Discovery and Validation of Novel Loci Associated with HDL Function

描述（由申请人提供）：血浆HDL-C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“胆固醇外排能力”是衡量HDL功能的一种典型指标，它与动脉粥样硬化性心血管疾病显著相关——然而，影响HDL胆固醇外排能力的因素尚不清楚。南亚人特别适合研究新型心血管危险因素的生物学决定因素及其遗传决定因素，因为这些人群的心脏代谢疾病负担高。我们现有的南亚研究合作框架为开展与HDL功能相关的基因研究提供了一个独特的机会。我们假设，结合对HDL功能的强大分析，相当大的统计能力，以及对心血管疾病发病率特别高的人群的参与，将增强发现关键HDL功能的遗传决定因素的能力，即胆固醇外排能力。我们将采用GWAS方法来发现与南亚人高密度脂蛋白胆固醇外排能力相关的基因位点，并在南亚人和欧洲人中进行复制。我们将评估南亚人和欧洲人发现的与胆固醇外排能力显著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外排能力显著相关的新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，并有助于优先考虑最终降低心血管疾病风险的转化策略。

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.