Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers
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Published:2023-01-09
Issue:6
Volume:16
Page:1251-1266
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ISSN:1937-5387
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Container-title:Journal of Cardiovascular Translational Research
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language:en
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Short-container-title:J. of Cardiovasc. Trans. Res.
Author:
Lopera-Maya Esteban A.ORCID, Li Shuang, de Brouwer Remco, Nolte Ilja M., van Breen Justin, Bosman Laurens P., Verstraelen Tom E., van Lint Freya H. M., Cox Moniek G. P. J., Groeneweg Judith A., Mast Thomas P., van der Zwaag Paul A., Volders Paul G. A., Evertz Reinder, Wong Lisa, de Groot Natasja M. S., Zeppenfeld Katja, van der Heijden Jeroen F., van den Berg Maarten P., Wilde Arthur A. M., Asselbergs Folkert W., Hauer Richard N. W., te Riele Anneline S. J. M., van Tintelen J. Peter, Aguirre-Gamboa Raul, Deelen PatrickORCID, Franke Lude, Kuivenhoven Jan A., Maya Esteban A. LoperaORCID, Nolte Ilja M., Sanna Serena, Snieder Harold, Swertz Morris A., Visscher Peter M., Vonk Judith M., Wijmenga Cisca, Jongbloed Jan D. H., Swertz Morris A., Snieder Harold, Franke Lude, Wijmenga Cisca, de Boer Rudolf A., Deelen PatrickORCID, van der Zwaag Paul A., Sanna SerenaORCID, ,
Abstract
AbstractThe c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN:c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N = 48) showed shorter QRS duration (− 5.73 ms, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (rPearson = 0.17) between polygenic predisposition to higher QRS (PGSQRS) and QRS (p value = 1.98 × 10–8), suggesting that the effect of the genetic variation on cardiac rhythm might be increased in symptomatic carriers. Our results allow for improved clinical interpretation for asymptomatic carriers, while our approach could guide future studies on genetic diseases with incomplete penetrance.
Graphical abstract
Funder
Ministerie van Volksgezondheid, Welzijn en Sport Universitair Medisch Centrum Groningen Nederlandse Organisatie voor Wetenschappelijk Onderzoek European Research Council Departamento Administrativo de Ciencia, Tecnología e Innovación Hartstichting Fondation Leducq
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Cardiology and Cardiovascular Medicine,Pharmaceutical Science,Genetics,Molecular Medicine
Cited by
2 articles.
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