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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Genetic analysis in more than a million people has identified new risk loci for atrial fibrillation (AF), in the largest such study of cardiac arrhythmias to date.

A subsequently developed polygenic risk score (PRS) was able to predict an increased risk of stroke and death from cardiovascular disease among at-risk individuals.

Reporting their findings in Nature Genetics, the researchers note that the PRS offers the potential to risk stratify complex traits and diseases based on genetic data.

They believe their newly developed risk score could lay the foundations to realize precision medicine in AF.

“By applying our model to a person’s genome, we can find clinically undetectable heart arrhythmias or other related conditions,” said Kazuo Miyazawa, PhD, from RIKEN Center for Integrative Medical Sciences in Yokohama, Japan, in a press statement.

“This is critical as finding those at risk before they have a stroke is the goal for any risk-prediction analysis.”

Miyazawa and team performed a genome-wide association study in 9826 individuals with AF and 140,446 control participants included in Biobank Japan, one of the world’s largest disease biobanks.

This revealed five new, previously unreported risk loci for AF among 31 identified of genome-wide significance.

The researchers then conducted a cross-ancestry meta-analysis that included this Japanese study as well as two other European genome-wide association studies.

Collectively, they comprised 77,690 people with AF and 1,167,040 without the condition.

The meta-analysis revealed 33 new susceptibility loci for AF, including three from the first Japanese biobank study, making 35 newly reported loci in all.

A PRS developed and tested using the data revealed that the age at which AF first appeared decreased as score increased, with individuals scoring in the top one percent having an age of AF onset that was approximately four years earlier than others.

The risk score was also significantly associated with an increased risk of cerebral infarction and cardioembolic stroke, and cardiovascular mortality.

A transcriptome-wide association analysis revealed the possible involvement of the IL6R gene in AF, which implicated inflammatory signaling as a key pathway in the pathogenesis of the arrhythmia and a possible therapeutic target.

The team also found evidence implicating estrogen-related receptor gamma (ERRg)  as a transcription factor that bound to genetic loci associated with AF and orchestrated the expression of causative genes.

Further studies using human induced pluripotent stem cell-derived cardiomyocytes demonstrated that ERRg had a key role in the transcriptional regulation of genes associated with AF.

Reporting their findings, the researchers note: “Our study… demonstrated that, in addition to the predictive ability for AF itself, AF-PRS segregated individuals with AF-related phenotypes, such as early onset of AF and cardioembolic stroke, and those with increased risks of long-term cardiovascular and stroke mortalities.”

They add: “This indicated that the cumulative genetic risk for AF could be an indicator for early therapeutic intervention, including anticoagulation in at-risk individuals as a primary prevention of stroke.

“Taken together, our results have several implications for the clinical utility of AF-PRS, which will be clues for the realization of future precision medicine.”

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