Genetic determinants of cardiac repolarization

心脏复极的遗传决定因素

• 批准号: 7228133
• 负责人: Christopher Holmes Newton-Cheh
• 金额: $ 15.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228133
• 关键词: Address; Affect; Arrhythmia; Beta Adrenergic Receptor Gene; Candidate Disease Gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Cisapride; Collaborations; Complex; Congestive Heart Failure; DNA Resequencing; Development Plans; Diabetes Mellitus; Educational Curriculum; Electrocardiogram; Epidemiologist; Exons; Family; Framingham Heart Study; General Hospitals; General Population; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Individual; Institutes; Ion Channel; K-Series Research Career Programs; Lead; Long QT Syndrome; Maps; Massachusetts; Medicine; Mentors; Mentorship; Myocardial; Numbers; Participant; Pharmaceutical Preparations; Phenotype; Population; Preparation; Range; Research; Research Personnel; Research Proposals; Retrospective Studies; Risk; Risk Factors; Sampling; Science; Single Nucleotide Polymorphism; Societies; Structure; Study Subject; Subgroup; Sudden Death; Testing; Time; Torsades de Pointes; Training; Universities; Variant; Withdrawal; base; beta-adrenergic receptor; career; case control; cost; defined contribution; genetic epidemiology; genetic resource; genetic risk factor; genetic variant; genome wide association study; improved; insight; instructor; medical schools; member; novel; patient oriented research; programs; response; skills; sudden cardiac death; trait

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.

描述（由申请人提供）： 博士克里斯托弗·牛顿-谢是马萨诸塞州总医院的心脏病专家和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，作为一个遗传流行病学家，定义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（BI）布罗德研究所和Fracket心脏研究（FHS）的研究员，候选人研究了心电图QT间期变异的遗传决定因素，以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型室性心动过速的潜在遗传风险因素。拟议的职业发展计划涉及一个明确的指导以病人为导向的研究建议，以扩大这些研究，与先进的统计，流行病学和遗传课程的结构化教学课程。在Joel赫什霍恩博士和Christopher奥唐纳博士的指导下，Newton-Cheh博士在确定与先天性长QT综合征相关的几个候选基因中的常见遗传变异方面取得了重大进展。拟议项目将实现以下具体目标：1）完成1811名FHS受试者中QT间期变异的候选基因关联研究，2）确定通过对FHS受试者中候选基因重新测序鉴定的罕见变异是否有助于极端QT间期延长，以及3）使用220名FHS受试者进行QT间期持续时间的全基因组关联研究，通过与洛克菲勒大学研究人员的现有合作，对南太平洋人群中的2000名成员进行了基因分型。这些研究将提供迄今为止对一般人群心肌复极的遗传决定的最全面的评估。通过拟议的研究和教育培训，Newton-Cheh博士将获得在基因组科学前沿进行独立心血管研究所需的技能。