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

Autor: van der Voorn SM; Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands., van Drie E; Department of Genetics, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands.; Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands., Proost V; Departments of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers Location Academic Medical Center, 1105 AZ Amsterdam, The Netherlands., Dimitrova K; Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands., Netherlands Acm/Pln Registry, Ernst RF; Department of Genetics, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands., James CA; Department of Medicine, Division Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA., Tichnell C; Department of Medicine, Division Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA., Murray B; Department of Medicine, Division Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA., Calkins H; Department of Medicine, Division Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA., Saguner AM; Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, 8091 Zurich, Switzerland., Duru F; Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.; Center for Integrative Human Physiology (ZIHP), University of Zurich, 8091 Zurich, Switzerland., Ellinor PT; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Bezzina CR; Departments of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers Location Academic Medical Center, 1105 AZ Amsterdam, The Netherlands., Jurgens SJ; Departments of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers Location Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., van Tintelen JP; Department of Genetics, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands.; Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands., van Veen TAB; Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Nov 03; Vol. 24 (21). Date of Electronic Publication: 2023 Nov 03.
DOI: 10.3390/ijms242115931
Abstrakt: 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.
Databáze: MEDLINE
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