Rare coding variation and risk for myocardial infarction

罕见的编码变异和心肌梗塞的风险

• 批准号: 8352120
• 负责人: Nathan Oliver Stitziel
• 金额: $ 13.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2012-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352120
• 关键词: Address; Alleles; Bioinformatics; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Cause of Death; Clinical; Code; Communication Research; Complex; Computing Methodologies; DNA Sequence; Data; Disease; Disease Association; Doctor of Philosophy; Elderly; Environment; Fellowship; Foundations; Frequencies; Funding; Gene Frequency; General Hospitals; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Grouping; Guidelines; Hospitals; Human Genetics; Individual; Institutes; Internal Medicine; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Large-Scale Sequencing; Lead; Massachusetts; Medicine; Mentors; Methods; Minor; Modeling; Myocardial Infarction; Open Reading Frames; Pathway interactions; Performance; Phenotype; Physicians; Play; Population; Population Genetics; Positioning Attribute; Prevention; Principal Investigator; Research; Research Ethics; Research Personnel; Residencies; Risk; Risk Factors; Role; Sampling; Scientist; Solid; Stratification; Technology; Testing; Training; United States; Variant; Woman; Work; base; career development; case control; design; disorder risk; early onset; exome; experience; genetic association; genetic variant; genome wide association study; high risk; improved; lifetime risk; next generation; novel; novel strategies; novel therapeutics; population based; skills; success

DESCRIPTION (provided by applicant): Myocardial infarction (MI) is the leading cause of death in the United States and is heritable. Large studies focusing on common genetic variation have now identified over 30 loci associated with risk for MI. Despite this success, these common variants explain only a small proportion of the genetic basis of MI. Population genetics and candidate gene studies support the hypothesis that less common genetic variation plays a significant role in complex disorders such as MI. In this proposal, we outline several methods to explore the role of rare genetic variation in risk for MI. Using a set of rare (minor allele frequecy < 5%) coding variants identified through whole exome sequencing (i.e. all protein coding regions of the genome), we will test the hypotheses that rare variants contribute to MI risk both individually and collectively and further that this knowledge can improve population-based risk stratification. To test these hypotheses, we propose the following specific aims: in Aim 1, we will genotype exome variants in a well-powered case/control study to identify rare variants that individually contribute to risk of MI; in Aim 2, we will develop novel computational methods for rare variant analysis to identify rare variants collectively associated with MI; and in Aim 3, we will develop a rare variant method for population-based MI risk stratification. In addition to elucidating the role of rare coding variation in risk for MI, this five-year proposal outlines a comprehensive strategy for the principal investigator's career development in academic cardiovascular medicine. This strategy logically builds on the principal investigator's previous research experience and clinical training. After obtaining a Ph.D. in Bioinformatics, the principal investigator completed residency training in Internal Medicine and is currently finishing fellowship training in Cardiovascular Disease. This proposal now focuses on expanding his scientific skills by attaining additional knowledge and practical research experience in human genetics and genomics, statistical genetics, and risk modeling. The career development goals will be achieved through a multi-faceted approach involving mentoring by Dr. Sekar Kathiresan (human genetics and genomics) and Dr. Shamil Sunyaev (statistical genetics, risk modeling), didactic coursework, scientific investigation, and training in scientific communication and research ethics. This work will take place in a unique training environment comprised of complementary experiences at Massachusetts General Hospital, Brigham and Women's Hospital, and the Broad Institute. Successful completion of this career development award will result in a better understanding of the genetic basis for MI, result in the principal investigator' transition to an independent physician-scientist, and provide a solid foundation from which he will apply for RO1-level funding. PUBLIC HEALTH RELEVANCE: Heart attack is the leading cause of death in the United States and although it is heritable, its genetic basis is incompletely characterized. This proposal outlines several methods aimed at understanding the role of rare genetic variation in risk for heart attack. Success has the potential to identify new mechanisms of disease and novel strategies for prevention.

描述（由申请人提供）：心肌梗死（MI）是美国的主要死亡原因，具有遗传性。针对常见遗传变异的大型研究现已确定了30多个与MI风险相关的基因座。尽管取得了这一成功，但这些常见的变异只能解释MI遗传基础的一小部分。群体遗传学和候选基因研究支持这一假设，即不太常见的遗传变异在复杂的疾病，如心肌梗死中起着重要作用。在这个建议中，我们概述了几种方法来探索罕见的遗传变异在心肌梗死风险中的作用。使用通过全外显子组测序（即基因组的所有蛋白质编码区）鉴定的一组罕见（次要等位基因频率< 5%）编码变体，我们将检验罕见变体单独和共同导致MI风险的假设，并进一步验证该知识可以改善基于人群的风险分层。为了验证这些假设，我们提出了以下具体目标：在目标1中，我们将 在一项把握度良好的病例/对照研究中，我们将开发基因型外显子组变异，以识别单独导致MI风险的罕见变异;在目标2中，我们将开发用于罕见变异分析的新型计算方法，以识别与MI共同相关的罕见变异;在目标3中，我们将开发用于基于人群的MI风险分层的罕见变异方法。除了阐明罕见的编码变异在MI风险中的作用外，这份为期五年的提案还概述了主要研究者在学术心血管医学领域职业发展的全面战略。该策略逻辑上建立在主要研究者先前的研究经验和临床培训的基础上。获得博士学位后，在生物信息学中， 研究者已完成内科住院医师培训，目前正在完成心血管疾病研究金培训。该提案现在的重点是通过获得人类遗传学和基因组学，统计遗传学和风险建模方面的额外知识和实践研究经验来扩展他的科学技能。职业发展目标将通过多方面的方法实现，包括Sekar Kathiresan博士（人类遗传学和基因组学）和Shamil Sunyaev博士（统计遗传学，风险建模），教学课程，科学调查以及科学传播和研究伦理培训。这项工作将在一个独特的培训环境中进行，包括在马萨诸塞州总医院、布里格姆妇女医院和布罗德研究所的互补经验。成功完成这项职业发展奖将导致更好地了解MI的遗传基础，导致主要研究者转变为独立的医生-科学家，并为他申请RO 1级资助提供坚实的基础。 公共卫生相关性：心脏病发作是美国的主要死因，虽然它是遗传的，但其遗传基础并不完全。这项建议 概述了几种方法，旨在了解罕见的遗传变异在心脏病发作风险中的作用。成功有可能发现疾病的新机制和新的预防策略。