| Title: | Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human |
| Journal: | Genome Medicine |
| Published: | 18 Sep 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37723491/ |
| DOI: | https://doi.org/10.1186/s13073-023-01221-3 |
| URL: | https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-023-01221-3 |
Publication 9567
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Abstract
BackgroundDilated 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.MethodsWe 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.ResultsOur 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.ConclusionsCollectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.</p>
31 Authors
- Julia E. Niskanen
- Åsa Ohlsson
- Ingrid Ljungvall
- Michaela Drögemüller
- Robert F. Ernst
- Dennis Dooijes
- Hanneke W. M. van Deutekom
- J. Peter van Tintelen
- Christian J. B. Snijders Blok
- Marion van Vugt
- Jessica van Setten
- Folkert W. Asselbergs
- Aleksandra Domanjko Petrič
- Milla Salonen
- Sruthi Hundi
- Matthias Hörtenhuber
- Juha Kere
- W. Glen Pyle
- Jonas Donner
- Alex V. Postma
- Tosso Leeb
- Göran Andersson
- Marjo K. Hytönen
- Jens Häggström
- Maria Wiberg
- Jana Friederich
- Jenny Eberhard
- Magdalena Harakalova
- Frank G. van Steenbeek
- Gerhard Wess
- Hannes Lohi
1 Application
| Application ID | Title |
|---|---|
| 24711 | On the quest for tissue-specific contributions to disease |
Enabling scientific discoveries that improve human health