The Genetic Basis of Novel Loci Influencing Myocardial Repolarization

影响心肌复极的新位点的遗传基础

• 批准号: 7708608
• 负责人: David J Milan
• 金额: $ 44.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708608
• 关键词: Action Potentials; Arrhythmia; Biology; Candidate Disease Gene; Cardiac; Cardiac Death; Cardiotoxicity; Catecholamines; Clinical; Complex; Drug Interactions; Drug Prescriptions; Electrocardiogram; Electrolytes; Electrophysiology (science); Environment; Environmental Exposure; Event; Exposure to; Gene-Modified; Genes; Genetic; Genetic Screening; Heritable Quantitative Trait; Human; Human Genetics; Hypokalemia; Ion Channel; Maps; Marketing; Measures; Modeling; Muscle Cells; Myocardial; Myocardial Ischemia; Neighborhoods; Optics; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological Processes; Play; Process; Proteins; Risk; Risk Assessment; Risk Factors; Rodent Model; Role; Sudden Death; Testing; Toxic effect; Translations; Variant; Withdrawal; Zebrafish; base; genome wide association study; heart rhythm; human disease; improved; insight; new therapeutic target; novel; population based; public health relevance; research study; response; sudden cardiac death; trait; voltage

DESCRIPTION (provided by applicant): Project Summary Cardiac repolarization, assessed in myocytes as action potential (AP) duration and on the electrocardiogram as the QT interval, requires the tightly regulated function of multiple ion channels and their accessory proteins. In the last decade, perturbations of repolarization have been directly implicated in the genesis of drug-induced arrhythmias and sudden cardiac death (SCD). While QT interval is a predictor of arrhythmias and sudden death, it is clear that a prolonged QT interval by itself is insufficient to cause such catastrophic events; additional environmental insults are usually required. There are several identified triggers including, myocardial ischemia, electrolyte imbalances (especially hypokalemia), and elevated catecholamine states, but perhaps the greatest environmental challenge to cardiac repolarization comes in the form of prescribed drugs. In the past decade, the single most common cause of the withdrawal or restriction of drugs that have already been marketed has been undesired QT prolongation. While the QT interval is a heritable quantitative trait, the genes that influence the QT interval as well as the response to QT prolonging drugs remain unknown. Common variants have long been thought to play a significant role in this complex trait and there are now several novel loci associated with QT interval through recent genome-wide association studies. Along with the power to identify novel loci, genome wide association studies do have limitations: they cannot distinguish which gene at a given locus is causal, nor do they reveal mechanistic insights. As we begin to unravel the discoveries of GWA studies, the first step will be to identify the functional gene(s) at each associated locus. We propose the use of a tractable zebrafish model that faithfully recapitulates key features of human myocardial repolarization. Using an approach that allows translation of human genetic discoveries into a tractable relevant model, we will test the hypothesis that gene knockdown in zebrafish will confirm candidate genes for each of five novel human repolarization loci. Once novel repolarization genes are identified, they will be tested for gene x drug interactions in our model. We propose the following specific aims: Aim 1: Validate candidate myocardial repolarization genes from five recently discovered novel genetic loci in a zebrafish model of cardiac repolarization. This will involve targeted knockdown of genes from these five loci and determination of effects on myocardial repolarization using optical voltage mapping. Aim 2: Quantitatively identify gene x drug interactions in myocardial repolarization. The most clinically important environmental exposures to myocardial repolarization are QT prolonging drugs. All 25 candidate repolarization genes will be tested for interactions in gene x drug experiments with QT prolonging drugs. PUBLIC HEALTH RELEVANCE: The QT interval on the electrocardiogram is a predictor of cardiac rhythm problems and sudden death, but the genes that govern this process remain largely unknown. Recently, large population-based studies have narrowed the search for these genes, identifying five genetic neighborhoods where these genes lie. We propose to use a zebrafish model to systematically knockdown the genes in these neighborhoods and measure the impact on the equivalent of the QT interval; we hope to conclusively identify the genes that modify the QT interval and achieve a better understanding of heart rhythm problems and sudden death.

描述（由申请人提供）：项目总结心脏复极化（在肌细胞中作为动作电位（AP）持续时间进行评估，在心电图中作为QT间期进行评估）需要多个离子通道及其辅助蛋白的严格调节功能。在过去的十年中，复极的扰动已直接涉及药物诱导的心律失常和心脏性猝死（SCD）的发生。虽然QT间期是心律失常和猝死的预测因子，但很明显，QT间期延长本身不足以导致此类灾难性事件;通常需要额外的环境损伤。有几个确定的触发因素，包括心肌缺血，电解质失衡（特别是低钾血症），和升高的儿茶酚胺状态，但也许最大的环境挑战心脏复极的形式是处方药。在过去十年中，停用或限制已上市药物的最常见原因是非预期QT间期延长。虽然QT间期是一种可遗传的数量性状，但影响QT间期的基因以及对QT延长药物的反应仍然未知。长期以来，人们一直认为常见的变异在这种复杂的性状中起着重要作用，通过最近的全基因组关联研究，现在有几个与QT间期相关的新基因座。沿着鉴定新基因座的能力，全基因组关联研究确实有局限性：它们不能区分给定基因座上的哪个基因是因果关系，也不能揭示机理性的见解。当我们开始解开GWA研究的发现时，第一步将是鉴定每个相关位点的功能基因。我们建议使用一个听话的斑马鱼模型，忠实地概括了人类心肌复极的关键特征。使用的方法，允许翻译人类遗传学的发现到一个易于处理的相关模型，我们将测试的假设，基因敲除斑马鱼将确认候选基因的五个新的人类复极位点。一旦发现新的复极基因，将在我们的模型中测试它们的基因x药物相互作用。我们提出了以下具体目标：目的1：从斑马鱼心脏复极模型中最近发现的五个新的基因位点中筛选候选心肌复极基因。这将涉及有针对性地敲除来自这五个位点的基因，并使用光学电压映射确定对心肌复极的影响。目的2：定量研究心肌复极过程中基因与药物的相互作用。临床上最重要的心肌复极环境暴露是QT延长药物。将在基因x药物实验中检测所有25个候选复极基因与QT延长药物的相互作用。 公共卫生相关性：心电图上的QT间期是心律问题和猝死的预测因子，但控制这一过程的基因在很大程度上仍然未知。最近，大量基于人群的研究缩小了对这些基因的搜索范围，确定了这些基因所在的五个遗传邻域。我们建议使用斑马鱼模型来系统地敲除这些邻域中的基因，并测量对QT间期等效值的影响;我们希望最终确定修改QT间期的基因，并更好地了解心律问题和猝死。