The Genetic Basis of Atrial Fibrillation

描述(由申请人提供)： 应聘者具有细胞生理学方面的基础科学背景，最近完成了医学住院医师、心脏病学和电生理学奖学金培训。他目前是一名临床研究员，将于2002年7月加入马萨诸塞州综合医院心脏科的工作人员。候选人寻求在临床研究方法方面获得正式培训，同时开发一项研究计划，以阐明心房颤动的分子基础。 房颤是最常见的严重心律失常，影响着200多万美国人。尽管房颤在年轻人中很少见，但随着年龄的增长，房颤的患病率会增加，80岁以上的人中有十分之一会受到影响。房颤是一种相当大的社会经济负担，与长期用药有关，占老年人所有中风的近四分之一，并降低了受影响个人的预期寿命。大多数房颤被认为是继发于其他疾病，如甲状腺功能亢进症、高血压、心肌病或瓣膜紊乱；然而，有相当一部分没有明显原因的患者被认为只有一种房颤。房颤的临床异质性限制了以往定义这种疾病的遗传病因的尝试。因此，我们建议使用个人和家庭的互补策略来进一步确定这种疾病的临床表型、遗传流行病学和遗传基础。 在房颤患者中，我们假设孤立性房颤患者的病情最有可能有遗传因素。我们建议对这些个体及其一级亲属进行前瞻性研究，以便正式确定心房颤动的遗传结构，同时确定适合位置克隆方法的较大家系。通过这种方法，我们已经确定了100多名孤立性心房颤动的先证者的特征，并确定了多个遗传性心房颤动的大家族。识别致病基因的进一步努力正在进行中。 识别这些基因将有助于确定导致心房颤动的分子途径，而先证者的出现将使使用基因类型预测结果的纵向研究成为可能，并能够对基因-基因和基因-药物相互作用进行详细评估。这些互补战略的最终目标是导致预防和治疗这种常见和病态疾病的新的治疗战略。

DESCRIPTION (provided by the applicant): The candidate has a basic science background in cellular physiology and has recently completed medical residency, cardiology and electrophysiology fellowship training. He is currently a clinical research fellow and will join the staff of the Cardiology Division at Massachusetts General Hospital in July 2002. The candidate seeks to obtain formal training in clinical research methods while developing a research program to elucidate the molecular basis of atrial fibrillation. Atrial fibrillation is the most common significant arrhythmia, affecting over 2 million Americans. Although rare in youth, the prevalence of atrial fibrillation increases with age and afflicts one in ten individuals over eighty. Atrial fibrillation presents a considerable socioeconomic burden, associated with chronic medication use, nearly one fourth of all strokes in the elderly, and a reduced life expectancy in affected individuals. Most atrial fibrillation is considered secondary to other conditions such as hyperthyroidism, hypertension, cardiomyopathy or valvular disorder; however, a substantial minority of patients without obvious cause are said to have "!one" atrial fibrillation. The clinical heterogeneity of atrial fibrillation has restricted previous attempts to define the genetic etiology of this disorder. We therefore propose use of a complementary strategy of individuals and families to further define the clinical phenotypes, the genetic epidemiology, and the genetic basis of this disorder. Of patients with atrial fibrillation, we hypothesize that individuals with lone atrial fibrillation are the most likely to have a genetic component to their condition. We propose to prospectively study these individuals and their first-degree relatives in order to formally define the genetic architecture of atrial fibrillation while identifying larger kindreds suitable for positional cloning approaches. With this approach, we have characterized over one hundred probands with lone atrial fibrillation and identified multiple extended families with inherited atrial fibrillation. Further efforts to identify the causal genes are underway. Identification of these genes will permit definition of the molecular pathways that contribute to atrial fibrillation, while the availability of the probands will enable longitudinal studies using genotypes to predict outcomes and enable detailed evaluation of gene-gene and gene-drug interactions. The ultimate goal of these complementary strategies is to lead to novel therapeutic strategies for the prevention and treatment of this common and morbid condition.