Identification of Disease Genes for Atrial Fibrillation

心房颤动疾病基因的鉴定

• 批准号: 7037987
• 负责人: Timothy Mark OLSON
• 金额: $ 29.4万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-20 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037987
• 关键词: African; atrial fibrillation; autosomal dominant trait; clinical research; disease /disorder etiology; family genetics; gene expression profiling; genetic screening; genetic susceptibility; human subject; linkage mapping; nuclear membrane; racial /ethnic difference; sodium channel

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common sustained arrhythmia, reaching epidemic proportions in the aging U.S. population and resulting in significant morbidity, mortality, and socioeconomic burden. Preliminary studies indicate that idiopathic or lone AF is familial in at least 15% of patients, highlighting the importance of genetic factors in the pathogenesis of this disorder. The overall objective of this study is to identify genes for AF by linkage and mutational analyses. The first aim is to determine the chromosomal location of AF genes by genome-wide linkage analyses. Mapping studies will be carried out in 4 large families with autosomal dominant AF in which linkage to known loci for AF have been excluded. The second aim is to identify mutations in candidate genes for AF based on chromosomal location, cardiac expression, and physiological rationale. Novel genes, once identified, will be screened for additional inherited and de novo mutations in a cohort of 154 unrelated patients with familial and sporadic AF. The third aim is to determine the frequency and spectrum of heritable ion channel and nuclear membrane defects in racially-diverse cohorts with lone AF. The long-term objectives of this work are to gain new insights into molecular mechanisms of arrhythmogenesis and to improve prediction, prevention, and treatment of AF.

描述（由申请人提供）：心房颤动（AF）是最常见的持续性心律不齐，在美国老龄化的人群中达到了流行比例，导致了明显的发病率，死亡率和社会经济负担。初步研究表明，在至少15％的患者中，特发性或孤独的AF是家族性的，强调了遗传因素在该疾病发病机理中的重要性。这项研究的总体目的是通过连锁和突变分析鉴定AF的基因。第一个目的是通过全基因组链接分析来确定AF基因的染色体位置。将在4个具有常染色体显性AF的大型家庭中进行映射研究，其中已排除了与已知位点的链接。第二个目的是根据染色体位置，心脏表达和生理原理鉴定AF的候选基因突变。一旦鉴定出来的新型基因将在154名无关家族和零星AF的无关患者的队列中进行筛查，以获取额外的遗传和从头突变。第三个目的是确定与孤独AF的种族多样性队列中可遗传离子通道和核膜缺陷的频率和光谱。这项工作的长期目标是获得对心律失常发生的分子机制的新见解，并改善AF的预测，预防和治疗。