Abstract 332: Coronary Artery Disease-Protective Variant A43T in APOC3 Alters Circulating ApoC-III Levels In vivo

Elevated plasma triglycerides (TG) raise risk of coronary artery disease (CAD) independently of low-density lipoprotein cholesterol (LDL-C). Recent human genetics studies have shown that genetically lower TG through loss-of-function (LoF) of APOC3 lowers risk of developing CAD. APOC3 encodes apolipoprotein C-III (ApoC-III), an apolipoprotein on VLDLs and HDLs that inhibits the lipoprotein lipase (LPL) pathway of postprandial TG clearance. The specific molecular mechanisms underlying the reduction of TG and CAD risk by APOC3 LoF mutations are not known. Here, we study the mechanism of LoF for one of the 4 disease-protective APOC3 coding variants, A43T, in humans and rodent models. We recruited human subjects with this variant for deep phenotyping of TG metabolism and show that carriers of this variant have lower plasma ApoC-III in vivo, and possibly increased LPL activity. Using an adeno-associated virus (AAV) vector to express WT vs. mutant human APOC3 in mice, we show that the A43T variant also lowers circulating ApoC-III levels. Additional studies are ongoing to determine the mechanism of lower stability of ApoC-III A43T on TG-rich lipoprotein particles.