ANGPTL3 DEFICIENCY AND ATHEROSCLEROSIS IN HUMANS

 描述（由申请方提供）：血管生成素样3（ANGPTL3）是一种肝脏分泌的循环蛋白，影响脂蛋白代谢。ANGPTL3中的功能丧失突变导致家族性组合性低脂血症（FHBL2），这是一种孟德尔疾病，其特征在于所有三种主要脂蛋白组分的水平非常低。尽管ANGPTL3无效等位基因似乎导致有益作用（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作用（例如降低高密度脂蛋白胆固醇介导的外排能力）相关。因此，目前尚不确定人类的净生理效应是否会防止动脉粥样硬化和心肌梗死（MI）的发展。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缺陷的净生理后果。我们假设：（1）ANGPTL3功能丧失等位基因的携带者具有降低的动脉粥样硬化和MI的风险，和（2）ANGPTL3缺乏与在某些其他遗传形式的低脂血症中观察到的不良代谢作用无关。为了验证这些假设，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无效等位基因的FHBL2激酶成员来研究完全和部分ANGPTL3缺陷。这些家族成员的表型表征将包括冠状动脉计算机断层扫描血管造影以评估亚临床动脉粥样硬化，磁共振成像研究以量化肝脂肪变性和纤维化的程度，以及激发性代谢试验以评估餐后葡萄糖和脂质处理。这些研究将在具有完全和部分ANGPTL3缺乏沿着的个体中以及来自每个家族的选定对照个体（即，ANGPTL3中没有任何功能丧失突变的个体）中进行。在目标2中，我们将研究ANGPTL3缺陷在人群中的表型效应。我们将在88，000名个体中收集ANGPTL3的现有序列数据，全面鉴定遗传变异，使用体外测定法通过实验确定哪些罕见等位基因导致功能丧失，并测试这些功能丧失突变与MI和代谢表型的相关性。成功完成拟议的目标有望产生关于人类ANGPTL3缺乏的生理效应的基本见解，并提供抑制ANGPTL3将安全降低MI风险的信心，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.