Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5)
Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (Na...
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PeerJ Inc.
2022-08-01
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| Online Access: | https://peerj.com/articles/13913.pdf |
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| author | Monica Lopes-Marques Raquel Silva Catarina Serrano Verónica Gomes Ana Cardoso Maria João Prata Antonio Amorim Luisa Azevedo |
| author_facet | Monica Lopes-Marques Raquel Silva Catarina Serrano Verónica Gomes Ana Cardoso Maria João Prata Antonio Amorim Luisa Azevedo |
| author_sort | Monica Lopes-Marques |
| collection | DOAJ |
| description | Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (NaV1.5) encoded by the SCN5A gene is a case in point, as several studies have shown it can modify the clinical phenotype in a number of cardiac diseases. To evaluate the genetic backgrounds associated with this modulating effect, we reanalysed previous electrophysiological findings regarding the p.His558Arg variant and further assessed its patterns of genetic diversity in human populations. The NaV1.5 p.His558Arg variant was found to be in linkage disequilibrium with six other polymorphic variants that previously were also associated with cardiac traits in GWAS analyses. On account of this, incongruent reports that Arg558 allele can compensate, aggravate or have no effect on NaV1.5, likely might have arose due to a role of p.His558Arg depending on the additional linked variants. Altogether, these results indicate a major influence of the epistatic interactions between SCN5A variants, revealing also that phenotypic severity may depend on the polymorphic background associated to each individual genome. |
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| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T05:15:32Z |
| publishDate | 2022-08-01 |
| publisher | PeerJ Inc. |
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| spelling | doaj.art-f89c4b59619145ec8c285dd3e8a6c8b42023-12-03T12:46:38ZengPeerJ Inc.PeerJ2167-83592022-08-0110e1391310.7717/peerj.13913Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5)Monica Lopes-Marques0Raquel Silva1Catarina Serrano2Verónica Gomes3Ana Cardoso4Maria João Prata5Antonio Amorim6Luisa Azevedo7IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalCenter for Interdisciplinary Research in Health (CIIS), Universidade Católica Portuguesa, Faculdade de Medicina Dentária, Viseu, PortugalIPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalIPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalIPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalIPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalIPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalIPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalCommon genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (NaV1.5) encoded by the SCN5A gene is a case in point, as several studies have shown it can modify the clinical phenotype in a number of cardiac diseases. To evaluate the genetic backgrounds associated with this modulating effect, we reanalysed previous electrophysiological findings regarding the p.His558Arg variant and further assessed its patterns of genetic diversity in human populations. The NaV1.5 p.His558Arg variant was found to be in linkage disequilibrium with six other polymorphic variants that previously were also associated with cardiac traits in GWAS analyses. On account of this, incongruent reports that Arg558 allele can compensate, aggravate or have no effect on NaV1.5, likely might have arose due to a role of p.His558Arg depending on the additional linked variants. Altogether, these results indicate a major influence of the epistatic interactions between SCN5A variants, revealing also that phenotypic severity may depend on the polymorphic background associated to each individual genome.https://peerj.com/articles/13913.pdfSodium voltage-gated channel alpha subunit 5 (NaV1.5)SCN5A variantsGenetic backgroundLinkage disequilibriumGenetic modifierEpistasis |
| spellingShingle | Monica Lopes-Marques Raquel Silva Catarina Serrano Verónica Gomes Ana Cardoso Maria João Prata Antonio Amorim Luisa Azevedo Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5) PeerJ Sodium voltage-gated channel alpha subunit 5 (NaV1.5) SCN5A variants Genetic background Linkage disequilibrium Genetic modifier Epistasis |
| title | Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5) |
| title_full | Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5) |
| title_fullStr | Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5) |
| title_full_unstemmed | Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5) |
| title_short | Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5) |
| title_sort | complex interactions between p his558arg and linked variants in the sodium voltage gated channel alpha subunit 5 nav1 5 |
| topic | Sodium voltage-gated channel alpha subunit 5 (NaV1.5) SCN5A variants Genetic background Linkage disequilibrium Genetic modifier Epistasis |
| url | https://peerj.com/articles/13913.pdf |
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