Rare coding variation and risk for myocardial infarction

罕见的编码变异和心肌梗塞的风险

基本信息

批准号：
8523197
负责人：
Nathan Oliver Stitziel
金额：
$ 13.72万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523197
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 clinical risk design disorder risk early onset exome exome sequencing experience genetic association genetic variant genome wide association study high risk improved lifetime risk next generation novel novel strategies novel therapeutics population based rare variant skills success

项目摘要

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.

描述（由申请人提供）：心肌梗塞 (MI) 是美国的主要原因，并且具有遗传性。目前，针对常见遗传变异的大型研究已确定了 30 多个与 MI 风险相关的基因座。尽管取得了这一成功，但这些常见变异仅解释了 MI 遗传基础的一小部分。群体遗传学和候选基因研究支持以下假设：不太常见的遗传变异在心肌梗死等复杂疾病中发挥着重要作用。在本提案中，我们概述了几种探索罕见遗传变异在心肌梗死风险中的作用的方法。使用通过全外显子组测序（即基因组的所有蛋白质编码区域）鉴定的一组罕见（次要等位基因频率 < 5%）编码变体，我们将测试罕见变体单独和集体导致 MI 风险的假设，并进一步验证这些知识可以改善基于人群的风险分层。为了检验这些假设，我们提出以下具体目标：在目标 1 中，我们将在一项强有力的病例/对照研究中对外显子组变异进行基因分型，以识别单独导致心肌梗死风险的罕见变异；在目标 2 中，我们将开发用于罕见变异分析的新颖计算方法，以识别与 MI 相关的罕见变异；在目标 3 中，我们将开发一种罕见的变体方法，用于基于人群的 MI 风险分层。除了阐明罕见编码变异在心肌梗死风险中的作用外，这项为期五年的提案还概述了首席研究员在心血管医学学术领域职业发展的综合策略。该策略在逻辑上建立在主要研究者之前的研究经验和临床培训的基础上。获得博士学位后。在生物信息学领域，主要研究者完成了内科住院医师培训，目前正在完成心血管疾病的进修培训。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来实现，包括 Sekar Kathiresan 博士（人类遗传学和基因组学）和 Shaamil Sunyaev 博士（统计遗传学、风险建模）的指导、教学课程、科学研究和科学传播培训和研究伦理。这项工作将在一个独特的培训环境中进行，该环境由马萨诸塞州总医院、布莱根妇女医院和布罗德研究所的互补经验组成。成功完成该职业发展奖将有助于更好地了解 MI 的遗传基础，导致主要研究者转变为独立的医师科学家，并为他申请 RO1 级资助奠定坚实的基础。