Atrial fibrillation and normal or abnormal heart rate rythm concept as a cardiac disorder as a human organ with healthy and unhealthy ecg monitoring in a 3D illustration style to illustrate sudden cardiac death
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Combining rare genetic variants for atrial fibrillation (AF) with a polygenic risk score flags up considerable risk for this common heart arrhythmia, research shows.

The findings in more than 400,000 people provide an insight into the genetics underpinning AF and could aid future genetic risk stratification.

They suggest both rare and common genetic variants should be assessed to prevent AF and determine its future risk.

The genetic association study, outlined in JAMA Cardiology, identified six rare genetic variants, which were predicted to cause loss of function.

They were associated with AF as well as its progression to more severe cardiac disease.

“Although population-wide genetic screening for rare variants is unlikely in the near future, integrating genetic perspectives may aid in AF risk stratification as sequencing becomes cheaper and more readily available,” reported researchers Morten Olesen, PhD, from Copenhagen University Hospital, and co-workers.

“Future studies focused on identifying patient or population groups that may benefit from genetic testing are warranted.”

Genetics plays an important role in determining the risk of AF, the team noted. Large genome-wide association studies have revealed part of the complex genetic component underlying this cardiac arrhythmia and identified associations with primarily common genetic variants.

However, it has not always been possible to pinpoint a specific causal gene based on the associated locus.

To investigate further, the team studied 403,990 U.K. residents of European ancestry enrolled in the UK Biobank, who were aged 40 to 69 years at inclusion and among whom 31,124 had a diagnosis of AF.

The median age of participants was 58 years and 54.1 percent were women.

Overall, 6677 individuals had an AF diagnosis at inclusion in the biobank and 24 ,447 individuals were diagnosed with AF during a median follow up of 13.3 years.

The investigators focused on rare predicted loss-of-function variants across 17, 979 genes.

AF was associated with rare genetic variants in six of these genes: TTNRPL3L, PKP2, CTNNA3, KDM5B, with odds ratios of between 1.56 and 2.79. Of these, only C10orf71 was not possible to replicate in another group.

When combined with high polygenic risk score, the rare genetic variants conferred an odds ratio of 7.08 for AF.

Carriers with a high polygenic risk score also had a substantial 10-year risk of AF of 16% in women and 24% in men older than 60 years.

The rare variants were also associated with heart failure and cardiomyopathy, and an elevated risk of cardiomyopathy following AF diagnosis.

Rare genetic variants were associated with a hazard ratio of 3.13 for cardiomyopathy prior to AF and 2.98 subsequent to AF.

The researchers said their findings indicated that, for some variant carriers, AF may be the first disease manifestation preceding more severe cardiac disease.

“A deeper understanding of genetic causes of AF in the general population may elucidate novel targets for therapeutics and explore the potential of future genetic risk stratification,” they maintained.

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