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Deciphering the genetic mechanisms of atrial fibrillation

破译房颤的遗传机制

基本信息

批准号：
9981002
负责人：
Dawood Darbar
金额：
$ 65.52万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981002
关键词：
Address Adverse drug effect Affect African American Alleles American Arrhythmia Atrial Fibrillation Benign Bioinformatics Biological Biological Assay Calcium Channel Candidate Disease Gene Cardiac Cardiovascular Diseases Cardiovascular system Cessation of life Clinical Code Complex DNA Data Databases Dementia Development Developmental Gene Diabetes Mellitus Disease Drug Controls Elderly Electrophysiology (science)Enrollment Epidemic Ethnic Origin Etiology European Failure Familial atrial fibrillation Family Family history of Family member Frequencies Functional disorder Genes Genetic Genetic Polymorphism Genotype Goals Handedness Heart Atrium Heart Diseases Heart failure Hispanics Hypertension In Vitro Incidence Individual Investigation Ion Channel Knowledge Latino Link Long QT Syndrome Malignant Neoplasms Morbidity - disease rate Mutation Myocardial Infarction Nodal Outcome Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Population Predisposition Prevalence Public Health Publishing Registries Risk Risk Factors Role Signaling Molecule Sinus Therapeutic Toxic effect Trans-Omics for Precision Medicine Untranslated RNA Variant Ventricular Vision Work Zebrafish base cohort early onset effective therapy ethnic diversity exome sequencing genetic architecture genetic linkage analysis genetic variant genome sequencing human disease in vivo insight kindred member mortality next generation sequencing non-genetic novel novel therapeutic intervention positional cloning prevent proband randomized trial rare variant risk variant screening segregation stem stroke risk success targeted treatment treatment strategy whole genome

项目摘要

Atrial fibrillation (AF) is an important and increasing public health problem. Most cases occur in the elderly and so the incidence of the problem is rising; the number of Americans affected with AF is expected to surge to ~16 million by 2050. Other clinical features include hypertension and underlying heart disease while many relatively young patients have no apparent risk factors and are designated as “lone” or early-onset AF (EOAF). The AF epidemic is further complicated by the lack of effective therapies. The limited success of treatments stems in part from an incomplete understanding of the pathophysiology of AF and failure to target therapy to the underlying mechanisms. Traditionally, AF was considered to be a sporadic, non-genetic disorder but we and others have shown that EOAF has a substantial genetic basis. Positional cloning and candidate gene approaches have linked mutations in cardiac ion channels, and signaling molecules with EOAF. While these studies have provided important insights into underlying mechanisms, most of the rare variation in susceptibility to EOAF remains unknown. Given recent advances in next generation sequencing (NGS), discovery of novel genes in other cardiovascular phenotypes and our preliminary data, the overarching goal of this proposal is to use NGS to identify novel AF genes and decipher the underlying genetic mechanisms of EOAF. Our clinical-DNA registries have systematically enrolled over 60 families from diverse ethnic background with early-onset familial AF. We propose to use this large and well-characterized cohort to address two specific aims: Aim 1 will conduct a multi-tiered stepwise approach to identify rare genetic variants linked with EOAF. First whole exome sequencing (WES) will be performed in our existing 60 EOAF families, who do not harbor candidate gene variants, to identify rare variants predicated on rarity, ethnicity, co-segregation with AF, predicted pathogenicity and bioinformatics filtering. Second, the most promising variants will replicated in AFGen Consortium TOPMed Cohort in which over 3,500 probands with EOAF and 3,500 controls have undergone whole genome sequencing (WGS). This aim builds on our published study in which we identified five novel candidate AF genes using a WES approach and the recent successful completion of WGS in EOAF probands in the TOPMed Cohort. Aim 2 will determine the underlying genetic mechanisms of EOAF by functionally characterizing high priority rare variants using in vitro electrophysiology and in vivo functional assays in zebrafish to enable disease-association. This aim builds upon our prior work where we have functionally characterized a rare AF-linked variant in the Ca channel gene identified by WES and identified rare developmental genes that modulate cardiac conduction in zebrafish. These studies will not only identify novel AF genes and provide insights into underlying genetic mechanisms of EOAF but will also uncover novel therapeutic approaches for AF. They also represent the first step in the development of sub-type specific mechanism-based therapies for this common and morbid condition.

心房颤动（AF）是一个重要且日益严重的公共卫生问题。大多数病例发生在老年人和所以这个问题的发生率正在上升；患有 AF 的美国人人数预计将激增至约 16 人到 2050 年，其他临床特征包括高血压和潜在心脏病，而许多相对年轻患者没有明显的危险因素，被指定为“孤立性”或早发性房颤（EOAF）。 AF 由于缺乏有效的治疗方法，疫情变得更加复杂。治疗的成功有限源于部分原因是对房颤病理生理学的不完全了解以及未能针对房颤进行靶向治疗底层机制。传统上，房颤被认为是一种散发性、非遗传性疾病，但我们和其他人已经表明 EOAF 具有坚实的遗传基础。定位克隆及候选基因多种方法已将心脏离子通道和信号分子的突变与 EOAF 联系起来。虽然这些研究为潜在机制提供了重要的见解，大多数罕见的变异对 EOAF 的敏感性仍然未知。鉴于下一代测序（NGS）的最新进展，在其他心血管表型中发现新基因和我们的初步数据，总体目标该提案的目的是使用 NGS 来识别新的 AF 基因并破译其潜在的遗传机制 EOAF。我们的临床 DNA 登记处已系统性地登记了来自不同种族的 60 多个家庭有早发性家族性房颤的背景。我们建议利用这个庞大且特征鲜明的群体来解决两个具体目标：目标 1 将采用多层次逐步方法来识别相关的罕见遗传变异与 EOAF。首次全外显子组测序 (WES) 将在我们现有的 60 个 EOAF 家族中进行，这些家族不包含候选基因变异，以识别基于稀有性、种族、共分离的罕见变异 AF、预测致病性和生物信息学过滤。其次，最有希望的变体将在 AFGen 联盟 TOPMed 队列，其中超过 3,500 名具有 EOAF 的先证者和 3,500 名对照者已进行了全基因组测序（WGS）。这一目标建立在我们发表的研究的基础上，在该研究中我们确定了使用 WES 方法的五个新候选 AF 基因以及最近在 EOAF 中成功完成的 WGS TOPMed 队列中的先证者。目标 2 将通过以下方式确定 EOAF 的潜在遗传机制：使用体外电生理学和体内功能对高优先级罕见变异进行功能表征在斑马鱼中进行检测以实现疾病关联。这一目标建立在我们之前的工作基础上对通过 WES 鉴定的 Ca 通道基因中罕见的 AF 相关变异进行功能表征，并鉴定出罕见的调节斑马鱼心脏传导的发育基因。这些研究不仅会发现新颖的 AF 基因并提供对 EOAF 潜在遗传机制的见解，同时也将揭示新的发现 AF 的治疗方法。它们也代表了开发特定子类型的第一步针对这种常见病态的基于机制的疗法。