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Celera Researchers Investigating Genetic Risk Signature to Predict Atrial Fibrillation

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Originally published April 15.

Researchers from Celera, working with a Swedish team from the Malmö Diet and Cancer study, have shown that a multi-gene signature could help doctors identify individuals at higher risk of developing atrial fibrillation (AF) in order to better guide treatment and other preventive interventions.

Dov Shiffman, a scientific fellow in Celera's discovery research group, presented the data in a poster at the annual meeting of the American College of Cardiology last month. In the study, the Celera team genotyped patients from the Malmö Diet and Cancer Study, a longitudinal study of middle-aged men and women from southern Sweden, using a set of SNPs previously associated with AF. The group then evaluated whether genotype could predict which patients were at higher or lower risk of developing the abnormal heart rhythm.

Based on the data, the group found that if patients were divided into five groups based on the 12-SNP risk score, the top 20 percent had a two-fold greater risk of atrial fibrillation than those in the bottom quintile, even after adjustment for traditional risk factors such as hypertension, smoking, heart failure, or cardiovascular disease. The top quintile also had 23 percent greater risk of ischemic stroke than those in the lowest group.

Shiffman told PGx Reporter in an email that a test based on the team's gene signature could potentially "fill an unmet need" to identify individuals at elevated risk for AF, a condition that is often asymptomatic, but for which there are "clear actions a patient can undertake to reduce their risk."

"The [genetic risk score] would help identify those at the greatest genetic risk for AF, and who therefore should be particularly motivated to adhere to medications and lifestyle changes that are appropriate to treat modifiable risk factors. [The panel could] also help identify patients at risk for recurrent AF post-ablation or post-coronary artery bypass grafting," he added.

According to Shiffman, other studies have also found individual SNPs and multi-gene signatures can predict AF risk — including research from the Women’s Health Study published in the European Heart Journal in 2013 and another international study published in the Journal of the American College of Cardiology this month — but it hasn't necessarily been clear that this predictive power is independent of other clinical factors like hypertension. The Celera group hoped to demonstrate with its study that genetic factors could predict AF beyond such traditional risk factors.

In the Celera/Malmö study, the researchers used Cox proportional hazards models to assess the association of a 12-SNP score with the development of atrial fibrillation in 27,471 subjects of the Malmö cohort. The genes were chosen from previous genome-wide association research that linked them individually to AF, Shiffman explained.

During a median 14.4 years follow-up, 2,160 subjects from the larger Malmö cohort developed a first incident of AF. The gene score was able to identify 20 percent of the cohort who were at roughly double the risk of AF and 23 percent higher risk of ischemic stroke than those with the lowest risk.

In addition to showing an association with AF independent of hypertension and other factors, the Celera team also found that its gene signature predicted AF with the same magnitude as hypertension, which is itself considered a clinically important risk factor for the heart rhythm disorder.

In other words, patients with a high genetic risk but normal blood pressure had the same increase in their AF risk as did those with a low genetic risk but high blood pressure.

If the group can validate that the genetic risk score remains equally predictive as hypertension, Shiffman said at the conference, one could argue it would make just as much sense for clinicians to consider patients' genetic status as their blood pressure when deciding how to treat and advise them on potential preventive measures.

Shiffman said in his email that Celera "might consider" developing a commercial atrial fibrillation risk test based on the group's data.

At the conference, he said that though the results are only preliminary, the predictive ability of the SNP set suggests it could prove itself to be clinically useful, especially considering that genotype appeared to be equally as predictive as blood pressure, which clinicians already utilize as a standard part of AF risk assessment.

According to Shiffman, the Celera team is planning to further validate and investigate the signature, particularly in patients who have been treated for atrial fibrillation using ablation, or who have had a coronary artery bypass, to see if it could also predict recurrent or resultant AF in these patients.

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