Atrial Fibrillation: Bridging genetic discovery and clinical associations

心房颤动：连接基因发现和临床关联

• 批准号: 8508341
• 负责人: Steven A Lubitz
• 金额: $ 16.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508341
• 关键词: 4q25; Address; Affect; American; Applied Genetics; Appointment; Arrhythmia; Asses; Atrial Fibrillation; Base Pairing; Biometry; Cardiac; Cessation of life; Chromosomes; Clinical; Clinical Management; Clinical Research; Clinical Trials; Communities; Complication; Data; Development Plans; Early identification; Electrophysiology (science); Elements; European; Fostering; Framingham Heart Study; Future; Gene Mutation; General Hospitals; Genetic; Genetic Predisposition to Disease; Guide prevention; Health; Health Care Costs; Heart failure; Hospital Referrals; Hospitals; Incidence; Individual; Intercistronic Region; International; K-Series Research Career Programs; Knowledge; Massachusetts; Master of Public Health; Mentors; Mentorship; Methods; Morbidity - disease rate; Myocardial Infarction; Outcome; Pathogenesis; Patients; Pattern; Phenotype; Predisposition; Prevalence; Prevention; Process; Public Health; Reporting; Research Methodology; Research Training; Risk; Sampling; Scheme; Signal Transduction; Stratification; Stroke; Symptoms; Testing; Training; United States; Variant; attributable mortality; base; career development; clinical practice; cohort; design; epidemiology study; experience; genetic epidemiology; genetic variant; hazard; high risk; improved; insight; medical schools; multidisciplinary; novel; prevent; public health relevance; response; skills; socioeconomics; thrombolysis

DESCRIPTION (provided by applicant): The candidate has recently joined the staff at the Massachusetts General Hospital (MGH) and received an appointment at Harvard Medical School effective July 2012. Over the last four years the candidate has studied the epidemiology and genetics of atrial fibrillation (AF), achieved a Master of Public Health degree, completed cardiac electrophysiology training, and established scientifically productive relationships with hi mentors. This Career Development Award is motivated by the public health importance of AF, which affects over 3 million Americans and is increasing in incidence and prevalence worldwide. Substantial morbidity and mortality are attributable to AF, including increased risks of disabling stroke, heart failure, and death. Furthermore, AF is responsible for an estimated $26 billion in annual health care costs in the United States. A widespread heritable component underlying AF is now recognized, and common genetic variants associated with AF have been discovered. Despite advances in the understanding of AF genetics, knowledge gaps remain. Associated signals at discovered AF susceptibility loci span up to hundreds of thousands of base pairs and remain poorly characterized. Data suggest that independent susceptibility signals may exist at known loci, and may both facilitate the identification of individuals at risk for AF as well as localize functional elements involved in AF pathogenesis. Relations between AF susceptibility variants and morbidity from AF remain unexplored. Associations between AF associated variants and clinical manifestations of AF may enable efforts to apply genetic and other discoveries to patient management in an effort to prevent morbidity. The candidate seeks to address these knowledge gaps by leveraging the power and complementarity of well-phenotyped cohorts spanning hospital-referral, community-based, and clinical trials samples. Specifically, the candidate proposes to: 1) discover independent AF genetic susceptibility variants in the international CHARGE consortium; 2) determine the clinical and genetic predictors of AF progression in cohorts from MGH and the Framingham Heart Study; and 3) examine relations between AF susceptibility variants and stroke in individuals with and without AF in two Thrombolysis In Myocardial Infarction Study Group trials. This K23 is designed to foster independence through advanced training in genetic epidemiology, biostatistics, and clinical trial methods. The application draws upon strengths of different cohorts and experienced mentors in a multidisciplinary fashion. The aims will inform our understanding of the mechanisms, clinical features, and outcomes of AF, a morbid arrhythmia of substantial public health importance. In future R01 applications the candidate will be poised to test whether application of genetic knowledge can facilitate prevention of AF related morbidity, and whether genetic variants associate differentially with response to pharmacologic agents used to treat patients with AF.

描述（由申请人提供）：该候选人最近加入了马萨诸塞州总医院 (MGH)，并于 2012 年 7 月获得哈佛医学院的任命。在过去四年中，该候选人研究了心房颤动的流行病学和遗传学（AF），获得了公共卫生硕士学位，完成了心脏电生理学培训，并与导师建立了科学而富有成效的关系。 该职业发展奖的设立是因为房颤对公共卫生的重要性，房颤影响着超过 300 万美国人，并且其发病率和患病率在全球范围内不断增加。房颤导致大量发病率和死亡率，包括致残性中风、心力衰竭和死亡的风险增加。此外，AF 每年要承担美国约 260 亿美元的医疗费用。 现在已经认识到 AF 潜在的广泛遗传因素，并且已经发现了与 AF 相关的常见遗传变异。尽管对 AF 遗传学的理解取得了进展，但知识差距仍然存在。已发现的 AF 易感性位点的相关信号跨越数十万个碱基对，但特征仍然很差。数据表明，独立的易感性信号可能存在​​于已知位点，并且可能既有助于识别有房颤风险的个体，也有助于定位房颤发病机制中涉及的功能元件。房颤易感性变异与房颤发病率之间的关系仍有待探索。 AF 相关变异与 AF 临床表现之间的关联可能有助于将遗传学和其他发现应用于患者管理，以预防发病。 候选人寻求通过利用涵盖医院转诊、社区和临床试验样本的良好表型队列的力量和互补性来解决这些知识差距。具体来说，候选人提出：1）在国际CHARGE联盟中发现独立的AF遗传易感性变异； 2) 确定 MGH 和 Framingham 心脏研究队列中 AF 进展的临床和遗传预测因子； 3) 在两项心肌梗死溶栓研究组试验中检查患有和不患有 AF 的个体中 AF 易感性变异与卒中之间的关系。 K23 旨在通过遗传流行病学、生物统计学和临床​​试验方法的高级培训来培养独立性。该应用程序以多学科的方式利用了不同群体和经验丰富的导师的优势。这些目标将有助于我们了解房颤（一种对公共卫生具有重要意义的病态心律失常）的机制、临床特征和结果。在未来的 R01 应用中，候选人将准备测试遗传知识的应用是否可以促进预防 AF 相关发病率，以及遗传变异是否与用于治疗 AF 患者的药物反应存在差异相关。