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.

项目概要/摘要早发性心房颤动（35 岁之前首次发生心房颤动）与频繁发生心房颤动有关。复发，通常需要电击来阻止心律失常、药物预防心律失常或手术/介入治疗最近的工作表明，成人干预可治疗心房颤动。在临床实践中，（AF）不能有效改变儿童和年轻人的复发频率。儿科心脏病专家不遵循针对成人的 AF 治疗建议。尚未在早发性房颤中建立，部分原因是我们目前评估的标记物可能错误我们的中心假设是可识别的遗传因素与临床复发有关。我们将使用三种基因组方法来解决 35 岁以下患有 AF 的儿童和年轻人的问题。我们的中心假设：经过验证的基因组（目标 1）、常见变异分析（目标 2A）和罕见变异我们将在多中心招募早发性房颤患者。在一项前瞻性、观察性研究中，我们将记录表型信息并获取遗传物质。第311章与没有 P/LP 变异的患者相比，已确定的心脏基因导致首次 AF 复发的时间更短。在市售的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第一个目标是临床实践，第二个目标是关注新的基因组数据。老年人 AF 的全基因组关联研究产生了多基因风险评分 (PRS)。 PRS 与老年人发病率和死亡率增加有关，但尚不清楚。 AF PRS 是否与儿童和年轻人有任何相关性，或者它们是否是终生的标志因此，我们将验证早发性 AF 中 AF PRS 是否较高。最后，在第二次基因组分析中，我们确定了这一点。研究目标 1 中没有 P/LP 变异的先证者从这些 P/LP 阴性先证者中，我们将识别出这些先证者。先证者患有早发性房颤且父母双方心脏病均为阴性且阴性的三人组我们将进行三组全基因组测序，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风险。早发性房颤的危险因素的直接影响将是测试商业化基因的能力。识别早期 AF 复发风险和可能识别房颤进展的终生风险的异常肌病，对治疗和预防具有影响作为次要益处，P/LP 变异的识别。最后，研究先证者的基因组基础对家庭级联筛查具有影响。早发性房颤不仅对年轻人有影响，而且作为一种假设，房肌病的终生风险影响老年人心房颤动的后期发病率。