Researchers have significantly expanded the understanding of the genetic causes of atrial fibrillation (AF), a common heart condition that leads to an irregular heartbeat and increases the risk of stroke and heart failure.
Two large studies, led by scientists at the Broad Institute of MIT and Harvard and Mass General Brigham, have identified hundreds of new genetic variants linked to AF.
The findings provide valuable insights into the biological mechanisms of the disease and may lead to new treatments in the future.
Atrial fibrillation affects more than 5 million people in the U.S. and millions more worldwide.
Current treatments focus on managing symptoms and preventing complications like blood clots, often relying on blood thinners or surgical procedures that interrupt faulty electrical signals in the heart.
However, these approaches do not address the root causes of AF at a molecular level. Researchers hope that by identifying the specific genes involved, they can develop targeted therapies to prevent or better treat the condition.
The first study, published in Nature Genetics, analyzed genetic data from more than 180,000 people with AF and nearly 1.5 million without the condition.
Researchers combined results from 68 different studies worldwide and identified over 350 common genetic variants associated with AF risk, doubling the number of previously known genetic markers. Many of these genes are involved in heart muscle contraction and communication, suggesting that AF is closely linked to how the heart’s muscle cells function.
The second study, also published in Nature Genetics, focused on rare genetic variations that might have a direct impact on AF risk. The research team examined whole-genome and whole-exome sequencing data from over 50,000 people with AF and more than 270,000 people without it.
They discovered previously unknown genetic mutations in several key genes, including MYBPC3, LMNA, PKP2, and KDM5B. These genes play a role in heart muscle function, and mutations in them may contribute to both AF and structural heart diseases known as cardiomyopathies.
Additionally, the researchers identified significant genetic changes in two other genes: CTNNA3, where deletions increased AF risk, and GATA4, where duplications (extra DNA copies) were linked to the condition. Some of these genes have already been associated with inherited heart diseases, showing a genetic link between AF and other heart abnormalities.
To further investigate how these genetic changes affect heart function, the scientists used gene-editing technology to “turn off” the KDM5B gene in lab-grown heart cells. The results showed that this gene plays a crucial role in electrical activity in the atrium, the upper chamber of the heart, where AF occurs.
These studies mark a major step forward in understanding the genetic basis of AF. The findings not only confirm previous knowledge but also introduce many new genetic regions that could be explored for future treatments.
Scientists are now conducting additional research to determine how these genetic variations impact heart disease risk and how they might be used to develop new drugs.
The research highlights the power of collaboration, with scientists from multiple institutions sharing data to achieve meaningful discoveries. “No single study is big enough to get meaningful results anymore,” said lead researcher Patrick Ellinor.
“By working together and sharing resources and data openly, we can achieve real progress towards improving care for patients.”
While more work is needed to translate these genetic insights into treatments, these studies provide hope that, in the future, AF may be treated not just with surgery or blood thinners, but with targeted therapies that address its root causes at a genetic level.
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The research findings can be found in Nature Genetics.
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