies are needed, particularly at the molecular level, of patients showing high serum lipid values and / or risk of atherosclerotic vascular disease. The aim of this study was to characterise the molecular and clinical features of a family with familial hypercholesterolemia. Methods: A three-generation family was identified with several members with clinical characteristics suggestive of familial hypercholesterolemia. Blood tests for biochemical and molecular studies were performed. The genes studied were the ones associated with familial hypercholesterolemia (LDLR, APOB, PCSK9), and familial combined hyperlipidemia (LPL, APOC4, APOA5, APOC2, APOC3, USF1). APOE gene was study in all participants of the study because it is related with the lipid profile in blood. The study included polymerase chain reaction (PCR), DNA automated sequencing and MLPA was used to detect large genetic rearrangements or deletions in the LDLR gene. Results: No pathogenic mutation was identified in the studied genes. However, there were various polymorphisms found in the index-case, including the rs688, rs3737787 and rs2073658 polymorphisms which are associated with high levels of cholesterol and increased risk of developing atherosclerosis. Discussion and Conclusion: The studied family presents familial hypercholesterolemia although the presence of high triglycerides in some family members suggests that it could be a familial combined hyperlipidemia. However, no mutations were found in the known genes. Nevertheless, the presence of certain polymorphisms may predispose them to high levels of lipids in blood. The genetic load should be taken into consideration in the treatment in line with the environmental load because of the increased cardiovascular risk of this family.
Description
Keywords
Aterosclerose Endocrinologia Genética Hipercolesterolémia Familiar Hiperlipidémia Familiar Combinada Metabolismo Risco Cardiovascular