Probing Phenotype-Genotype Relations After Whole Genome Sequencing in Patients with Atrial Fibrillation

心房颤动患者全基因组测序后探索表型-基因型关系

• 批准号: 10478952
• 负责人: Moore Benjamin Shoemaker
• 金额: $ 85.63万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478952
• 关键词: Address; Adult; Affect; African American; African American population; Age; Arrhythmia; Atrial Fibrillation; Back; Brugada syndrome; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Caring; Catecholaminergic Polymorphic Ventricular Tachycardia; Clinical; Consent; Data Set; Diagnosis; Dilated Cardiomyopathy; Disease; Early Diagnosis; Early Intervention; Early identification; Electrocardiogram; Electronic Health Record; Enrollment; Ethnic Origin; Family; Fibrosis; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Screening; Genetic Variation; Genomics; Genotype; Goals; Guidelines; Heart failure; Hypertrophic Cardiomyopathy; Image; Individual; Inherited; Knowledge; Left; Life; Link; Logistic Regressions; Long QT Syndrome; Medical; Monitor; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Outpatients; Participant; Pathogenicity; Patient-Focused Outcomes; Patients; Performance; Phenotype; Play; Population; Positioning Attribute; Precision Medicine Initiative; Predisposition; Probability; Publishing; Race; Recommendation; Recontacts; Registries; Reporting; Research; Resources; Rest; Risk; Risk Factors; Role; Sample Size; Short QT syndrome; Signal Transduction; Stress; Subgroup; Syndrome; Technology; Testing; Therapeutic; Training; Trans-Omics for Precision Medicine; United States National Institutes of Health; Validation; Variant; Ventricular; Ventricular Arrhythmia; Visit; Work; adjudication; arrhythmogenic cardiomyopathy; cardiac magnetic resonance imaging; clinical care; clinical risk; clinically significant; cohort; demographics; diagnostic criteria; diagnostic value; disease phenotype; early onset; exome sequencing; genetic risk factor; genetic testing; genetic variant; genome sequencing; genome-wide; high risk; improved; individualized medicine; individualized prevention; inherited cardiomyopathy; medical schools; polygenic risk score; predicting response; programs; prospective; rare variant; recruit; screening; sex; sudden cardiac death; tool; whole genome

PROJECT SUMMARY/ABSTRACT Most cases of atrial fibrillation (AF) arise from a combination of clinical risk factors and genetic susceptibility. Moreover, it has recently become clear that AF can be the earliest manifestation of rare high effect size variants associated with potentially fatal cardiac channelopathies or cardiomyopathies (CM). When inherited arrhythmia/CM syndromes are suspected, current guidelines recommend genetic testing to enable early detection and reduce the risk of sudden cardiac death. However, current guidelines specifically state that genetic testing should not ordinarily be performed in patients presenting with AF alone. Thus, major knowledge gaps are how to identify those patients in whom AF is the first sign that they possess a potentially serious underlying genetic disease and what is the cardiac phenotype and clinical significance of those rare genetic variants. We are now in a position to address these issues using the NHLBI’s Trans-omics for Precision Medicine (TOPMed) and NHGRI’s Centers for Common Disease Genomics (CCDG) resources. TOPMed has performed whole genome sequencing (WGS) and CCDG has performed whole exome sequencing (WES) in large numbers of subjects with common cardiovascular diseases. Currently, this includes 2,852 participants with early onset AF (age <60 years, a group in which genetic factors may play an especially important role) from Vanderbilt (Vanderbilt TOPMed AF Cohort=1,161, Vanderbilt CCDG AF Cohort=1,691). These participants were recruited from Vanderbilt AF registries and have consented for potential recontact. To create a more diverse cohort, an additional 200 African Americans with early onset AF will be prospectively recruited from Meharry Medical College. Using these resources, Aim 1 will perform deep phenotyping to define the cardiac phenotype of AF patients with a pathogenic or likely pathogenic (P/LP) rare variant associated with an inherited cardiomyopathy (CM) syndrome (e.g. arrhythmogenic CM, hypertrophic CM, dilated CM; Aim 1A) or inherited arrhythmia syndrome (e.g. Brugada Syndrome, Long QT Syndrome; Aim 1B) and compared to controls. Participants from these defined genetic subgroups and controls will be recruited for an outpatient research visit to undergo a cardiac MRI, rest/stress/signal-averaged ECGs, and cardiac monitoring. If an inherited arrhythmia/CM syndrome is diagnosed, guideline-directed changes to medical care will be recommended. Aim 2 will create a prediction tool using clinical risk factors ± an AF polygenic risk score to identify patients with AF who have a P/LP rare genetic variant and therefore should undergo genetic testing. While advances in sequencing technology have improved the understanding of how rare and common genetic variation contributes to AF susceptibility, the phenotype of AF genetic subgroups remains incompletely defined. If genetic testing for AF is to add therapeutic value, our work to identify who should be tested and define the clinical implications of these results in a broad AF population is needed.

项目摘要/摘要 大多数房颤（AF）的病例是由临床危险因素和遗传易感性的组合产生的。 此外，最近很明显，AF可能是罕见高效尺寸变体的最早表现 与潜在的致命心脏通道病或心肌病（CM）相关。继承时 怀疑心律不齐/CM综合征，当前的指南建议基因检测以早期实现 检测并降低心脏突然死亡的风险。但是，当前的准则特别指出遗传 单独出现AF的患者不应通常进行测试。那是主要的知识差距 如何识别那些AF的患者是他们拥有潜在严重基础的第一个迹象 遗传疾病以及这些罕见遗传变异的心脏表型和临床意义是什么。 我们现在可以使用NHLBI的跨词来解决这些问题以解决这些问题 （最高）和NHGRI的常见疾病基因组学（CCDG）资源中心。上面表演 整个基因组测序（WGS）和CCDG已大量进行了整个外显子组测序（WES） 患有常见心血管疾病的受试者。目前，其中包括2852名参与者 （年龄<60岁，遗传因素可能起着特别重要的作用的群体）来自范德比尔特 （范德比尔特最高的AF群体= 1,161，范德比尔特CCDG AF队列= 1,691）。这些参与者被招募 来自Vanderbilt AF登记处，并同意潜在的重新连接。为了创建一个更加潜水队的队列， 预计将从Meharry Medical招募其他200名患有早期AF的非洲裔美国人 大学。使用这些资源，AIM 1将执行深层表型来定义AF的心脏表型 具有致病性或可能致病性（P/LP）稀有变体的患者与遗传性心肌病有关 （CM）综合征（例如心律失常CM，肥厚CM，扩张CM； AIM 1A）或遗传性心律失常 综合征（例如Brugada综合征，长QT综合征； AIM 1B），并与对照组进行了比较。来自 这些定义的遗传亚组和控制将被招募，以进行门诊研究访问，以进行一次 心脏MRI，静止/压力/信号平均心电图和心脏监测。如果遗传性心律失常/CM综合征 被诊断为指导医疗的指导更改。 AIM 2将创建一个预测 使用临床风险因素±AF多基因风险评分来识别患有P/LP罕见的AF患者的工具 遗传变异，因此应进行基因检测。 虽然测序技术的进步已经提高了人们对稀有和常见的理解 遗传变异有助于AF易感性，AF遗传亚组的表型不完全 定义。如果对AF的基因检测是增加治疗价值，那么我们的工作以确定谁应进行测试并定义 这些结果在广泛的AF人群中的临床意义。