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: 8585874
• 负责人: John Navid Danesh
• 金额: $ 66.99万
• 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/8585874
• 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.

项目摘要 HDL-C的血浆水平与动脉粥样硬化的风险成反比 心血管疾病（CVD）。 但是，该关联的因果基础已经 受到质疑，需要进一步研究HDL功能及其与之的关系 CVD。 HDL“胆固醇外排能力”是HDL功能的原型测量 然而，与动脉粥样硬化的CVD〜相关，影响HDL胆固醇外排的因素 能力知之甚少。 南亚人特别适合调查 新型心血管危险因素及其遗传决定因素的生物决定因素 由于这些人群中有氧代谢条件的负担很高。我们的现有 南亚人的协作框架提供了一个独特的机会 有力研究与HDL功能有关的基因。 我们假设 强大的HDL功能，相当大的统计能力和参与的组合组合 CVD率特别高的人群将增强发现遗传的能力 关键HDL功能的决定因素，即胆固醇外排能力。 我们将采用一个 GWAS的方法发现与HDL胆固醇外排相关的遗传基因座 南亚人在南亚和欧洲人中复制。 我们将评估发现的基因座 与胆固醇外排的能力显着相关 南亚和欧洲人的心血管结局（MI，缺血性中风）。 最后，我们会的 对至少一个与胆固醇显着相关的新型基因座进行功能验证 排出容量。 这些研究将提高对调节HDL的途径的理解 功能并有助于优先考虑转化策略，最终将降低 心血管疾病。