Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome is a rare cardiac rhythm disorder with a high risk of sudden cardiac death (SCD) in young adults and may account for 4 to 12% of the overall SCD. The diagnosis is based on specific  features on the electrocardiogram. Currently, only the implantation of a defibrillator has been shown to prevent severe arrhythmias and SCD. In 20% of these patients, genetic research has identified rare mutations in the SCN5A gene, which plays a central role in the electrical activity of the heart, crucial for the synchronization of heart contraction. However, the identification of these mutations is only a partial explanation for the occurrence of Brugada Syndrome. A large variability of the severity of the disease is observed among family members carrying the same mutation and the onset of the disease is also variable among individuals with the same mutation suggesting the involvement of additional (genetic) factors.

In order to better understand the complexity of this disease and to work on the prevention of the risk of rhythm disorders or sudden cardiac death, researchers explored the potential role of genetic variations frequently found in the general population that may play a modulator role? Initial results were obtained in 2013 in a pilot study* of about 300 Brugada patients. Three frequent variants in the general population that increase the susceptibility to develop Brugada Syndrome had then been discovered.

In this new study, we expanded the Brugada patient population to nearly 3,000 patients from 39 international centers. We identified 21 genetic variations relatively frequent in the general population and considerably increasing the risk of developing Brugada Syndrome when they come together (and accumulate) in the same individual. The combinatorial and preponderant role of these frequent variations in Brugada Syndrome thus reveals genetic bases much more complex than those described so far. These 21 frequent genetic variations affect the expression of surrounding genes. Among them, the researchers identified eight genes involved in cardiac development and electrical activity while three genes impact the organization of cardiac cells. This discovery opens up new avenues for understanding the biological mechanisms behind sudden cardiac death, which most often occurs in adulthood without warning signs and develop personalized medicine.

Interestingly, researchers also showed that these frequent variations were associated with other – much more frequent – heart diseases. For example, they increase the risk of developing conduction disorders, whereas they are conversely protective against atrial fibrillation (the most frequent cardiac arrhythmia in the population). These results underline the relevance of Brugada syndrome, a rare disease, as a model to study more complex diseases. The discovery of these new molecular bases opens also new avenues for therapeutic research.


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Translated by Julien Barc, CHU Nantes, Nantes, France

* Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Bezzina CR*, Barc J*, Mizusawa Y*, Remme CA*, Gourraud JB*, //, Wilde AA*, Probst V*, Schott JJ*, Dina C*, Redon R*. Nat Genet. 2013 Sep;45(9):1044-9.