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Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk f...

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Autores principales: Niskanen, Julia E., Ohlsson, Åsa, Ljungvall, Ingrid, Drögemüller, Michaela, Ernst, Robert F., Dooijes, Dennis, van Deutekom, Hanneke W. M., van Tintelen, J. Peter, Snijders Blok, Christian J. B., van Vugt, Marion, van Setten, Jessica, Asselbergs, Folkert W., Petrič, Aleksandra Domanjko, Salonen, Milla, Hundi, Sruthi, Hörtenhuber, Matthias, Kere, Juha, Pyle, W. Glen, Donner, Jonas, Postma, Alex V., Leeb, Tosso, Andersson, Göran, Hytönen, Marjo K., Häggström, Jens, Wiberg, Maria, Friederich, Jana, Eberhard, Jenny, Harakalova, Magdalena, van Steenbeek, Frank G., Wess, Gerhard, Lohi, Hannes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10506233/
https://www.ncbi.nlm.nih.gov/pubmed/37723491
http://dx.doi.org/10.1186/s13073-023-01221-3
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author Niskanen, Julia E.
Ohlsson, Åsa
Ljungvall, Ingrid
Drögemüller, Michaela
Ernst, Robert F.
Dooijes, Dennis
van Deutekom, Hanneke W. M.
van Tintelen, J. Peter
Snijders Blok, Christian J. B.
van Vugt, Marion
van Setten, Jessica
Asselbergs, Folkert W.
Petrič, Aleksandra Domanjko
Salonen, Milla
Hundi, Sruthi
Hörtenhuber, Matthias
Kere, Juha
Pyle, W. Glen
Donner, Jonas
Postma, Alex V.
Leeb, Tosso
Andersson, Göran
Hytönen, Marjo K.
Häggström, Jens
Wiberg, Maria
Friederich, Jana
Eberhard, Jenny
Harakalova, Magdalena
van Steenbeek, Frank G.
Wess, Gerhard
Lohi, Hannes
author_facet Niskanen, Julia E.
Ohlsson, Åsa
Ljungvall, Ingrid
Drögemüller, Michaela
Ernst, Robert F.
Dooijes, Dennis
van Deutekom, Hanneke W. M.
van Tintelen, J. Peter
Snijders Blok, Christian J. B.
van Vugt, Marion
van Setten, Jessica
Asselbergs, Folkert W.
Petrič, Aleksandra Domanjko
Salonen, Milla
Hundi, Sruthi
Hörtenhuber, Matthias
Kere, Juha
Pyle, W. Glen
Donner, Jonas
Postma, Alex V.
Leeb, Tosso
Andersson, Göran
Hytönen, Marjo K.
Häggström, Jens
Wiberg, Maria
Friederich, Jana
Eberhard, Jenny
Harakalova, Magdalena
van Steenbeek, Frank G.
Wess, Gerhard
Lohi, Hannes
author_sort Niskanen, Julia E.
collection PubMed
description BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01221-3.
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spelling pubmed-105062332023-09-19 Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human Niskanen, Julia E. Ohlsson, Åsa Ljungvall, Ingrid Drögemüller, Michaela Ernst, Robert F. Dooijes, Dennis van Deutekom, Hanneke W. M. van Tintelen, J. Peter Snijders Blok, Christian J. B. van Vugt, Marion van Setten, Jessica Asselbergs, Folkert W. Petrič, Aleksandra Domanjko Salonen, Milla Hundi, Sruthi Hörtenhuber, Matthias Kere, Juha Pyle, W. Glen Donner, Jonas Postma, Alex V. Leeb, Tosso Andersson, Göran Hytönen, Marjo K. Häggström, Jens Wiberg, Maria Friederich, Jana Eberhard, Jenny Harakalova, Magdalena van Steenbeek, Frank G. Wess, Gerhard Lohi, Hannes Genome Med Research BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01221-3. BioMed Central 2023-09-18 /pmc/articles/PMC10506233/ /pubmed/37723491 http://dx.doi.org/10.1186/s13073-023-01221-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Niskanen, Julia E.
Ohlsson, Åsa
Ljungvall, Ingrid
Drögemüller, Michaela
Ernst, Robert F.
Dooijes, Dennis
van Deutekom, Hanneke W. M.
van Tintelen, J. Peter
Snijders Blok, Christian J. B.
van Vugt, Marion
van Setten, Jessica
Asselbergs, Folkert W.
Petrič, Aleksandra Domanjko
Salonen, Milla
Hundi, Sruthi
Hörtenhuber, Matthias
Kere, Juha
Pyle, W. Glen
Donner, Jonas
Postma, Alex V.
Leeb, Tosso
Andersson, Göran
Hytönen, Marjo K.
Häggström, Jens
Wiberg, Maria
Friederich, Jana
Eberhard, Jenny
Harakalova, Magdalena
van Steenbeek, Frank G.
Wess, Gerhard
Lohi, Hannes
Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
title Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
title_full Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
title_fullStr Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
title_full_unstemmed Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
title_short Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
title_sort identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10506233/
https://www.ncbi.nlm.nih.gov/pubmed/37723491
http://dx.doi.org/10.1186/s13073-023-01221-3
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