Investigating structural and genetic substrates of early-onset atrial fibrillation

研究早发性房颤的结构和遗传基础

基本信息

批准号：
10735490
负责人：
Robert Gregory Webster
金额：
$ 55.99万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735490
关键词：
Address Adult Affect Age Age Years Age of Onset Apple watch Arrhythmia Atrial Fibrillation Biological Cardiac Cardiomyopathies Child Clinical Clinical Data Clinical Markers Data Disease Elderly Electrocardiogram Event Exclusion Family Family history of Frequencies Future Genes Genetic Genetic Markers Genetic Materials Genetic Predisposition to Disease Genetic Risk Genetic study Genomic approach Genomics Genotype Goals Heart Heart Atrium Heart Diseases Incidence Intervention Investments Link Medical Molecular Abnormality Morbidity - disease rate Myocardial Myopathy National Heart, Lung, and Blood Institute Observational Study Operative Surgical Procedures Outcome Parents Pathogenicity Pathway interactions Patient Recruitments Patients Persons Pharmaceutical Preparations Phenotype Population Control Prevalence Prevention Prospective Studies Recommendation Recording of previous events Recurrence Reporting Risk Risk Factors Risk Marker Shock Surgical Management Testing Time Translating United States National Institutes of Health Variant Work age group clinical care clinical practice clinical predictors clinically relevant cohort comparison control data analysis pipeline de novo mutation design early onset follow-up gene discovery gene panel genetic information genetic panel test genetic testing genome sequencing genome wide association study mortality novel novel strategies participant enrollment participant interview pediatric cardiologist polygenic risk score prevent proband progression risk prospective public health relevance rare variant risk variant screening wearable device whole genome young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Early-onset atrial fibrillation (a first event of atrial fibrillation before 35 years of age) is associated with frequent recurrences, often requiring electrical shocks to stop the arrhythmia, medication to prevent arrhythmia or surgical/interventional management. Recent work has demonstrated that adult interventions for atrial fibrillation (AF) are not effective in changing the frequency of recurrence in children and young adults. In clinical practice, pediatric cardiologists do not follow the AF recommendations designed for adults. Recommendations for therapy have not been established in early-onset AF, in part because we may be currently assessing the wrong markers for risk. Our central hypothesis is that identifiable genetic factors are associated with clinical recurrence in children and young adults with AF at ≤ 35 years of age. We will use three genomic approaches to addressing our central hypothesis: a validated gene panel (Aim 1), common-variant analysis (Aim 2A), and rare variant analysis with whole genome sequencing (Aim 2B). We will recruit patients with early-onset AF in a multicenter network. In a prospective, observational study, we will record phenotype information and obtain genetic material. In our first aim, we will determine if patients with pathogenic and likely pathogenic (P/LP) variants in 311 established cardiac genes have a shorter time to first AF recurrence than patients without a P/LP variant. By testing clinically relevant genes in commercially available panels, we will be able to rapidly translate the results of our first aim to clinical practice. In the second aim, we will focus on new genomic relationships. Data from genome-wide association studies of AF in older adults have generated polygenic risk scores (PRS). High scores on PRS have been associated with increased morbidity and mortality in older adults. However, it is not known whether AF PRS have any relevance in children and young adults, nor whether they are markers of lifelong genomic and myopathic risk. Therefore, we will validate whether existing AF PRS are higher in early-onset AF than in a control population without cardiac phenotype. Finally, in a second genomic analysis, we identify probands who have no P/LP variants in Aim 1 of the study. From those P/LP-negative probands, we will identify trios where the proband has early-onset AF and both parents are negative for cardiac disease with a negative family history of early-onset AF. We will perform trio whole genome sequencing to identify novel genetic markers of risk in early-onset AF. If our central hypothesis is correct, these three approaches will identify a novel set of risk factors in early-onset AF. The immediate impact will be the ability to test for commercially available genetic abnormalities that identify risk of early AF recurrence and that may identify lifelong risk for progression of myopathy, with implications for therapy and prevention. As a secondary benefit, the identification of P/LP variants in a proband has implications for cascade screening in families. Finally, work on the genomic underpinnings of early-onset AF has implications not only in the young, but as a hypothesis that the lifelong risks of atrial myopathy affect the later incidence of atrial fibrillation in older adults.

项目摘要/摘要早期心房颤动（35岁之前的房颤的第一个事件）与频率有关复发，通常需要电击以阻止心律不齐，以防止心律不齐或手术/介入管理。最近的工作表明，成人的房颤干预措施（AF）在改变儿童和年轻人复发频率时无效。在临床实践中，小儿心脏病专家不遵循为成年人设计的AF建议。治疗建议尚未在早期AF中建立，部分原因是我们目前可能正在评估错误的标记冒险。我们的中心假设是，可识别的遗传因素与临床复发有关 AF≤35岁的儿童和年轻人。我们将使用三种基因组方法来解决我们的中心假设：经过验证的基因面板（AIM 1），常用变化分析（AIM 2A）和罕见的变体通过整个基因组测序分析（AIM 2B）。我们将在多中心招募患有早期AF的患者网络。在一项前瞻性，观察性研究中，我们将记录表型信息并获得遗传物质。在我们的第一个目标中，我们将确定311的致病性和可能致病性（P/LP）变体的患者是否存在与没有P/LP变体的患者相比，已建立的心脏基因首先复发的时间更短。经过在市售面板中测试临床相关基因，我们将能够快速转化结果我们的首要目标是临床实践。在第二个目标中，我们将专注于新的基因组关系。来自 AF的全基因组关联研究已产生多基因风险评分（PRS）。高分 PRS与老年人的发病率和死亡率增加有关。但是，这是不知道的 AF PR与儿童和年轻人有任何相关性，还是它们是否是终身标志基因组和肌病风险。因此，我们将验证现有的AF PR在早期AF中是否较高比在没有心脏表型的对照人群中。最后，在第二个基因组分析中，我们确定在研究的AIM 1中没有P/LP变体的概率。从这些P/LP阴性问题中，我们将确定问题的三重奏患有早期AF，父母双方都对心脏病负阴性，阴性为阴性早期AF的家族史。我们将执行三重奏整个基因组测序以识别新的遗传标记早期AF的风险。如果我们的中心假设是正确的，这三种方法将确定一组新的早期AF的危险因素。直接影响将是测试市售通用的能力鉴定出早期AF复发风险的异常，并且可能确定终身的进展风险肌病，对治疗和预防有影响。作为次要好处，识别p/lp变体在一个概率中，对家庭的级联筛查有影响。最后，在基因组基础上工作早期发作不仅对年轻人有影响，而且是一种假设，即终生造成心房肌病的风险影响后来的老年人房颤事件。