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Publications

Journal Article Epublish 4 citations

PubMed: 37958923 DOI: 10.3390/ijms242115931

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

Int J Mol Sci 24(21)

Authors: Stephanie M van der Voorn, Esmée van Drie, Virginnio Proost, Kristina Dimitrova, Netherlands Acm/Pln Registry, Robert F Ernst, Cynthia A James, Crystal Tichnell, Brittney Murray, Hugh Calkins, Ardan M Saguner, Firat Duru, Patrick T Ellinor, Connie R Bezzina, Sean J Jurgens, J Peter van Tintelen, Toon A B van Veen

Affiliations

  • Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands.
  • Department of Genetics, Division Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands.
  • Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands.
  • Departments of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers Location Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
  • Department of Medicine, Division Cardiology, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 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.
  • Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Abstract

Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca) is crucially important for proper cardiac function, and dysregulation of Ca homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca binding (HRC) protein, relevant for sarcoplasmic reticulum Ca 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 () 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 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.

MeSH

Genes, Genetics, Heart Failure, Arrhythmias, Cardiac, Calcium, Histidine, Cardiomyopathies, Calcium-Binding Proteins