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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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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. |
format | Online Article Text |
id | pubmed-6469251 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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