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.

心脏复极，在肌细胞中被评估为动作电位（AP）持续时间，在心电图上被评估为QT间期，需要多个离子通道及其附属蛋白的功能严格调节。在过去的十年中，复极的扰动直接涉及药物性心律失常和心源性猝死（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，延长QT间期本身不足以引起此类灾难性事件；通常需要额外的环境损害。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）和儿茶酚胺状态升高，但也许对心脏复极最大的环境挑战来自处方药的形式。在过去的十年中，停药或限制已上市药物的最常见原因是不希望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延长药物的反应尚不清楚。长期以来，人们一直认为常见变异在这一复杂性状中起着重要作用，通过最近的全基因组关联研究，现在有几个新的位点与QT间期相关。除了识别新基因座的能力之外，全基因组关联研究也有局限性：它们不能区分给定基因座上的哪个基因是因果关系，也不能揭示机制见解。当我们开始揭示GWA研究的发现时，第一步将是确定每个相关位点的功能基因。我们建议使用一种易于处理的斑马鱼模型，忠实地概括了人类心肌复极的关键特征。使用一种允许将人类基因发现转化为可处理的相关模型的方法，我们将测试斑马鱼基因敲低将确认五个新的人类复极化位点中的每个候选基因的假设。一旦新的复极基因被确定，它们将在我们的模型中进行基因x药物相互作用的测试。我们提出以下具体目标：目的1：在斑马鱼心脏再极化模型中验证最近发现的五个新基因位点的候选心肌再极化基因。这将涉及靶向敲除这五个基因座的基因，并利用光学电压作图确定对心肌复极化的影响。目的2：定量鉴定基因x药物在心肌复极中的相互作用。临床上最重要的心肌复极环境暴露是QT延长药物。所有25个候选复极基因将在基因x药物实验中与QT延长药物进行相互作用测试。