Genetic Mediators of Metabolic Cardiovascular Disease Risk

代谢性心血管疾病风险的遗传介质

• 批准号: 7939827
• 负责人: WILLIAM E KRAUS
• 金额: $ 137.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939827
• 关键词: Addendum; Address; African American; Antidiabetic Drugs; Architecture; Biological Markers; Biology; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Cessation of life; Clinical; Cohort Studies; Coronary Arteriosclerosis; Country; DNA Sequence; Data; Diabetes Mellitus; Disease; Dyslipidemias; Enrollment; Environment; Event; Gene Expression; Gene Expression Profiling; Genetic; Genetic Markers; Genetic Variation; Genome; Glean; Goals; Grant; Health; Health Status; Hypertension; Immune; Individual; Inflammation Mediators; Jupiter; Knowledge; Laboratories; Lipids; Mediating; Mediator of activation protein; Medicine; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolism; Methods; Modeling; Molecular; Molecular Profiling; Myocardial Infarction; National Heart, Lung, and Blood Institute; Obesity; Overweight; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Plant Roots; Positioning Attribute; Prospective Studies; Proteins; Publishing; Resources; Risk; Risk Assessment; Risk Factors; Risk Marker; Study Subject; Surveys; Techniques; Testing; Whole Blood; Writing; base; biobank; burden of illness; cardiovascular disorder risk; cardiovascular risk factor; case control; cohort; disorder risk; follow-up; genetic profiling; genetic variant; genome-wide; improved; indexing; interest; lifestyle intervention; member; molecular marker; novel therapeutic intervention; prospective; public health relevance; repository; response

DESCRIPTION (provided by applicant): This Grand Opportunity (RC2) grant is written in response to NHLBI call for proposals on Large-scale DNA Sequencing and Molecular Profiling of Well-phenotyped NHLBI Cohorts and the addendum portion describing Molecular Profiling. The identification of molecular predictors of cardiovascular risk is of great interest, not only because of their potential to significant improve our ability to make more refined and accurate assessment of disease burden and risk in the clinical environment, but also because of the power they provide to understand the biology of coronary artery disease and event risk in this unpredictable disease. In order to make advancements in risk assessment and new therapeutic approaches, it is imperative that we understand the genetic architecture of molecular markers in prospective study cohorts where the study subjects have been exquisitely characterized and phenotyped and on which follow-up is complete and detailed. Cohort. The project will use the Duke CATHGEN biorepository, which is a prospective cohort of individuals enrolled upon first encounter with the Duke Cardiac Catheterization Laboratory between January 2001 and present. All individuals obtain follow-up health status surveys at six months and then yearly following their first encounter. Also, yearly death is assessed using publically available resources, such as the National Death Index. The project will focus on subsequent events (primarily myocardial infarction and death). Medication data are available on all members of the study cohort. Molecular Profiling. We have already obtained focused metabolic profiling on 2000 matched cases and controls (1000 of each) from this cohort and observed significant metabolic predictors of subsequent events irrespective of disease status. Also, we recently have published data from this cohort showing significant predictive power of peripheral gene expression biomarkers. Finally, a detailed predictor model is being constructed on this cohort, where the input is readily available and well know clinical predictors of cardiovascular risk. Aims. In this study, we propose to: 1) Perform peripheral gene expression profiling on the same 2000 subject cohort in which the metabolic profiling has been performed; 2) Perform a GWAs in this same cohort. Once significant genetic, and peripheral gene expression predictors are available, we will: 3) Define the predictive power of the molecular predictors alone and in combination with the clinical model; 4) Define the molecular pathways defined by the genetic variants and the proportion of risk that is due to genetic contributors. PUBLIC HEALTH RELEVANCE: Personalized medicine, a goal of the current health goals of the country, requires methods to identify and quantify individual risk. In order to make advancements in risk assessment and develop new therapeutic approaches, it is imperative that one understand the genetic architecture of molecular markers in prospective study cohorts where the study subjects have been exquisitely characterized and phenotyped and on which follow-up is complete and detailed. We will combine knowledge of peripheral small molecular metabolic markers of cardiovascular risk, peripheral gene expression profiles and a genome wide SNP screen to develop comprehensive molecular profiles of cardiovascular risk.

描述（由申请人提供）：这项重大机会 (RC2) 拨款是为了响应 NHLBI 征集关于良好表型 NHLBI 队列的大规模 DNA 测序和分子分析的提案以及描述分子分析的附录部分而编写的。心血管风险分子预测因子的识别引起了人们极大的兴趣，不仅因为它们有可能显着提高我们在临床环境中对疾病负担和风险进行更精细和准确评估的能力，而且还因为它们为了解冠状动脉疾病的生物学以及这种不可预测疾病的事件风险。为了在风险评估和新的治疗方法方面取得进展，我们必须了解前瞻性研究队列中分子标记的遗传结构，其中研究对象已经被精确地表征和表型，并且随访是完整和详细的。队列。该项目将使用杜克 CATHGEN 生物样本库，该样本库是 2001 年 1 月至今首次接触杜克心导管实验室时登记的前瞻性个体队列。所有个人都会在第一次接触后六个月和每年一次进行后续健康状况调查。此外，每年的死亡人数是使用公开资源（例如国家死亡指数）进行评估的。该项目将重点关注后续事件（主要是心肌梗塞和死亡）。研究队列所有成员的用药数据均可用。分子分析。我们已经获得了该队列中 2000 名匹配病例和对照（各 1000 名）的集中代谢分析，并观察到后续事件的重要代谢预测因子，无论疾病状态如何。此外，我们最近发布了该队列的数据，显示了外周基因表达生物标志物的显着预测能力。最后，正在该队列上构建详细的预测模型，其中的输入是容易获得的并且是众所周知的心血管风险的临床预测因子。目标。在本研究中，我们建议：1) 对已进行代谢分析的同一 2000 名受试者队列进行外周基因表达分析； 2) 在同一队列中进行 GWA。一旦获得重要的遗传和外周基因表达预测因子，我们将： 3）单独定义分子预测因子以及与临床模型相结合的预测能力； 4) 定义由遗传变异定义的分子途径以及遗传因素造成的风险比例。 公共卫生相关性：个性化医疗是国家当前健康目标的一个目标，需要识别和量化个人风险的方法。为了在风险评估方面取得进展并开发新的治疗方法，必须了解前瞻性研究队列中分子标记的遗传结构，其中研究对象已被精确表征和表型，并且后续工作是完整和详细的。我们将结合心血管风险的外周小分子代谢标志物、外周基因表达谱和全基因组 SNP 筛选的知识，开发心血管风险的全面分子谱。

项目成果

Sex-dimorphic gene effects on survival outcomes in people with coronary artery disease.

性别二态基因对冠状动脉疾病患者生存结果的影响。

• 发表时间: 2022-05
• 作者: Dungan, Jennifer R;Qin, Xue;Gregory, Simon G;Cooper;Duarte, Julio D;Qin, Huaizhen;Gulati, Martha;Taylor, Jacquelyn Y;Pepine, Carl J;Hauser, Elizabeth R;Kraus, William E
• 通讯作者: Kraus, William E