Despite the widespread nature of atrial fibrillation, our understanding of the disease remains limited, according to Patrick T Ellinor, director Cardiac Step Down Unit, Massachusetts General Hospital Corrigan Minehan Heart Centre (Boston, USA) and associate professor, Harvard Medical School. He spoke to Cardiac Rhythm News about current research on genetics of atrial fibrillation.
What led you to study the genetics of atrial fibrillation?
We all know that atrial fibrillation is the most common arrhythmia affecting nearly three million Americans, and that it is associated with an increased risk of stroke, heart failure, dementia and death. Our treatment options, including anticoagulation, antiarrhythmic therapy, and ablation procedures, have variable success and can be associated with side effects or complications. Yet despite the profound socio-economic impact of atrial fibrillation, we still have a relatively limited understanding of the molecular pathways leading to the arrhythmia.
When I was an electrophysiology fellow I noticed that many patients with early-onset atrial fibrillation had a family history of the disease which at times was quite pronounced. Given this disconnect between morbidity of atrial fibrillation and our understanding of its biology, I found it intriguing to use genetics as a potential window into the mechanisms of atrial fibrillation.
Atrial fibrillation is not typically thought of as heritable-is it really as a genetic condition?
Simply put, yes. In individuals of European descent, studies have been remarkably consistent in demonstrating an increased risk of atrial fibrillation among those with affected family members. If you have a parent with atrial fibrillation, then your own risk for atrial fibrillation doubles. With two affected parents, your risk triples. Furthermore, the younger someone in your family develops atrial fibrillation, the greater your own risk for developing the disease.
Interestingly, despite on average having a higher burden of risk factors for atrial fibrillation, its prevalence in African-Americans is about half that in Europeans, pointing towards a different genetic predisposition to this condition.
What have we learned from families with atrial fibrillation?
Large families with atrial fibrillation are rare, but can be an invaluable resource when a specific genetic cause is identified. To date, mutations in over 20 genes have been reported in individuals and families with atrial fibrillation. However, in total these genes appear to be specific to a given individual or family, accounting for only a fraction of the disease. Unlike long QT syndrome, in which greater than 60% of the disease can be traced to just three genes, atrial fibrillation is more complex. Given that atrial fibrillation was strongly heritable, yet we were not able to identify the genetic basis of atrial fibrillation using families, about six years ago we turned to population genetics, or genome wide association studies, to help identify atrial fibrillation-related genes.
What are genome wide association studies and what have they taught us about atrial fibrillation?
In recent years, we have used large populations with and without atrial fibrillation to identify common genetic variants associated with the arrhythmia. Last year, we studied over 6,000 individuals with atrial fibrillation and 50,000 without. By examining common variants throughout the genome, we have identified nine genetic regions that were strongly associated with atrial fibrillation. The genes identified include a number of transcription factors, some of which have been implicated in atrial or pulmonary vein development. Other implicated genes include ion channels, signaling molecules, and sarcomeric proteins. The advantage of using this approach is that we have been able to find a new series of atrial fibrillation-related genes that had not previously been considered.
Where are we headed?
I think that the two most exciting lines of research in my laboratory currently are the study of the newly identified genes for atrial fibrillation in model systems, and determining whether these genetic variants will have a role in patient care. Our lab and others are studying these genes in cell lines and in animal models to learn more about how they are related to each other and ultimately predispose to atrial fibrillation. With a greater understanding of the molecular basis for atrial fibrillation, a long-term goal will be to design novel therapeutics more specifically directed at the pathways leading to atrial fibrillation.
I also find it fascinating that we can use a handful of genetic markers to identify individuals at high and low risk for atrial fibrillation. We are currently exploring whether these genetic variants will help to determine whether someone has an increased or decreased likelihood of response to a specific treatment such as a medication, cardioversion or ablation. It will also be interesting to see if we can identify those at greater or lesser risk from the sequelae of atrial fibrillation including stroke and heart failure.
