Abstract 17: APOC3 A43T Variant Promotes ApoC-III Catabolism and Accelerates TG-rich Lipoprotein Clearance in Mice and Humans

Humans with loss-of-function (LoF) variants in APOC3 , the gene encoding apolipoprotein C-III (apoC-III), have significantly reduced plasma triglycerides (TG) and protection from coronary disease. These findings suggest that apoC-III may be a viable therapeutic target for decreasing vascular risk through TG reduction, and that elucidation of the protective mechanism of APOC3 LoF variants would inform such strategies. We report here the protective mechanism of the APOC3 A43T missense variant, one of four recently identified CAD-protective variants. By genotyping >8,000 human participants with low TG, we identified 17 APOC3 A43T carriers and phenotyped 6 carriers and 54 matched controls. A43T heterozygotes demonstrate a significant reduction in apoC-III levels relative to non-carriers (50% reduction, P3-fold higher apoC-III clearance rate in vivo (Pin vivo . We are currently performing analogous studies of WT vs. A43T apoC-III turnover and VLDL clearance in human APOC3 A43T carriers. Collectively, our results support the rationale for therapeutic efforts to target circulating apoC-III through disruption of its binding to lipoproteins, mirroring the genetics-driven approaches for targeting PCSK9 that have recently yielded novel therapies.