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心血管疾病（CVD）的风险成反比。 但是，该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“胆固醇外排能力”是HDL功能的原型测量，与动脉粥样硬化CVD显着相关 - 但是，影响HDL胆固醇外排能力的因素知之甚少。 南亚人特别非常适合研究新型心血管危险因素及其遗传决定因素的生物学决定因素，因为这些人群中有心脏代谢条件的负担很高。我们现有的南亚研究协作框架为进行强大的研究提供了一个独特的机会，以研究与HDL功能相关的基因。 我们假设对HDL功能的强大测定法的结合，相当大的统计能力以及CVD率特别高的人群的参与将增强发现关键HDL功能（即胆固醇外排能力）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和南亚人和欧洲人复制HDL胆固醇外排相关的遗传基因座。 我们将评估发现与南亚和欧洲人与心血管结局（MI，缺血性中风）相关的胆固醇外排能力显着相关的基因座。 最后，我们将对至少一个与胆固醇外排能力显着相关的新型基因座进行功能验证。 这些研究将促进对调节HDL功能的途径的理解，并有助于优先考虑转化策略，以最终降低心血管疾病的风险。 公共卫生相关性：我们将在巴基斯坦的心肌梗塞研究风险（Promis）中执行与HDL功能（胆固醇外排能力和副氧酶）有关的测定。 我们将利用现有的基因组广泛的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，并确定较大人群中与冠状动脉疾病的关系。 我们将使用鼠标模型进一步探索机制。