Genetic variants strongly affect risk of atrial fibrillation

One in three adults in Denmark is expected to develop atrial fibrillation – an irregular heartbeat that can increase the risk of other heart conditions such as stroke and heart failure – during their lifetime.

Research published in June in JAMA Cardiology identifies new genetic variants associated with atrial fibrillation and finds that they elevate the chances of developing it more dramatically than lifestyle factors.

“This is a really great breakthrough in understanding what causes atrial fibrillation and heart disease,” says co-author Morten Olesen, a geneticist at the University of Copenhagen.

What is atrial fibrillation?

Atrial fibrillation is a kind of arrythmia – “an electrical disturbance in the heart that makes the heart pump less efficiently,” Olesen explains.

Specifically, atrial fibrillation makes the upper chambers of the heart pump faster and more erratically. Untreated, this increased stress on the heart can increase the risk of heart failure or stroke.

To help ward off these dire outcomes, many people diagnosed with atrial fibrillation need to take an anticoagulant medicine for the rest of their lives. The cumulative cost adds up. “Denmark’s public health system spends 1% of all health money on atrial fibrillation,” Olesen says.

Although lifestyle factors such as high blood pressure and elevated body-mass index contribute to the risk of developing atrial fibrillation, researchers like Olesen have begun to suspect that genetic typos called loss-of-function variants could cause early-onset atrial fibrillation before other stress factors have time to accumulate.

Many genes act as instruction manuals for building proteins, the functional units of the cell. Loss of function occurs when a random mutation to a gene, often affecting a single nucleotide, changes the structure of the resulting protein so radically that it cannot assume its normal role in the body.

“That is, for instance, a stop codon” – a genetic sequence that signals to the machinery of the cell that the protein it is building is complete – “before we expect the protein to end,” Olesen says. “This can lead to a truncated protein.”

Most visionary

To hunt down these tiny errors in the genetic code, Olesen and colleagues need access to an usually large store of DNA.

They found their answer in the UK Biobank, a long-running project that collected extensive biometric data, biological samples and genetic information from 500,000 United Kingdom residents in the early 2000s. Crucially for Olesen’s research, the UK Biobank also tracked later developments in the participants’ health records – including diagnoses of heart conditions.

Olesen says that overstating the scientific value of the UK Biobank is difficult. “It is one of the most visionary projects in the world,” he says. The UK Biobank has sequenced the full exome –all the regions of DNA that code for protein – of 400,000 participants, giving researchers access to more genetic data than they would otherwise be able to afford.

“Usually we pay DKK 5,000 to sequence a single exome – 400,000 of those would be quite expensive,” Olesen explains.

Olesen and colleagues combed “gene by gene” through the genetic sequences of the approximately 31,000 participants who developed atrial fibrillation and the 370,000 participants who did not.

New markers with a big impact

Olesen and his team identified six potential loss-of-function variants associated with atrial fibrillation, including three that had not previously been documented. Most of the genes affected appear to be related to cardiomyocytes: cardiac muscle cells. The variants were rare, Olesen emphasises – about 5,000 people, 1.3% of the people with atrial fibrillation in the UK Biobank cohort, carried at least one of these variants.

The researchers found that these variants powerfully affect the likelihood of developing the arrythmia. Just one variant “is actually worse than having both hypertension and a high body-mass index in affecting your risk of getting atrial fibrillation,” Olesen explains.

For example, “if you have a loss-of-function variant in the TTN gene, then your risk of getting atrial fibrillation is three times higher than a person without the variant,” he says.

The participants’ other diagnoses revealed another wrinkle to the story. People with one of the loss-of-function variants were more likely to develop serious heart conditions than other people with atrial fibrillation. This includes heart failure and cardiomyopathy, in which the muscles of the heart become stiff or thick.

However, Olesen emphasises that, although the genetic variants more than triple the risk of developing cardiomyopathy, the overall risk remains quite low. “The risk for cardiomyopathy is greatly increased for young people, but in terms of absolute risk, the numbers are still small,” he says.

Genetic screening could help to prevent heart disease

Olesen says that future studies should examine other populations. The UK Biobank cohort only includes people of European ancestry, and different variants could be present elsewhere in the world.

Nevertheless, these findings suggest that healthcare providers referring people diagnosed with atrial fibrillation for genetic screening at an “early age” – perhaps before 45 or 50 years old – could be beneficial, he says.

If a loss-of-function variant associated with atrial fibrillation is flagged, healthcare providers could implement regular tests to check for a dilated heart or other signs of heart failure.

Knowing that a person has an increased risk of developing cardiomyopathy and heart failure could encourage healthcare providers to more proactively treat high blood pressure and other sources of stress on the heart, Olesen says.

And for people with multiple risk factors including a loss-of-function variant, “it might be a good idea to be very aggressive and make sure that they do not walk around with the atrial fibrillation” at all, Olesen says. This includes more invasive treatments such as ablation, in which the muscle around the veins that lead into the atrium of the heart is surgically burned.

“Atrial fibrillation might be a first symptom of something really bad, and identifying it early might avoid these complications,” Olesen says.