ANGPTL3 DEFICIENCY AND ATHEROSCLEROSIS IN HUMANS

 说明(申请人提供)：血管生成素样蛋白3(Angptl3)是一种肝脏分泌的循环蛋白，影响脂蛋白代谢。Angptl3功能丧失突变导致家族性混合性低脂血症(FHBL2)，这是一种孟德尔疾病，其特征是所有三种主要脂蛋白组分的水平都非常低。虽然Angptl3零等位基因似乎会带来有益的影响(降低低密度脂蛋白胆固醇和甘油三酯)，但它们也与潜在的有害影响有关(例如，降低高密度脂蛋白胆固醇介导的外排能力)。因此，目前还不确定人类的净生理效应是否能预防动脉粥样硬化和心肌梗死(MI)的发生。为了解决这个问题，我们建议利用Angptl3基因中自然发生的遗传变异来研究Angptl3缺乏的净生理后果。我们假设：(1)Angptl3功能缺失等位基因携带者降低了动脉粥样硬化和心肌梗死的风险，(2)Angptl3缺乏与其他一些遗传形式的低脂血症的不良代谢影响无关。为了检验这些假设，我们提出了以下目标。在目标1中，我们将通过检查携带两个、一个或零个Angptl3零等位基因的FHBL2家族成员来研究完全和部分Angptl3缺乏症。这些家庭成员的表型特征将包括用于评估亚临床动脉粥样硬化的冠状动脉计算机断层扫描血管成像，用于量化肝脏脂肪变性和纤维化程度的磁共振成像研究，以及用于评估餐后血糖和脂肪处理的刺激性代谢测试。这些研究将在完全和部分Angptl3缺乏的个人以及从每个家庭中选择的对照个人(即没有任何Angptl3功能丧失突变的个人)中进行。在目标2中，我们将研究Angptl3缺乏症在人群中的表型效应。我们将收集88,000个个体的现有Angptl3序列数据，全面识别遗传变异，使用体外分析实验定义哪些稀有等位基因会导致功能丧失，并测试这些功能丧失突变与心肌梗死和代谢表型的相关性。建议的目标的成功完成有望对Angptl3缺乏对人类的生理影响产生基本的见解，并提供信心，即抑制Angptl3将安全地降低MI的风险，MI是美国的主要死亡原因。

 DESCRIPTION (provided by applicant): Angiopoietin-like 3 (ANGPTL3) is a hepatically-secreted circulating protein that influences lipoprotein metabolism. Loss-of-function mutations in ANGPTL3 lead to familial combined hypolipidemia (FHBL2), a Mendelian disorder characterized by very low levels of all three major lipoprotein fractions. Although ANGPTL3 null alleles seem to lead to beneficial effects (lower low-density lipoprotein cholesterol and triglycerides), they ae also associated with potentially harmful effects (decreased high-density lipoprotein cholesterol-mediated efflux capacity, for example). Thus, it is currently uncertain if the net physiologic effet in humans will protect against the development of atherosclerosis and myocardial infarction (MI). To address this question, we propose to leverage naturally-occurring genetic variation in the ANGPTL3 gene to study the net physiologic consequences of ANGPTL3 deficiency. We hypothesize that: (1) carriers of ANGPTL3 loss-of-function alleles have reduced risk of atherosclerosis and MI and (2) ANGPTL3 deficiency is not associated with the adverse metabolic effects seen in some other genetic forms of hypolipidemia. To test these hypotheses, we propose the following aims. In Aim 1, we will study complete and partial ANGPTL3 deficiency by examining members of FHBL2 kindreds who carry two, one, or zero ANGPTL3 null alleles. The phenotypic characterization of these family members will include coronary computed tomography angiograms to assess for subclinical atherosclerosis, magnetic resonance imaging studies to quantify the degree of hepatic steatosis and fibrosis, and provocative metabolic tests to assess post-prandial glucose and lipid handling. These studies will be performed in individuals with complete and partial ANGPTL3 deficiency along with selected control individuals (i.e. individuals without any loss-of-function mutation in ANGPTL3) from each family. In Aim 2, we will study the phenotypic effects of ANGPTL3 deficiency in the population. We will assemble existing sequence data for ANGPTL3 in 88,000 individuals, comprehensively identify genetic variation, experimentally define which rare alleles lead to loss-of-function using in vitro assays, and test these loss-of-function mutations for association with MI and metabolic phenotypes. Successful completion of the proposed aims promises to yield fundamental insights regarding the physiologic effects of ANGPTL3 deficiency in humans and provide confidence that inhibiting ANGPTL3 will safely reduce risk for MI, the leading cause of death in the United States.