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; ... (2023). Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human. Genome medicine, 15(1), p. 73. BioMed Central 10.1186/s13073-023-01221-3
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) 05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics |
UniBE Contributor: |
Drögemüller, Michaela, Leeb, Tosso |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 590 Animals (Zoology) 600 Technology > 610 Medicine & health |
ISSN: |
1756-994X |
Publisher: |
BioMed Central |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
19 Sep 2023 09:51 |
Last Modified: |
29 Oct 2023 02:23 |
Publisher DOI: |
10.1186/s13073-023-01221-3 |
PubMed ID: |
37723491 |
Uncontrolled Keywords: |
Arrhythmia Cardiac Cardiology Companion animal Complex trait GWAS Genetics Transcriptomics |
BORIS DOI: |
10.48350/186390 |
URI: |
https://boris.unibe.ch/id/eprint/186390 |
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