Variante genética da doença de Parkinson encontrada em algumas pessoas de ascendência africana
Uma variante genética encontrada quase exclusivamente nos genomas de pessoas de ascendência africana aumenta o risco de desenvolver a doença de Parkinson, de acordo com um estudo internacional realizado com quase 198 mil participantes...
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Os cientistas descobriram uma variante genética, encontrada quase exclusivamente nos genomas de indivíduos de ascendência africana, que aumenta o risco de contrair a doença de Parkinson. Crédito: Imagem criada com BioRender.com, cortesia do laboratório Singleton, NIH CARD, Bethesda, MD.
Uma variante genética encontrada quase exclusivamente nos genomas de pessoas de ascendência africana aumenta o risco de desenvolver a doença de Parkinson, de acordo com um estudo internacional realizado com quase 198 mil participantes com esta formação genética. Publicados no The Lancet Neurology , os resultados do estudo sugerem que o risco pode estar ligado a uma variante no gene que codifica a ?-glucocerebrosidase (GBA1), uma proteína conhecida por controlar a forma como as células do corpo reciclam proteínas.
O estudo foi liderado por cientistas dos Institutos Nacionais de Saúde; o University College, Londres; e a Universidade de Lagos, Nigéria. Embora sejam necessárias mais pesquisas para compreender o papel dos fatores ambientais e outros nessas populações, os cientistas descobriram que aqueles que carregam uma cópia do gene têm cerca de 1,5 vezes mais probabilidade de ter a doença de Parkinson do que aqueles que não têm cópias, enquanto aqueles que carregam duas cópias são cerca de 3,5 vezes mais prováveis.
"Para tratar efetivamente o Parkinson e qualquer doença, devemos estudar diversas populações para compreender completamente quais são os fatores e fatores de risco para esses distúrbios", disse Andrew B. Singleton, Ph.D., diretor do Centro Intramural do NIH para Demências Relacionadas ao Alzheimer. (CARD) e um autor do estudo. “Estes resultados apoiam a ideia de que a base genética para uma doença comum pode diferir consoante a ascendência, e a compreensão destas diferenças pode fornecer novos conhecimentos sobre a biologia da doença de Parkinson”.
Nas últimas décadas, os pesquisadores encontraram vários fatores de risco genéticos para a doença de Parkinson. Casos hereditários raros da doença foram associados a cerca de 20 genes que abrigam variantes patogénicas – anteriormente conhecidas como mutações causadoras de doenças – enquanto mais de 100 regiões do genoma humano estão associadas a formas esporádicas mais comuns da doença. No entanto, a maioria destas conclusões baseia-se em estudos de pessoas de ascendência europeia e muito poucos foram realizados em pessoas de ascendência africana.
Para este projeto, os pesquisadores conduziram um estudo de associação genômica ampla (GWAS) envolvendo 1.488 pessoas que tinham doença de Parkinson e 196.430 pessoas que não tinham.
Os cientistas do NIH trabalharam com pesquisadores de todo o mundo que fazem parte do Programa Global de Genética do Parkinson (GP2), incluindo o Black and African American Connections to Parkinson's Study e o International Parkinson Disease Genomics Consortium (IPDGC) – África.
Juntos, os pesquisadores coletaram amostras de DNA e analisaram dados genéticos de indivíduos principalmente da Nigéria e de quatro locais nos Estados Unidos. Esses dados foram combinados com dados genéticos e fenotípicos desidentificados de 195.587 pessoas de ascendência afro-americana ou afro-caribenha que consentiram em participar da pesquisa 23andMe.
Uma análise preliminar dos dados mostrou uma associação significativa entre o risco da doença de Parkinson e a variante recentemente identificada do gene GBA1. Uma revisão de estudos anteriores também mostrou que esta nova variante raramente aparece em pessoas de ascendência europeia e asiática, sugerindo que está quase exclusivamente ligada à ascendência africana.
"Ficamos completamente surpresos. O objetivo da análise inicial era ajudar a treinar pesquisadores do GP2 na Nigéria e em outras partes do mundo sobre como analisar dados GWAS", disse Sara Bandrés-Ciga, Ph.D., cientista da equipe do NIH CARD. e um autor do estudo. “O fato de a variante GBA1 ter uma associação significativa enquanto outras não sugere que ela esteja fortemente ligada à doença de Parkinson nesta população”.
Uma análise mais aprofundada dos dados do GWAS deste estudo sugeriu que o risco associado à variante GBA1 é aditivo.
Estudos anteriores realizados por investigadores do NIH e outros demonstraram que variantes patogénicas do gene GBA1 também estão associadas à doença de Parkinson e de Gaucher, uma doença genética rara causada por problemas nos lisossomas. Os lisossomos são pequenos sacos dentro das células que decompõem as proteínas para reciclagem.
Os resultados deste estudo sugerem que a nova variante pode alterar a atividade lisossomal do GBA1 de uma forma até então desconhecida. A maioria das variantes identificadas anteriormente aparecem na parte do código genético que orienta como o corpo produz a glicocerebrosidase, uma enzima codificada pelo GBA1. Isto interrompe o processo de fabricação ou altera a atividade da enzima. Em contraste, esta variante da doença de Parkinson recentemente descoberta aparece fora da região codificadora. Mais pesquisas são necessárias para determinar como a variante pode alterar a atividade.
Atualmente, os pesquisadores estão desenvolvendo terapias genéticas para o tratamento da doença de Gaucher e de outras doenças lisossômicas.
“Nossos resultados representam um bom primeiro passo para a compreensão plena da complexidade genética e biológica de cada indivíduo ao redor do mundo que tem a doença de Parkinson”, disse Singleton. “Nossa esperança é que resultados como esses forneçam aos pesquisadores um roteiro para o desenvolvimento de novos tratamentos e terapias genéticas para a doença de Parkinson”.
De acordo com a Organização Mundial da Saúde , mais de 8,5 milhões de pessoas em todo o mundo têm Parkinson, um distúrbio cerebral que normalmente afeta pessoas com 60 anos de idade ou mais. Inicialmente, a doença pode causar lentidão, bem como problemas de equilíbrio e movimento, incluindo tremores e rigidez. Com o tempo, o distúrbio pode piorar, causando problemas para andar, falar, dormir, lembrar e humor.
Os pesquisadores podem obter dados do estudo acessando a plataforma do programa Accelerating Medicines Partnership (AMP) . O programa AMP PD é uma parceria público-privada gerida pela Fundação dos Institutos Nacionais de Saúde.
Mais informações: Mie Rizig et al, Identificação de loci de risco genético e insights causais associados à doença de Parkinson em populações africanas e misturadas em África: um estudo de associação genômica ampla, The Lancet Neurology (2023). DOI: 10.1016/S1474-4422(23)00283-1
Informações do periódico: Lancet Neurology