Original paper:Miyazawa K, Ito K, Ito M, Zou Z, Kubota M, Nomura S, Matsunaga H, Koyama S, Ieki H, Akiyama M, Koike Y, Kurosawa R, Yoshida H, Ozaki K, Onouchi Y, BioBank Japan Project, Takahashi A, Matsuda K, Murakami Y, Aburatani H, Kubo M, Momozawa Y, Terao C, Oki S, 4AF-PRS may be one of the effective tools for•Early detection of the disease (without clinical risk factors)•Prediction of disease prognosis•Prediction of cerebral embolisms (without AF diagnosis)Can be calculated at any ageAkazawa H, Kamatani Y, Komuro I. Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction. Nat Genet 55, 187-197 (2023)InexpensiveCalculate once and use foreverResearchers at IMS have developed a polygenic risk score to predict atrial fibrillation onset and progno-sis – paving the way for personalised treatment of the disease.Japan’s aging population is creating a pressing need to study and develop strategies to mitigate the growing risk of disease. One condition that becomes more prevalent with age is atrial fibrillation, which is characterized by an ir-regular and often fast heartbeat that can increase the likeli-hood of further cardiovascular problems such as stroke.“Prevention and prediction of atrial fibrillation are im-portant to keep aged people healthy,” said Kaoru Ito, Team Leader of the Laboratory for Cardiovascular Genomics and Informatics at IMS. “Our goal is to combine clinical and genomic information to realise precision medicine for atrial fibrillation.”However, because it is impossible to understand the mechanism of a disease by simply studying the genome, Ito and his team sought to achieve their goal through a multi-omics approach that combined genome-wide association studies (GWAS) with gene expression and transcription factor analyses.In their study published in Nature Genetics, the re-searchers conducted the largest cross-ancestry meta-GWAS to date of more than 1 million individuals from Japan and Europe. In the process, they uncovered 150 significant loci – the largest number of atrial fibrillation-associated loci to ever be identified.When the team integrated these genomic results with gene expression and transcription factor analyses, they un-covered two novel genes associated with atrial fibrillation. Discovery of the first, a commonly known inflammatory gene called IL-6R, confirmed for the first time that inflam-matory factors play a role in the disease. The second gene was a transcription factor called ERRg, which, Ito notes, was a surprising finding.“I didn’t imagine there was another important tran-scription factor to be discovered for atrial fibrillation,” he remarked, adding that through cell culture experiments, the team confirmed that ERRg indeed regulates genes that control vital functions that are disrupted in the disease.The researchers went on to demonstrate the clinical utility of their large cross-ancestry meta-GWAS findings by developing a tool that measures a patient’s cumulative genetic risk of atrial fibrillation, called the atrial fibrillation polygenic risk score (AF-PRS). While other PRS have been developed in the past, those versions were only used to predict disease before onset.For the first time, Ito and his team showed that their AF-PRS can predict disease prognosis in patients already diagnosed with atrial fibrillation, including their risk of cardiovascular and stroke death. The AF-PRS also accu-rately predicted the risk of cardioembolic stroke in people without a diagnosis of atrial fibrillation, possibly pointing to an increased risk of the disease or other related condi-tions in those individuals.The AF-PRS, which can be calculated in anyone at any age, is inexpensive to perform, and applicable through-out a patient’s lifetime, could help physicians personalise treatments for patients. However, Ito notes that the AF-PRS is not yet clinic-ready because it was developed based on retrospective data. The team is currently working with a number of collaborators to evaluate the AF-PRS under prospective settings to confirm its clinical utility.Figure: An atrial fibrillation polygenic risk score (AF-PRS) could help physicians personalise treat-ments for patients with atrial fibrillationAn AF-PRS derived from the largest cross-ancestry meta-genome-wide association study (GWAS) to date can predict atrial fibrillation onset and prognosis. Its many advantages make it an appealing tool for realising preci-sion medicine for patients.Kaoru ItoPredicting atrial fibrillation with genetics
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