Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset

Detalhes bibliográficos
Autor(a) principal: Santos, D.
Data de Publicação: 2017
Outros Autores: Coelho, T., Alves-Ferreira, M., Sequeiros, J., Mendonça, D., Alonso, I., Lemos, C., Sousa, A.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.16/2075
Resumo: OBJECTIVES: Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach. METHODS: We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO. RESULTS: We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors. INTERPRETATION: These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.
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spelling Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onsetOBJECTIVES: Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach. METHODS: We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO. RESULTS: We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors. INTERPRETATION: These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.American Neurological AssociationRepositório Científico do Centro Hospitalar Universitário de Santo AntónioSantos, D.Coelho, T.Alves-Ferreira, M.Sequeiros, J.Mendonça, D.Alonso, I.Lemos, C.Sousa, A.2017-04-24T14:30:26Z20172017-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2075engAnn Clin Transl Neurol. 2017 20;4(2):98-1052328-950310.1002/acn3.380info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-20T10:59:00Zoai:repositorio.chporto.pt:10400.16/2075Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:38:21.213932Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
title Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
spellingShingle Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
Santos, D.
title_short Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
title_full Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
title_fullStr Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
title_full_unstemmed Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
title_sort Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset
author Santos, D.
author_facet Santos, D.
Coelho, T.
Alves-Ferreira, M.
Sequeiros, J.
Mendonça, D.
Alonso, I.
Lemos, C.
Sousa, A.
author_role author
author2 Coelho, T.
Alves-Ferreira, M.
Sequeiros, J.
Mendonça, D.
Alonso, I.
Lemos, C.
Sousa, A.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Centro Hospitalar Universitário de Santo António
dc.contributor.author.fl_str_mv Santos, D.
Coelho, T.
Alves-Ferreira, M.
Sequeiros, J.
Mendonça, D.
Alonso, I.
Lemos, C.
Sousa, A.
description OBJECTIVES: Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach. METHODS: We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO. RESULTS: We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors. INTERPRETATION: These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.
publishDate 2017
dc.date.none.fl_str_mv 2017-04-24T14:30:26Z
2017
2017-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.16/2075
url http://hdl.handle.net/10400.16/2075
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Ann Clin Transl Neurol. 2017 20;4(2):98-105
2328-9503
10.1002/acn3.380
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Neurological Association
publisher.none.fl_str_mv American Neurological Association
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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