The Role of Scavenger Receptor Class B Type 1 in Humans

描述（由申请人提供）：高密度脂蛋白胆固醇（HDL-C）水平被认为可以预防心血管疾病。这在某些人群中可能是正确的，也可能不是。该研究项目的长期目标是确定脂蛋白受体（清道夫受体B类I型或SR-BI）的缺乏是否是高水平HDL-C的原因，也许是矛盾的，心血管疾病的风险增加。在特定目标1中，我们将进行体外实验，以检查某些SR-BI基因（SCARB1）变异影响SR-BI蛋白表达的机制。在特定目标2中，我们将继续招募HDL-C水平高于60 mg/dl的受试者（这是因为高于60 mg/dl的水平被认为具有心脏保护作用），并获取血液标本来测量胆固醇水平、DNA和表达SR-BI蛋白的单核细胞来源的巨噬细胞。我们将研究SCARB1基因内的遗传变异与脂质水平、巨噬细胞SR-BI蛋白和RNA表达以及SR-BI功能（通过放射性标记HDL摄取胆固醇酯来测量）的关系。我们还将在多种族动脉粥样硬化研究（MESA）的参与者和早发心肌梗死（心肌梗死遗传学联合研究）的受试者中研究SCARB1多态性与脂质水平和亚临床动脉粥样硬化的关系。我们的研究结果将进一步深入研究SR-BI对HDL-C水平升高受试者、以白人、非裔美国人、西班牙裔和亚洲血统为代表的更大人群（MESA）以及早发心肌梗死受试者的脂质水平和心血管疾病的作用。

DESCRIPTION (provided by applicant): High density lipoprotein cholesterol (HDL-C) levels are thought to protect against cardiovascular disease. This may or may not be true in certain populations. The long-term goal of this research project is to determine if a deficiency in the lipoprotein receptor, scavenger receptor class B type I or SR-BI, is a cause of high levels of HDL-C and, perhaps paradoxically, an increased risk for cardiovascular disease. In specific aim 1, we will perform in vitro experiments to examine the mechanism(s) by which certain SR-BI gene (SCARB1) variants affect SR-BI protein expression. In specific aim 2, we will continue recruiting subjects with HDL-C levels above 60 mg/dl (this is because levels above 60 mg/dl are thought to be cardioprotective) and obtaining blood specimens to measure cholesterol levels, DNA, and monocyte-derived macrophage that express SR-BI protein. We will examine the association of genetic variations within the SCARB1 gene with lipid levels, macrophage SR-BI protein and RNA expression and SR-BI function (as measured by the uptake of cholesteryl esters from radiolabeled HDL). We will also examine the association of SCARB1 polymorphisms and lipid levels and subclinical atherosclerosis in participants of the Multi-Ethnic Study of Atherosclerosis (MESA) and in subjects with premature myocardial infarction (Myocardial Infarction Genetics Consortium Study). The results from our studies will provide further insight into the role of SR-BI on lipid levels and cardiovascular disease in subjects with elevated levels of HDL-C, in a larger population (MESA) well-represented by persons of Caucasian, African-American, Hispanic and Asian ancestry, and in subjects with premature myocardial infarction. PUBLIC HEALTH RELEVANCE: High density lipoproteins (HDL) are considered the "healthy" or "good" fraction of the blood cholesterol levels. However, heart disease can occur despite a person having desirable levels of HDL. Our study will examine whether variations in the gene for the HDL receptor, scavenger receptor class B type I or SR-BI, might be associated with good levels of HDL and heart disease.