Genetic Mediators of Metabolic Cardiovascular Disease Risk

描述（由申请人提供）：这一重大机会（RC2）拨款是为了响应NHLBI关于高表型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。确定心血管风险的分子预测因子是非常有趣的，不仅因为它们有可能显著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，而且还因为它们提供了了解冠状动脉疾病生物学和这种不可预测疾病事件风险的能力。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物的遗传结构，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。该项目将使用杜克大学CATHGEN生物库，这是一个前瞻性队列，在2001年1月至今首次与杜克大学心导管实验室接触时注册的个体。所有个体在6个月后进行随访健康状况调查，然后在第一次接触后每年进行一次。此外，每年的死亡人数是利用国家死亡指数等公共资源进行评估的。该项目将侧重于后续事件（主要是心肌梗死和死亡）。研究队列中所有成员的用药数据均可获得。分子分析。我们已经从该队列中获得了2000例匹配病例和对照（各1000例）的集中代谢分析，并观察到与疾病状态无关的后续事件的显著代谢预测因子。此外，我们最近发表了来自该队列的数据，显示外周基因表达生物标志物的显著预测能力。最后，一个详细的预测模型正在这个队列中构建，其中输入是现成的和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)对已进行代谢谱分析的2000名受试者进行外周基因表达谱分析；2)在同一队列中执行GWAs。一旦有了重要的遗传和外周基因表达预测因子，我们将：3)确定单独的分子预测因子和结合临床模型的预测能力；4)确定由遗传变异定义的分子途径和由遗传因素引起的风险比例。

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.