@article{48e8a0391b134caf96ea5d785ed33d77,
title = "Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies",
abstract = "Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca2+) is crucially important for proper cardiac function, and dysregulation of Ca2+ homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca2+ binding (HRC) protein, relevant for sarcoplasmic reticulum Ca2+ 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.",
keywords = "arrhythmia, cardiomyopathies, genetic modifier, genetics, heart failure",
author = "{van der Voorn}, {Stephanie M.} and {van Drie}, Esm{\'e}e and Virginnio Proost and Kristina Dimitrova and Ernst, {Robert F.} and James, {Cynthia A.} and Crystal Tichnell and Brittney Murray and Hugh Calkins and Saguner, {Ardan M.} and Firat Duru and Ellinor, {Patrick T.} and Bezzina, {Connie R.} and Jurgens, {Sean J.} and {van Tintelen}, {J. Peter} and {van Veen}, {Toon A. B.}",
note = "Funding Information: This research was funded by a grant from the Netherlands Cardio Vascular Research Initiative (CVON): the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON-eDETECT 2015-12, PREDICT2 2018-30 and DoubleDose 2020B005), and the Leducq CUREPLaN. Further financial support was obtained from the Netherlands Heart Institute in conjunction with the PLN patient foundation (to TABvV). This work was also supported by a grant from the Dutch Heart Foundation (grant No. 03-007-2022-0035), an Amsterdam UMC Doctoral Fellowship to S.J.J., and a CVON-PREDICT2 Young Talent Program Grant to E.v.D. The Zurich ARVC Program is supported by the Georg und Bertha Schwyzer-Winiker Foundation, Baugarten Foundation, USZ Foundation (Dr. Wild Grant), Swiss Heart Foundation grant No. FF17019 and FF21073 to A.M.S., and Swiss National Science Foundation grant No. 160327 to F.D. The Johns Hopkins ARVD/C Program is supported by the Leonie-Wild Foundation; the Leyla Erkan Family Fund for ARVD Research; The Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; the Dr. Francis P. Chiramonte Private Foundation; the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; the Bogle Foundation; the Campanella family; the Patrick J. Harrison Family; the Peter French Memorial Foundation; and the Wilmerding Endowments. Publisher Copyright: {\textcopyright} 2023 by the authors.",
year = "2023",
month = nov,
day = "1",
doi = "https://doi.org/10.3390/ijms242115931",
language = "English",
volume = "24",
journal = "International journal of molecular sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "21",
}