Elevated levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease, and activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. In this study the exons of ANGPTL4 were sequenced in nearly 43,000 subjects from the DiscovEHR human genetics study to identify missense variants, including the previously known E40K variant, and other inactivating variants. Carriers of E40K and other inactivating mutations in ANGPTL4 had 13% lower levels of triglycerides and a 19% lower risk of coronary artery disease than did noncarriers. Additional experiments revealed that the inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. These results highlight the strategy of inhibition of angiopoietin-like 4 for coronary heart disease prevention.
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- Research Center: Mid-Atlantic, Maryland
- Center Contribution: The Center helped support maintenance and analyses of the MyCode biobank used in this study.