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Rare coding variation and risk for myocardial infarction

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

CARLSON, DREW E.

项目受资助机构

WASHINGTON UNIVERSITY

项目编号

5K08HL114642-04

立项年度

2015

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

137160.00美元

学科

Cardiovascular; Clinical Research; Genetics; Heart Disease; Heart Disease - Coronary Heart Disease; Human Genome; Prevention;

学科代码

未公开

基金类别

Other Research Related

关键词

未公开

参与者

STITZIEL, NATHAN OLIVER

参与机构

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

项目标书摘要：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.

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  • 1.Human genetic insights into lipoproteins and risk of cardiometabolic disease

    • 关键词：
    • coronary artery disease; human genetics; lipoprotein metabolism; type 2diabetes;OF-FUNCTION MUTATIONS; DIABETES-MELLITUS; REDUCING LIPIDS; HDLCHOLESTEROL; CORONARY; VARIANTS; ASSOCIATION; TRIGLYCERIDES; EFFICACY;SAFETY

    Purpose of review Human genetic studies have been successfully used to identify genes and pathways relevant to human biology. Using genetic instruments composed of loci associated with human lipid traits, recent studies have begun to clarify the causal role of major lipid fractions in risk of cardiometabolic disease.Recent findings The causal relationship between LDL cholesterol and coronary disease has been firmly established. Of the remaining two major fractions, recent studies have found that HDL cholesterol is not likely to be a causal particle in atherogenesis, and have instead shifted the causal focus to triglyceride-rich lipoproteins. Subsequent results are refining this view to suggest that triglycerides themselves might not be causal, but instead may be a surrogate for the causal cholesterol content within this fraction. Other studies have used a similar approach to address the association between lipid fractions and risk of type 2 diabetes. Beyond genetic variation in the target of statin medications, reduced LDL cholesterol associated with multiple genes encoding current or prospective drug targets associated with increased diabetic risk. In addition, genetically lower HDL cholesterol and genetically lower triglycerides both appear to increase risk of type 2 diabetes.Summary Results of these and future human genetic studies are positioned to provide substantive insights into the causal relationship between lipids and human disease, and should highlight mechanisms with important implications for our understanding of human biology and future lipid-altering therapeutic development.

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