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

• 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
• 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

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.

项目总结/摘要 早发性房颤（35岁之前的首次房颤事件）与频繁的 复发性心律失常，通常需要电击来停止心律失常，药物预防心律失常或 手术/介入治疗。最近的研究表明，成人房颤干预 (AF)不能有效改变儿童和年轻人的复发频率。在临床实践中， 儿科心脏病专家不遵循为成人设计的AF建议。治疗建议 在早发性房颤中尚未建立，部分原因是我们目前可能评估了错误的标志物 风险。我们的中心假设是，可识别的遗传因素与临床复发相关， 年龄≤ 35岁的儿童和青年房颤患者。我们将使用三种基因组方法来解决 我们的中心假设：一个经过验证的基因面板（目标1），常见变异分析（目标2A），和罕见变异 全基因组测序分析（Aim 2B）。我们将在多中心招募早发性房颤患者， 网络在一项前瞻性的观察性研究中，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例患者中是否存在致病性和可能致病性（P/LP）变异。 与没有P/LP变异的患者相比，已建立的心脏基因的患者首次AF复发的时间更短。通过 在商业上可用的面板中测试临床相关基因，我们将能够快速翻译结果， 我们的第一个目标是临床实践。在第二个目标中，我们将专注于新的基因组关系。数据从 老年人AF的全基因组关联研究产生了多基因风险评分（PRS）。高分 减贫战略与老年人发病率和死亡率的增加有关。但殊不知 AF PRS是否与儿童和年轻人有任何相关性，或者它们是否是终身的标志物， 基因组和肌病风险。因此，我们将验证早发性AF患者的现有AF PRS是否更高 比没有心脏表型的对照群体中的要多。最后，在第二次基因组分析中，我们确定了 在研究的目标1中没有P/LP变体的先证者。从这些P/LP阴性先证者中，我们将确定 先证者有早发性房颤，父母双方心脏病阴性， 我们将进行三重全基因组测序，以确定新的遗传标记 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 直接的影响将是测试商业可用的基因的能力， 确定早期AF复发风险和可能确定终身AF进展风险的异常 肌病，与治疗和预防的影响。作为次要受益，P/LP变体的鉴定 对家族级联筛查有意义。最后，研究基因组基础 早发性房颤不仅对年轻人有影响，而且作为一种假设， 影响老年人房颤的后期发病率。