Discovery and Validation of Novel Loci Associated with HDL Function

项目摘要 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，这种关联的因果关系基础一直是 有必要进一步研究HDL的功能及其与 CVD。 HDL“胆固醇流出能力”是HDL功能的一个典型指标， 与动脉粥样硬化性CVD相关~然而，影响HDL胆固醇流出的因素 能力知之甚少。 南亚人特别适合调查 新的心血管危险因素的生物学决定因素及其遗传决定因素 因为在这些人群中心脏代谢状况的高负担。我们现有 南亚人研究的合作框架提供了一个独特的机会，进行 研究HDL功能相关基因的有力研究。 我们假设 结合HDL功能的稳健测定、相当大的统计功效和参与 心血管疾病发病率特别高的人群将提高发现遗传因素的能力， 关键HDL功能的决定因素，即胆固醇流出能力。 我们将雇用一名 GWAS方法发现与HDL胆固醇流出能力相关的遗传位点 在南亚人和欧洲人身上复制。 我们将评估发现的位点， 与胆固醇流出能力显著相关， 南亚人和欧洲人的心血管结局（MI、缺血性卒中）。 最后我们将 对至少一个与胆固醇显著相关的新基因座进行功能验证 外排能力 这些研究将促进对调节HDL的途径的理解 功能，并帮助优先考虑翻译策略，最终降低风险， 心血管疾病

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.