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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要大多数心房颤动 (AF) 病例是由临床危险因素和遗传易感性共同引起的。此外，最近已经明确，AF 可能是罕见的高效应尺寸变异的最早表现遗传时与潜在致命的心脏通道病或心肌病 (CM) 相关。怀疑心律失常/CM 综合征，目前的指南建议进行基因检测，以便尽早进行检测并降低心源性猝死的风险然而，当前的指南特别指出，遗传。通常不应在仅患有 AF 的患者中进行测试，因此存在重大知识差距。如何识别那些房颤患者，这是他们患有潜在严重潜在疾病的第一个迹象遗传病以及这些罕见遗传变异的心脏表型和临床意义是什么。我们现在能够利用 NHLBI 的精准医学跨组学来解决这些问题 (TOPMed) 和 NHGRI 常见疾病基因组学中心 (CCDG) 资源已执行。全基因组测序（WGS）和CCDG已大量进行全外显子组测序（WES）目前，这包括 2,852 名患有早发 AF 的受试者。（年龄<60岁，遗传因素可能在其中发挥特别重要作用的群体）来自范德比尔特（范德比尔特 TOPMed AF 队列 = 1,161，范德比尔特 CCDG AF 队列 = 1,691）。来自范德比尔特 AF 登记处，并同意进行潜在的重新联系。 Meharry Medical 将另外招募 200 名患有早发性房颤的非裔美国人学院。目标 1 将利用这些资源进行深度表型分析，以确定 AF 的心脏表型。患有与遗传性心肌病相关的致病性或可能致病性（P/LP）罕见变异的患者 (CM) 综合征（例如致心律失常 CM、肥厚性 CM、扩张性 CM；目标 1A）或遗传性心律失常综合征（例如 Brugada 综合征、长 QT 综合征；目标 1B）并与对照组参与者进行比较。这些定义的遗传亚组和对照将被招募用于门诊研究访问，以进行心脏 MRI、休息/压力/信号平均心电图和心脏监测（如果有遗传性心律失常/CM 综合征）。一旦确诊，将建议对医疗护理进行指南指导的改变，目标 2 将创建预测。使用临床风险因素± AF 多基因风险评分的工具来识别患有 P/LP 罕见的 AF 患者遗传变异，因此应进行基因检测。虽然测序技术的进步提高了人们对稀有和常见的理解遗传变异导致房颤易感性，房颤遗传亚群的表型仍然不完全如果 AF 基因检测是为了增加治疗价值，我们的工作就是确定谁应该接受检测并确定。需要了解这些结果对广泛的房颤人群的临床意义。