荷兰阿姆斯特丹大学Connie R. Bezzina、法国南特大学Julien Barc等研究人员合作发现新的布鲁加达综合征风险位点，并强调了疾病易感性中钠通道调节的新机制。相关论文于2022年2月24日在线发表于国际学术期刊《自然—遗传学》。

研究人员进行了一项全基因组关联荟萃分析，包括2,820例无血缘关系的布鲁加达综合征（BrS）患者和10,001例对照组，并在12个位点上发现了21个关联信号（10个新的）。单核苷酸多态性（SNP）-遗传性估计表明有强烈的多基因影响。基于21个易感变体的多基因风险评分分析表明，在不同的患者亚群中，共同的风险等位基因的累积贡献各不相同，而且与一般人群中的心电特征和疾病有遗传关联。

心脏转录因子位点的优势表明，转录调节是BrS发病机制的一个关键特征。此外，对编码微管加端结合蛋白EB2的MAPRE2进行的功能研究指出，与微管相关的贩运对NaV1.5表达的影响是一个新的分子机制。总之，这些发现扩大了人们对BrS遗传结构的理解，并对其分子基础提供了新的见解。

据介绍，BrS是一种与年轻成年人猝死有关的心律失常疾病。除了编码心脏钠离子通道NaV1.5的SCN5A外，易感基因在很大程度上仍是未知的。

附：英文原文

Title: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author: Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuo, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphal P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurlie, Kyndt, Florence, Mazzanti, Andrea, Clmenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Nol, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., kori-Milosavljevi, Doris, Bikker, Hennie, Manevy, Federico C., Lichtner, Peter, Ribass, Marta, Meitinger, Thomas, Mller-Nurasyid, Martina

Issue&Volume: 2022-02-24

Abstract: Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism.

DOI: 10.1038/s41588-021-01007-6

Source: https://www.nature.com/articles/s41588-021-01007-6