ANGPTL3 DEFICIENCY AND ATHEROSCLEROSIS IN HUMANS

ANGPTL3 缺陷与人类动脉粥样硬化

基本信息

批准号：
9083441
负责人：
Nathan Oliver Stitziel
金额：
$ 69.54万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9083441
关键词：
ANGPTL3 gene Address Adverse effects Alleles Angiography Atherosclerosis Biological Assay Biology Blood Vessels Cause of Death Cholesterol Clinical Cohort Studies Coronary Coronary Arteriosclerosis Data Development Disease Drug Targeting European Evaluation Family Family member Fatty Liver Fatty acid glycerol esters Functional Imaging Genes Genetic Genetic Variation Genetic study Glucose Goals Health Hepatic High Density Lipoprotein Cholesterol Human Human Genetics Individual International LDL Cholesterol Lipoproteins Laboratories Lead Lipids Lipoproteins Liver Fibrosis Magnetic Resonance Imaging Measurement Measures Mediating Mendelian disorder Metabolic Metabolic Diseases Metabolism Methods Missense Mutation Mutation Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Oral Other Genetics Pathway interactions Pharmaceutical Preparations Phenotype Physiological Population Population Genetics Protein Secretion Proteins Reagent Reporting Research Infrastructure Research Personnel Resources Risk Risk Factors Single Nucleotide Polymorphism Testing Triglycerides United States Variant X-Ray Computed Tomography clinical effect clinical phenotype cohort computerized data processing disorder prevention experience functional genomics hypolipidemia improved in vitro Assay insight kindred lipid metabolism lipoprotein lipase lipoprotein triglyceride loss of function loss of function mutation member metabolic phenotype mutational status new therapeutic target novel novel strategies novel therapeutics null mutation public health relevance rare variant spectroscopic imaging success therapeutic development

项目摘要

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.

描述（由申请人提供）：血管生成素样 3 (ANGPTL3) 是一种肝分泌的循环蛋白，影响脂蛋白代谢。ANGPTL3 的功能丧失突变会导致家族性混合性低脂血症 (FHBL2)，这是一种以极低脂血症为特征的孟德尔疾病。尽管 ANGPTL3 无效等位基因似乎会产生有益的影响（较低的低密度）。脂蛋白胆固醇和甘油三酯），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流出能力），因此，目前尚不确定对人类的净生理影响是否会预防动脉粥样硬化的发展。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其净生理后果。我们勇敢地承认：（1）ANGPTL3 功能丧失等位基因的携带者可以降低动脉粥样硬化和 MI 的风险，（2）ANGPTL3 缺乏与其他一些遗传形式的低脂血症中出现的不良代谢影响无关。为了检验这些假设，我们提出以下目标：在目标 1 中，我们将通过检查携带 2 个、1 个或 0 个 FHBL2 亲属的成员来研究完全和部分 ANGPTL3 缺陷。这些家族成员的 ANGPTL3 无效等位基因的表型特征将包括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造影、量化肝脏脂肪变性和纤维化程度的磁共振成像研究以及评估餐后葡萄糖和脂质处理的激发代谢测试。这些研究将在完全和部分 ANGPTL3 缺陷的个体以及选定的对照个体（即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 缺陷在群体中的表型影响。我们将收集 88,000 名个体中 ANGPTL3 的现有序列数据，全面鉴定遗传变异，通过实验确定哪些罕见等位基因导致缺失。使用体外测定来检测功能丧失，并测试这些功能丧失突变与 MI 和代谢表型的关联。成功完成所提出的目标有望产生有关生理学的基本见解。 ANGPTL3 缺陷对人类的影响，并提供了抑制 ANGPTL3 将安全降低心肌梗死风险的信心，心肌梗死是美国的主要死亡原因。