Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.
Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.
Cells. 2023 Dec 19;13(1):4. doi: 10.3390/cells13010004.
Genetic predisposition to cardiac arrhythmias has been a field of intense investigation. Research initially focused on rare hereditary arrhythmias, but over the last two decades, the role of genetic variation (single nucleotide polymorphisms) in heart rate, rhythm, and arrhythmias has been taken into consideration as well. In particular, genome-wide association studies have identified hundreds of genomic loci associated with quantitative electrocardiographic traits, atrial fibrillation, and less common arrhythmias such as Brugada syndrome. A significant number of associated variants have been found to systematically localize in non-coding regulatory elements that control the tissue-specific and temporal transcription of genes encoding transcription factors, ion channels, and other proteins. However, the identification of causal variants and the mechanism underlying their impact on phenotype has proven difficult due to the complex tissue-specific, time-resolved, condition-dependent, and combinatorial function of regulatory elements, as well as their modest conservation across different model species. In this review, we discuss research efforts aimed at identifying and characterizing-trait-associated variant regulatory elements and the molecular mechanisms underlying their impact on heart rate or rhythm.
遗传性心律失常易感性一直是研究的热点。最初的研究集中在罕见的遗传性心律失常上，但在过去的二十年中，人们也开始考虑遗传变异（单核苷酸多态性）在心率、节律和心律失常中的作用。特别是，全基因组关联研究已经确定了数百个与定量心电图特征、心房颤动以及不那么常见的心律失常（如 Brugada 综合征）相关的基因组位点。大量相关的变异已被发现系统地定位于非编码调控元件中，这些元件控制着编码转录因子、离子通道和其他蛋白质的基因的组织特异性和时间转录。然而，由于调控元件的组织特异性、时间分辨、条件依赖性和组合功能复杂，以及它们在不同模式物种之间的适度保守性，鉴定因果变异及其对表型影响的机制一直很困难。在这篇综述中，我们讨论了旨在鉴定和描述与性状相关的变异调控元件及其对心率或节律影响的分子机制的研究进展。
