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    • Rare-variant Collapsing and Bioinformatic Analyses for Different Types of Cardiac Arrhythmias in the UK Biobank Reveal Novel Susceptibility Loci and Candidate Amyloid-Forming Proteins

    Bengt Zoller,Eric Manderstedt,Christina Lind-Hallden,Christer Hallden

    Cardiovascular Digital Health Journal（2023）

    Skane Univ Hosp

    Cited 1|Views7
    Abstract
    Background:Cardiac arrhythmias are a common health problem. Both common and rare genetic risk factors exist for cardiac arrhythmias. Cardiac amyloidosis is a rare disease that may manifest various arrhythmias. Few large-scale whole exome sequencing studies elucidating the contribution of rare variations to arrhythmias have been published.Objective:To access gene collapsing analysis of rare variations for different types of cardiac arrhythmias in UK Biobank. Identified genes were analyzed in silico for probability to form amyloid fibrils.Methods:We used 2 published UK Biobank portals (https://azphewas.com/ and https://app.genebass.org/) to access gene collapsing analysis of rare variations for different types of cardiac arrhythmias. Diagnosis of arrhythmia was based on the International Classification of Diseases, 10th Revision (ICD-10) codes: conduction disorders (I44, I45), paroxysmal tachycardia (I47), atrial fibrillation (I48), and other arrhythmias (I49).Results:Rare variations in 5 genes were linked to conduction disorders (SCN5A, LMNA, SMAD6, HSPB9, TMEM95). The TTN gene was associated with both paroxysmal tachycardia and other arrhythmias. Atrial fibrillation was associated with rare variations in 8 genes (TTN, RPL3L, KLF1, TET2, NME3, KDM5B, PKP2, PMVK). Two of the genes linked to heart conduction disorders were potential amyloid-forming proteins (HSPB9, TMEM95), while none of the 8 genes linked to other types of arrhythmias were potential amyloid-forming proteins.Conclusion:Rare variations in 13 genes were associated with arrhythmias in the UK Biobank. Two of the heart conduction disorder-linked genes are potential amyloid-forming candidates. Amyloid formation may be an underestimated cause of heart conduction disorders.
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    Epidemiology,Genetics,Mutation,Arrhythmias,Cardiac
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    【要点】：该研究通过在英国生物银行中进行稀有变异基因坍缩分析，发现了与不同类型的心律失常相关的13个基因，并识别出两个可能与淀粉样形成相关的基因，提出了淀粉样形成可能是心脏传导障碍被低估的原因。
    

    【方法】：研究者利用两个已发表的英国生物银行门户网站进行稀有变异基因的坍缩分析，并根据国际疾病分类第十版（ICD-10）代码对心律失常进行诊断。
    

    【实验】：通过分析英国生物银行数据，发现与传导障碍相关的5个基因（SCN5A、LMNA、SMAD6、HSPB9、TMEM95），与阵发性心动过速和其他心律失常相关的TTN基因，以及与心房颤动相关的8个基因（TTN、RPL3L、KLF1、TET2、NME3、KDM5B、PKP2、PMVK）。其中，HSPB9和TMEM95两个与心脏传导障碍相关的基因可能是淀粉样形成蛋白。