Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease

Abstract

BACKGROUND Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. METHODS We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys. RESULTS We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P = 0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels. CONCLUSIONS Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.)

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…The inverse correlation between ANGPTL4 and high‐density lipoprotein‐cholesterol HDL‐c (high‐density lipoprotein‐cholesterol) has been reported in European and American populations 12, 13. In line with these findings, ANGPTL4 variants have been identified in European subjects 14, 15, 16, 17. For instance, E40K carriers, who have loss‐of‐function mutation of ANGPTL4, display higher HDL‐c with reduced risk of coronary heart disease when compared with noncarriers 14, 15, 16, 17.…”

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

“…ANGPTL4 inhibits LPL and is a major regulator of LPL activity during fasting and exercise (101). Loss-offunction variants in ANGTPL4 are associated with reduced plasma TG levels and a lower risk of coronary artery disease (102)(103)(104)(105). The inhibition of ANGPTL4 with antibody reduced serum TG levels in mice and monkeys (105).…”

“…Loss-offunction variants in ANGTPL4 are associated with reduced plasma TG levels and a lower risk of coronary artery disease (102)(103)(104)(105). The inhibition of ANGPTL4 with antibody reduced serum TG levels in mice and monkeys (105). The hypolipidemic effects of the pharmacological inhibition of ANGPTL3 and ANGPTL4 in humans await further studies.…”

Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes

“…Furthermore, ANGPTL4 has become extremely topical lately due to recent reports showing that carriers of either rare inactivating mutations or common loss-of-function variants (10,53) had an improved plasma lipid profile, with reduced TGs and higher HDL cholesterol, together with reduced CHD risk. In particular, the ANGPTL4 p.E40K variant, which is present in ~3% of Caucasians and has virtually no inhibitory activity due to attenuated (54).…”