Researchers identifiy the genetic background of dilated cardiomyopathy

Researchers have made a significant finding in determining the genetic background of dilated cardiomyopathy in Dobermanns. This research helps us understand the genetic risk factors related to fatal diseases of the heart muscle and the mechanisms underlying the disease, and offers new tools for their prevention.

Researchers from the University of Helsinki and the Folkhälsan Research Center, together with their international partners, have identified the genetic background of dilated cardiomyopathy, a disease that enlarges the heart muscle, in dogs and humans.

Based on a dataset encompassing more than 500 Dobermanns, the disease was associated with two nearby genomic loci, where changes were identified in genes that affect the functioning, energy metabolism and structure of the heart muscle. The study revealed that these same risk genes cause heart muscle disease in human patients.

A variety of factors can cause cardiomyopathy, but genetics play a significant role. Although dozens of genes underlying cardiomyopathy in humans have been identified, the hereditary nature and genetic background of the disease in dogs have remained unclear.

The situation with Dobermanns is serious in terms of both their health and breeding. The disease has been studied from various angles for decades without significant gene discoveries. Better diagnostic tools are needed, particularly in early diagnostics. Our new research might improve the situation."

Professor Hannes Lohi, principal investigator in the project

The study has significant implications for veterinary medicine, providing a basis for developing a new genetic test for early diagnostics and breeding.

Two novel risk genes identified in an extensive European cohort

Various research data collected over decades on more than 500 Dobermanns from across Europe were combined for the research. The dogs in the study cohort were categorized into five different groups:

• Dogs with only dilated cardiomyopathy
• Dogs with only arrhythmia
• Dogs with dilated cardiomyopathy and arrhythmia
• Dogs with congestive heart failure
• Healthy dogs aged at least six years as a control subcohort

With the help of genetic mapping, two adjacent gene loci in chromosome 5 were associated with dilated cardiomyopathy. Among the numerous genes in the loci, two, namely RNF207 and PRKAA2, demonstrated structural variation, which could have a detrimental effect on the functioning of the genes and cause heart failure.

"The genetic mapping we conducted produced important observations. Until now, it has been unclear whether Dobermanns with differing symptoms have the same disease. The genes we identified are only associated with a dilated heart and affected cardiac function. Arrhythmia appears to be a genetically distinct disease. Our dataset was insufficient to identify genes causing arrhythmia only. We also observed that several genes affect cardiac function and identified a model of two genes that increase the disease risk," explains Professor Lohi.

Gene discovery in dogs associated with cardiac muscle disorders in humans

The significance of the gene discovery in dogs was investigated in human patients diagnosed with dilated cardiomyopathy using Dutch, English (UK Biobank) and Finnish (FinnGen) cohorts. Fifteen potentially harmful and predisposing variants in the same RNF207 and PRKAA2 genes, which had been identified in dogs, were discovered in humans.

"The identical genetic background suggests that, to a degree, similar problems with the functioning of the heart muscle lead to dilated cardiomyopathy in both humans and dogs. A deeper understanding of the pathogenetic mechanisms is important, and Dobermanns represent a natural model organism for further research," Lohi states.

A genetic test for breeding

The DNA markers associated with the disease found in the study may be a step toward a genetic test, but it is important to confirm its clinical significance before such tests are offered.

"We discovered how the variants of the two genes together increase the disease risk. However, a pilot is needed to combine genetic and health data to monitor how frequently individuals who belong to the at-risk group develop the disease for varying genetic reasons. Then, we can obtain a more accurate estimate of how the gene discoveries should be ideally interpreted and utilized. In any case, this is a hope-inspiring finding because, in the past, we lacked such tools," Lohi describes.

The new gene discoveries enable new research hypotheses

For the consistent synchronized pumping of the heart, the heart muscle cells must interact with each other. Unlike in skeletal muscles, in the cell membrane of the heart muscle are finger-like discs that conduct the undulation required for pumping.

"Our study revealed that the RNF207 gene is expressed exactly in these discs. Earlier research has shown that RNF207 plays an important role in heart muscle contraction. The absence of these discs has also earlier been linked with cardiomyopathy. The other gene identified, PKAA2, serves as an energy sensor in the heart muscle, and its malfunction can reduce cardiac efficiency. Further research is required to understand the pathogenic mechanism, but we are in a good position to continue. A while ago, the disease was a total mystery, but now we have opened a view to its cellular-level secrets," Professor Lohi concludes.

The research was funded by, among others, the Finnish Foundation for Cardiovascular Research, the Jane and Aatos Erkko Foundation, the Sigrid Jusélius Foundation, and many other funders from different countries.

The study is part of Professor Hannes Lohi's canine gene research project, and the related article was published in the prestigious journal Genome Medicine.