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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.