Genetic determinants of cardiac repolarization

描述(由申请人提供)： 克里斯托弗·牛顿-谢博士是马萨诸塞州总医院的心脏病专家，也是哈佛医学院的医学讲师。候选人的长期目标是发展一个独立的职业生涯，成为一名基因流行病学家，确定遗传学对常见心血管疾病的贡献。作为哈佛和麻省理工学院博德研究所(Bl)和弗雷明翰心脏研究(FHS)的研究员，这位候选人研究了心电图QT间期变异的遗传决定因素，以努力更好地了解普通人群的心肌复极，并确定猝死和药物诱导的尖端扭转的潜在遗传危险因素。拟议的职业发展计划包括一项明确的、有指导的、以患者为导向的研究建议，以延长这些研究，并与高级统计学、流行病学和遗传学课程的结构化教学课程相一致。在乔尔·赫希霍恩博士和克里斯托弗·奥唐奈博士的指导下，牛顿-谢博士在确定与先天性长QT综合征相关的几个候选基因的共同遗传变异方面取得了重大进展。拟议的项目将实现以下具体目标：1)在1811名FHS受试者中完成QT间期变异的候选基因关联研究，2)确定通过对FHS受试者候选基因重新测序确定的更罕见的变异是否有助于QT间期的极端延长，以及3)通过与洛克菲勒大学的研究人员现有的合作，利用在2000名南太平洋人群分离的成员中进行的22万个单核苷酸多态对QT间期持续时间进行全基因组关联研究。这些研究将提供迄今为止对普通人群中心肌复极遗传决定的最全面的评估。通过拟议的研究和教育培训，牛顿-谢博士将获得在基因组科学前沿从事独立心血管研究所需的技能。

DESCRIPTION (provided by applicant): Dr. Christopher Newton-Cheh is a cardiologist at the Massachusetts General Hospital and Instructor in Medicine at Harvard Medical School. The candidate's long-term goal is to develop an independent career as a genetic epidemiologist defining the contribution of genetics to common cardiovascular disease. As a fellow at the Broad Institute of Harvard and MIT (Bl) and the Framingham Heart Study (FHS), the candidate has studied the genetic determinants of electrocardiographic QT interval variation in an effort to better understand myocardial repolarization in the general population and to identify potential genetic risk factors for sudden death and drug-induced torsade de pointes. The proposed career development plan involves a well-defined mentored patient-oriented research proposal to extend these studies, in concert with a structured didactic curriculum of advanced statistical, epidemiologic and genetic coursework. Under the mentorship of Dr. Joel Hirschhorn and Dr. Christopher O'Donnell, Dr. Newton-Cheh has made significant progress defining the common genetic variation in several candidate genes associated with the congenital Long QT Syndrome. The proposed projects will achieve the following specific aims: 1) to complete candidate gene association studies of QT interval variation in 1811 FHS subjects, 2) to determine whether rarer variants identified by resequencing candidate genes in FHS subjects contribute to extreme QT interval prolongation and 3) to carry out genome-wide association studies of QT interval duration using 220,000 single nucleotide polymorphisms being genotyped in 2000 members of a South Pacific population isolate through an existing collaboration with investigators at Rockefeller University. These studies will provide the most comprehensive assessment of the genetic determination of myocardial repolarization in the general population to date. Through the proposed research and educational training, Dr. Newton-Cheh will acquire the skills needed to pursue independent cardiovascular research at the cutting edge of genomic science.