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Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies

Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca(2+)) is crucially important for proper cardiac function, and dysregulation of Ca(2+) homeostasis seems to underly cardiomyopathy etiolog...

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Autores principales: van der Voorn, Stephanie M., van Drie, Esmée, Proost, Virginnio, Dimitrova, Kristina, Ernst, Robert F., James, Cynthia A., Tichnell, Crystal, Murray, Brittney, Calkins, Hugh, Saguner, Ardan M., Duru, Firat, Ellinor, Patrick T., Bezzina, Connie R., Jurgens, Sean J., van Tintelen, J. Peter, van Veen, Toon A. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648441/
https://www.ncbi.nlm.nih.gov/pubmed/37958923
http://dx.doi.org/10.3390/ijms242115931
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author van der Voorn, Stephanie M.
van Drie, Esmée
Proost, Virginnio
Dimitrova, Kristina
Ernst, Robert F.
James, Cynthia A.
Tichnell, Crystal
Murray, Brittney
Calkins, Hugh
Saguner, Ardan M.
Duru, Firat
Ellinor, Patrick T.
Bezzina, Connie R.
Jurgens, Sean J.
van Tintelen, J. Peter
van Veen, Toon A. B.
author_facet van der Voorn, Stephanie M.
van Drie, Esmée
Proost, Virginnio
Dimitrova, Kristina
Ernst, Robert F.
James, Cynthia A.
Tichnell, Crystal
Murray, Brittney
Calkins, Hugh
Saguner, Ardan M.
Duru, Firat
Ellinor, Patrick T.
Bezzina, Connie R.
Jurgens, Sean J.
van Tintelen, J. Peter
van Veen, Toon A. B.
author_sort van der Voorn, Stephanie M.
collection PubMed
description Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca(2+)) is crucially important for proper cardiac function, and dysregulation of Ca(2+) homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca(2+) binding (HRC) protein, relevant for sarcoplasmic reticulum Ca(2+) cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban (PLN) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European–American population (control cohort, 40.3–42.2%) and the different cardiomyopathy cohorts (cohorts 1–3, 40.9–43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.
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spelling pubmed-106484412023-11-03 Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies van der Voorn, Stephanie M. van Drie, Esmée Proost, Virginnio Dimitrova, Kristina Ernst, Robert F. James, Cynthia A. Tichnell, Crystal Murray, Brittney Calkins, Hugh Saguner, Ardan M. Duru, Firat Ellinor, Patrick T. Bezzina, Connie R. Jurgens, Sean J. van Tintelen, J. Peter van Veen, Toon A. B. Int J Mol Sci Article Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca(2+)) is crucially important for proper cardiac function, and dysregulation of Ca(2+) homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca(2+) binding (HRC) protein, relevant for sarcoplasmic reticulum Ca(2+) cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban (PLN) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European–American population (control cohort, 40.3–42.2%) and the different cardiomyopathy cohorts (cohorts 1–3, 40.9–43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes. MDPI 2023-11-03 /pmc/articles/PMC10648441/ /pubmed/37958923 http://dx.doi.org/10.3390/ijms242115931 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
van der Voorn, Stephanie M.
van Drie, Esmée
Proost, Virginnio
Dimitrova, Kristina
Ernst, Robert F.
James, Cynthia A.
Tichnell, Crystal
Murray, Brittney
Calkins, Hugh
Saguner, Ardan M.
Duru, Firat
Ellinor, Patrick T.
Bezzina, Connie R.
Jurgens, Sean J.
van Tintelen, J. Peter
van Veen, Toon A. B.
Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
title Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
title_full Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
title_fullStr Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
title_full_unstemmed Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
title_short Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
title_sort lack of evidence for the role of the p.(ser96ala) polymorphism in histidine-rich calcium binding protein as a secondary hit in cardiomyopathies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648441/
https://www.ncbi.nlm.nih.gov/pubmed/37958923
http://dx.doi.org/10.3390/ijms242115931
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