美国麻省总医院Steven A. Lubitz小组报道了，常见和罕见基因变异对慢性心律失常发展的影响。这一研究成果于2025年1月2日发表在国际顶尖学术期刊《自然—遗传学》上。

为了深入了解缓慢性心律失常和传导疾病，课题组在高达130万人中进行了常见变异的全基因组关联分析，并在46万人中进行了稀有变异负担测试，研究了窦房结功能障碍（SND）、远端传导病（DCD）和起搏器植入（PM）的相关性。课题组人员分别鉴定出SND、DCD和PM的13个、31个和21个共同变异位点。

他们已知的位点（SCN5A/SCN10A, CCDC141， TBX20和CAMK2D）是SND和DCD共有的，而其他位点则是SND或DCD的特异性位点。SND与DCD呈中等遗传相关（r_g = 0.63）。心肌细胞表达的基因在远端传导病（DCD）的遗传力中占有重要贡献。

罕见变异分析表明，LMNA与所有慢性心律失常表型相关，SMAD6和SCN5A与DCD相关，TTN，MYBPC3和SCN5A与PM相关。这些结果表明，多种遗传途径的变异（例如，离子通道功能、心脏发育程序、肌肉结构和细胞稳态）似乎对慢速心律失常的发展至关重要。

附：英文原文

Title: The impact of common and rare genetic variants on bradyarrhythmia development

Author: Weng, Lu-Chen, Rm, Joel T., Jurgens, Sean J., Khurshid, Shaan, Chaffin, Mark, Hall, Amelia Weber, Morrill, Valerie N., Wang, Xin, Nauffal, Victor, Sun, Yan V., Beer, Dominik, Lee, Simon, Nadkarni, Girish N., Duong, ThuyVy, Wang, Biqi, Czuba, Tomasz, Austin, Thomas R., Yoneda, Zachary T., Friedman, Daniel J., Clayton, Anne, Hyman, Matthew C., Judy, Renae L., Skanes, Allan C., Orland, Kate M., Treu, Timothy M., Oetjens, Matthew T., Alonso, Alvaro, Soliman, Elsayed Z., Lin, Honghuang, Lunetta, Kathryn L., van der Pals, Jesper, Issa, Tariq Z., Nafissi, Navid A., May, Heidi T., Leong-Sit, Peter, Roselli, Carolina, Choi, Seung Hoan, Khan, Habib R., Knight, Stacey, Karlsson Linnr, Richard, Bezzina, Connie R., Ripatti, Samuli, Heckbert, Susan R., Gaziano, J. Michael, Loos, Ruth J. F., Psaty, Bruce M., Smith, J. Gustav, Benjamin, Emelia J., Arking, Dan E., Rader, Daniel J., Shah, Svati H., Roden, Dan M., Damrauer, Scott M., Eckhardt, Lee L., Roberts, Jason D., Cutler, Michael J., Shoemaker, M. Benjamin, Haggerty, Christopher M., Cho, Kelly, Palotie, Aarno

Issue&Volume: 2025-01-02

Abstract: To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg=0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

DOI: 10.1038/s41588-024-01978-2

Source: https://www.nature.com/articles/s41588-024-01978-2