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: 8220555
• 负责人: John Navid Danesh
• 金额: $ 67.53万
• 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/8220555
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We will perform assays related to HDL function (cholesterol efflux capacity and paraoxonase) in the Pakistan Risk of Myocardial Infarction Study (PROMIS). We will utilize existing genome wide association data to identify loci associated with the phenotypes perform replication studies in additional South Asian and European populations and determine the relationship with coronary artery disease in larger populations. We will further explore the mechanism using mouse models.

描述（由申请人提供）：HDL-C 的血浆水平与动脉粥样硬化性心血管疾病 (CVD) 的风险呈负相关。 然而，这种关联的因果基础受到质疑，需要进一步研究 HDL 功能及其与 CVD 的关系。 HDL“胆固醇流出能力”是 HDL 功能的典型指标，与动脉粥样硬化性 CVD 显着相关 - 然而，影响 HDL 胆固醇流出能力的因素却知之甚少。 南亚人特别适合研究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较重。我们现有的南亚人研究合作框架提供了一个独特的机会来开展强有力的研究，以调查与 HDL 功能相关的基因。 我们假设，对 HDL 功能的稳健检测、相当大的统计能力以及 CVD 发病率特别高的人群的参与相结合，将增强发现关键 HDL 功能（即胆固醇流出能力）的遗传决定因素的能力。 我们将采用 GWAS 方法来发现与南亚人 HDL 胆固醇流出能力相关的遗传位点，并在南亚人和欧洲人中复制。 我们将评估与南亚人和欧洲人的胆固醇流出能力显着相关的基因座与心血管结局（心肌梗死、缺血性中风）的关系。 最后，我们将对至少一个与胆固醇流出能力显着相关的新位点进行功能验证。 这些研究将增进对调节 HDL 功能的途径的理解，并有助于确定最终降低心血管疾病风险的转化策略的优先顺序。 公共健康相关性：我们将在巴基斯坦心肌梗死风险研究 (PROMIS) 中进行与 HDL 功能（胆固醇流出能力和对氧磷酶）相关的测定。 我们将利用现有的全基因组关联数据来识别与表型相关的基因座，在其他南亚和欧洲人群中进行复制研究，并确定与更大人群中冠状动脉疾病的关系。 我们将使用小鼠模型进一步探索该机制。