Genetic Mediators of Metabolic Cardiovascular Disease Risk

描述(由申请人提供)：这项重大机遇(RC2)拨款是为了响应NHLBI呼吁对表型良好的NHLBI队列进行大规模DNA测序和分子图谱分析的建议以及描述分子图谱的附录部分而写的。识别心血管风险的分子预测因子非常有意义，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做出更精细和准确评估的能力，还因为它们提供了了解这种不可预测疾病的冠状动脉疾病生物学和事件风险的力量。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，这些研究对象已经被精确地表征和表型，并对其进行了完整和详细的随访。一群人。该项目将使用杜克CATHGEN生物资料库，这是在2001年1月至今与杜克心脏导管实验室首次相遇时登记的个人的预期队列。所有个人都在六个月后获得后续健康状况调查，然后在第一次接触后每年进行一次。此外，每年的死亡人数是使用公共可用的资源进行评估的，例如国家死亡指数。该项目将重点关注后续事件(主要是心肌梗死和死亡)。研究队列中的所有成员都有用药数据。分子图谱。我们已经从这个队列中获得了2000个匹配的病例和对照(每个1000个)的集中代谢谱，并观察到无论疾病状态如何，后续事件的重要代谢预测因子。此外，我们最近公布的数据显示，外周基因表达生物标记物具有显著的预测能力。最后，在这个队列上正在构建一个详细的预测模型，其中的输入是现成的，并且众所周知的心血管风险的临床预测因素。目标。在这项研究中，我们建议：1)对已经进行代谢分析的同一2000名受试者进行外周基因表达分析；2)在相同的队列中进行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)单独定义分子预测因子的预测能力，并结合临床模型；4)定义由遗传变异定义的分子途径以及由遗传贡献者引起的风险比例。 公共卫生相关性：个性化医疗是该国当前健康目标的一个目标，它需要确定和量化个人风险的方法。为了在风险评估和开发新的治疗方法方面取得进展，人们必须了解前瞻性研究队列中分子标记的遗传结构，这些研究对象已经被精确地表征和表型，并且对其进行了完整和详细的随访。我们将结合心血管风险的外周小分子代谢标记物、外周基因表达谱和全基因组SNP筛查的知识来开发心血管风险的全面分子图谱。

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.