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.

Public Health Relevance

Although ANGPTL3 deficiency causes combined familial hypolipidemia, characterized by reduced levels of all three major lipid fractions, it is unknown if this deficiency protects against heart attack. Our proposal outlines several methods aimed at understanding the impact of ANGPTL3 deficiency in humans. Success has the potential to validate ANGPTL3 as a novel therapeutic target for disease prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL131961-05
Application #
9858413
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Papanicolaou, George
Project Start
2016-04-01
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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