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Gene Identified for Atrial Fibrillation

By analyzing data from multiple genome-wide association studies (GWAS), scientists have identified common variants in the KCNN3 gene that are associated with a form of irregular heartbeat known as “lone atrial fibrillation” (lone AF). This is a type of AF seen in younger individuals with no other signs of heart disease. The finding may open the way to the development of innovative treatments not only for lone AF in specific, but for AF in general. The KCNN3 gene, located on chromosome 1, codes for a potassium channel protein that carries signals across cell membranes in organs including the brain and the heart. While the exact cardiac role of the protein is unknown, it may play a part in resetting the electrical activity of the atria, a process that goes awry in AF. Animal studies have suggested that a related protein, KCNN2, may help control signals originating in the atria and in the pulmonary veins, areas known to be involved in lone AF. The researchers replicated the association of KCNN3 variants with lone AF in data from two additional GWAS involving another 1,000 lone AF patients and 3,500 controls. "The genetic location we have identified could be a new drug target for the treatment of AF," said cardiologist Dr. Patrick Ellinor of the Massachusetts General Hospital Cardiovascular Research Center and Cardiac Arrhythmia Service and an assistant professor of medicine at Harvard Medical School, the first author of the report. "We also will be investigating whether these variants can help us predict patients' clinical outcomes or their response to the various treatments for AF."

AF is a chronic irregularity of heartbeat that affects more than 2.2 million people in the United States and an estimated 600 million people worldwide. Although the condition is not acutely life-threatening, it does increase the risk of developing more serious illnesses, such as cardiac insufficiency, stroke, and dementia.

In AF, the upper chambers of the heart, called the atria, beat in a rapid and uncoordinated fashion, which can cause blood to pool within the heart. If blood clots form within the heart, they can break loose, travel to the brain, and cause a stroke.

While AF is most commonly seen in older individuals with hypertension, heart failure, or other forms of heart disease, about 10 percent of AF patients begin having symptoms when they are younger and have no other known cardiovascular disease, a condition called lone AF.

Patients with lone AF are more likely to have overt symptoms and to require treatment, which includes the use of blood-thinning drugs to prevent clots and other medications that slow heart rhythm. If AF persists, procedures such as minimally invasive catheter ablation can inactivate the regions of the heart that trigger the arrhythmia.

Dr. Ellinor and his colleagues noted that additional study is required to clarify exactly how variations in KCNN3 and associated genes may affect the risk for lone AF, to determine whether these and other gene variants can predict how a patient's symptoms will progress, and to investigate their usefulness as treatment targets.

"Our results improve our understanding of the pathophysiological mechanisms that contribute to the manifestation of atrial fibrillation," said Dr. Stefan Kääb, senior author of the study. "We also hope that in the longer term, they will allow us to predict individual levels of risk."

This work was published online on February 21, 2010 in Nature Genetics. [Press release 1] [Press release 2] [Nature Genetics abstract]