Discovery and Validation of Novel Loci Associated with HDL Function

与 HDL 功能相关的新基因座的发现和验证

• 批准号: 8403772
• 负责人: John Navid Danesh
• 金额: $ 64.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403772
• 关键词: Atherosclerosis; Biological; Biological Assay; Biological Markers; Biology; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Clinical; Clinical Medicine; Collaborations; Computer Simulation; Coronary Arteriosclerosis; Data; Data Set; Etiology; European; Funding; Genes; Genetic; Genetic Determinism; Genotype; Health Professional; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Housing; International; Ischemic Stroke; Joints; Lipids; Measurement; Measures; Metabolic; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nurses' Health Study; Outcome; Pakistan; Participant; Pathway interactions; Phenotype; Plasma; Population; Property; Publishing; Risk; South Asian; Staging; Translating; Validation; aryldialkylphosphatase; base; cardiovascular disorder risk; cardiovascular risk factor; cohort; cost effective; follow-up; genetic epidemiology; genetic manipulation; genome wide association study; genome-wide; in vivo; macrophage; mouse model; novel; reverse cholesterol transport; skills

PROJECT SUMMARY Plasma levels of HDL-C are inversely associated with the risk of atherosclerotic cardiovascular disease (CVD). However, the causal basis of this association has been questioned and there is a need for further studies on HDL functionality and its relationship to CVD. HDL "cholesterol efflux capacity," a prototypical measure of HDL function, is significantly associated with atherosclerotic CVD~ however, the factors that influence HDL cholesterol efflux capacity are poorly understood. South Asians are particularly well-suited to investigate biological determinants of novel cardiovascular risk factors and their genetic determinants because of the high burden of cardio-metabolic conditions in these populations. Our existing collaborative framework of studies in South Asians provides a unique opportunity to conduct powerful studies to investigate genes related to HDL function. We hypothesize that the combination of a robust assay for HDL function, considerable statistical power, and involvement of a population that has particularly high rates of CVD will enhance ability to discover genetic determinants of a key HDL function, namely cholesterol efflux capacity. We will employ a GWAS approach to discover genetic loci associated with HDL cholesterol efflux capacity in South Asians and replicate in both South Asians and Europeans. We will evaluate loci found to be significantly associated with cholesterol efflux capacity for their association with cardiovascular outcomes (MI, ischemic stroke) in South Asians and Europeans. Finally, we will perform functional validation of at least one novel locus significantly associated with cholesterol efflux capacity. These studies will advance understanding of the pathways that modulate HDL function and help to prioritize translational strategies that will ultimately reduce the risk of cardiovascular diseases.

项目概要 血浆 HDL-C 水平与动脉粥样硬化风险呈负相关 心血管疾病（CVD）。 然而，这种关联的因果基础是 质疑，需要进一步研究 HDL 功能及其与 化学气相沉积。 HDL“胆固醇流出能力”是 HDL 功能的典型指标，它显着影响 与动脉粥样硬化CVD相关〜然而，影响HDL胆固醇流出的因素 能力了解甚少。 南亚人特别适合调查 新型心血管危险因素的生物决定因素及其遗传决定因素 因为这些人群的心脏代谢状况负担很重。我们现有的 南亚人研究的合作框架提供了一个独特的机会来开展 调查与 HDL 功能相关的基因的有力研究。 我们假设 结合了对 HDL 功能的稳健检测、相当大的统计能力和参与度 CVD发病率特别高的人群的研究将增强发现遗传性疾病的能力 HDL 关键功能的决定因素，即胆固醇流出能力。 我们将聘请一名 GWAS 方法发现与 HDL 胆固醇流出能力相关的遗传位点 南亚人并在南亚人和欧洲人中复制。 我们将评估发现的基因座 与胆固醇流出能力显着相关，因为它们与 南亚人和欧洲人的心血管结局（心肌梗死、缺血性中风）。 最后，我们将 对至少一个与胆固醇显着相关的新位点进行功能验证 流出能力。 这些研究将增进对调节 HDL 途径的理解 发挥作用并帮助确定转化策略的优先顺序，最终降低风险 心血管疾病。