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）是美国死亡的主要原因，是可遗传的。关注常见遗传变异的大型研究现已鉴定出与MI风险相关的30多个基因座。尽管取得了成功，但这些常见变体仅解释了MI的遗传基础的一小部分。种群遗传学和候选基因研究支持以下假设：较不常见的遗传变异在复杂疾病（例如MI）中起重要作用。在此提案中，我们概述了几种探索罕见遗传变异在MI风险中的作用的方法。使用一组稀有的（次要等位基因频率<5％）编码变体通过整个外显子组测序（即基因组的所有蛋白质编码区域）鉴定出来，我们将测试稀有变体对MI的风险有助于单独，集体和进一步进一步促进这种知识可以改善人群风险分层的假设。为了检验这些假设，我们提出以下具体目的：在AIM 1中，我们将基因型外显子体变体在供应良好的病例/对照研究中，以识别稀有的变体，这些变体单独促进MI风险；在AIM 2中，我们将开发用于稀有变体分析的新型计算方法，以识别与MI共同相关的稀有变体。在AIM 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。除了阐明罕见的编码变化在MI风险中的作用外，该五年提案还概述了主要研究者在学术心血管医学中的职业发展的综合战略。从逻辑上讲，该策略是基于主要研究者先前的研究经验和临床培训的基础。获得博士学位后在生物信息学中，校长研究人员完成了内科居住培训，目前正在完成心血管疾病的奖学金培训。现在，该提议专注于通过获得人类遗传学和基因组学，统计遗传学和风险建模的其他知识和实践研究经验来扩大他的科学技能。职业发展目标将通过涉及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，科学研究以及科学沟通和科学沟通和研究伦理学的培训的多方面方法来实现。这项工作将在一个独特的培训环境中进行，包括马萨诸塞州综合医院，杨百翰和妇女医院以及广大研究所的补充经历。成功完成这项职业发展奖将使MI的遗传基础有更好的了解，从而导致首席调查员向独立的医师科学家的过渡，并为他提供坚实的基础，他将向他申请RO1级资金。