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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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Detalles Bibliográficos
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
Descripción
Sumario: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.