C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients

OBJECTIVES: Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age‐at‐onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR‐FAP Val30Met Portuguese patients. METHODS: We anal...

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Autores principales: Dias, Andreia, Santos, Diana, Coelho, Teresa, Alves‐Ferreira, Miguel, Sequeiros, Jorge, Alonso, Isabel, Sousa, Alda, Lemos, Carolina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469251/
https://www.ncbi.nlm.nih.gov/pubmed/31019999
http://dx.doi.org/10.1002/acn3.748
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author Dias, Andreia
Santos, Diana
Coelho, Teresa
Alves‐Ferreira, Miguel
Sequeiros, Jorge
Alonso, Isabel
Sousa, Alda
Lemos, Carolina
author_facet Dias, Andreia
Santos, Diana
Coelho, Teresa
Alves‐Ferreira, Miguel
Sequeiros, Jorge
Alonso, Isabel
Sousa, Alda
Lemos, Carolina
author_sort Dias, Andreia
collection PubMed
description OBJECTIVES: Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age‐at‐onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR‐FAP Val30Met Portuguese patients. METHODS: We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the non‐independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene–gene interactions. RESULTS: Two variants for C1QA gene, GA genotype of rs201693493 (P < 0.001) and CT genotype of rs149050968 (P < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1QC, we found three statistically significant results: GA genotype of rs2935537 (P = 0.003), GA genotype of rs201241346 (P < 0.001) and GA genotype of rs200952686 (P < 0.001). The first two were associated with earlier AO, whereas the third was associated with later‐onset. INTERPRETATION: C1QA was associated with later onset, whereas C1QC may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR‐FAP Val30Met.
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spelling pubmed-64692512019-04-24 C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients Dias, Andreia Santos, Diana Coelho, Teresa Alves‐Ferreira, Miguel Sequeiros, Jorge Alonso, Isabel Sousa, Alda Lemos, Carolina Ann Clin Transl Neurol Research Articles OBJECTIVES: Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age‐at‐onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR‐FAP Val30Met Portuguese patients. METHODS: We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the non‐independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene–gene interactions. RESULTS: Two variants for C1QA gene, GA genotype of rs201693493 (P < 0.001) and CT genotype of rs149050968 (P < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1QC, we found three statistically significant results: GA genotype of rs2935537 (P = 0.003), GA genotype of rs201241346 (P < 0.001) and GA genotype of rs200952686 (P < 0.001). The first two were associated with earlier AO, whereas the third was associated with later‐onset. INTERPRETATION: C1QA was associated with later onset, whereas C1QC may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR‐FAP Val30Met. John Wiley and Sons Inc. 2019-03-07 /pmc/articles/PMC6469251/ /pubmed/31019999 http://dx.doi.org/10.1002/acn3.748 Text en © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Dias, Andreia
Santos, Diana
Coelho, Teresa
Alves‐Ferreira, Miguel
Sequeiros, Jorge
Alonso, Isabel
Sousa, Alda
Lemos, Carolina
C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
title C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
title_full C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
title_fullStr C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
title_full_unstemmed C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
title_short C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients
title_sort c1qa and c1qc modify age‐at‐onset in familial amyloid polyneuropathy patients
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469251/
https://www.ncbi.nlm.nih.gov/pubmed/31019999
http://dx.doi.org/10.1002/acn3.748
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