Abstract 14556: Deep Phenotyping APOC3 Knockouts in a Population With High Consanguinity

Apolipoprotein C-III (APOC3) plays an integral role in the regulation of triglyceride-rich lipoproteins, by inhibiting the clearance of triglycerides carried by VLDL and chylomicron remnants in the blood. Prior work has shown that heterozygous loss of function (LOF) carriers of APOC3 have lower triglyceride levels and a lower risk of coronary artery disease (CAD). The quantitative impact of disease risk remains unknown in complete knockouts (KOs). Additionally, the effects and safety implications of complete APOC3 LOF have not been characterized. APOC3 inhibition is an active therapeutic strategy to lower CAD risk; hence these questions have therapeutic relevance. Among 37,244 unrelated sequenced individuals, including 19,681 cases of myocardial infarction (MI), in the Pakistan Genomic Resource - a biobank with high levels of consanguinity - we identified 207 heterozygous LOF carriers and 14 KOs. As expected, the KOs had undetectable APOC3 levels. We also observed a decrease in plasma triglycerides (P = 9E-85), VLDL-C levels (P = 2E-73), APOE levels (P = 5.4E-9) and an increase in HDL-C levels (P = 1E-34) and APOA1 levels (P = 6E-5) consistent with a gene-dosage effect. We observed a significant decrease in the risk of MI among heterozygous carriers (P = 0.01); however, we did not observe any protection from MI risk in complete KOs. Conversely, we observed a non-significant increase in the risk of MI in complete KOs compared to non-carriers; of the 14 knockouts identified, 9 were found to have MI. The loss of protection against MI could not be explained by the genetic background or by the increase in levels of homozygosity of the KOs. By recalling complete KOs and their family members, we were able to identify and phenotype an additional 33 complete KOs and 152 heterozygotes and assess other safety concerns related to complete APOC3 inhibition (i.e., glucose intolerance, fat content in the liver, etc.). In conclusion, by leveraging a highly consanguineous cohort, we have identified and phenotyped APOC3 KOs that have, hitherto, not been identified elsewhere. We did not observe APOC3 LOF to confer protection in complete KOs and observed other biomarker and phenotypic associations; these findings should inform existing therapeutic programs targeting APOC3.