1451-P: Associations between Circulating PCSK9 and ANGPTL3, ANGPTL8, and APOA5 in a Population-Based Cohort: Insights into Lipid Metabolism and Cardiometabolic Risk

Introduction and Objective: PCSK9 is a central regulator of LDL receptor metabolism, but emerging evidence suggests it may also influence triglyceride-rich lipoproteins via interaction with angiopoietin-like proteins and apolipoproteins. This study evaluates associations between PCSK9 and ANGPTL3, ANGPTL8, and ApoA5 in a well-characterized population cohort. Our objective is to assess the relationship between circulating PCSK9 and ANGPTL3, ANGPTL8, and ApoA5, and to explore how their levels vary across PCSK9 quartiles. Methods: Data from 1,501 adults were analysed. PCSK9 levels were stratified into quartiles and log-transformed for analysis. Associations were assessed using partial correlation and multivariable log-log regression adjusted for age, sex, BMI, and diabetes status. Quartile trends were evaluated using Kruskal-Wallis tests and Spearman correlations. Results: ANGPTL3 showed a significant positive association with PCSK9 (partial r = 0.270, p < 0.001; β = 0.224, 95% CI: 0.1815-0.2665). Median ANGPTL3 levels increased by 30.2% from Q1 to Q4 (KW p < 0.001). ANGPTL8 also exhibited a strong positive association (partial r = 0.264, p < 0.001; β = 0.195, 95% CI: 0.1611-0.2293), with a 39.7% increase across quartiles (KW p < 0.001). ApoA5 was inversely correlated with PCSK9 (partial r = -0.099, p < 0.001; β = -0.075, 95% CI: -0.1102 to -0.0398) and decreased by 8.4% across quartiles (KW p = 0.0103). All associations remained statistically significant after correction for multiple comparisons (FDR < 0.001). Conclusion: Circulating PCSK9 is positively associated with ANGPTL3 and ANGPTL8 and inversely associated with ApoA5. These findings support a broader role for PCSK9 in triglyceride metabolism, suggesting novel metabolic interactions relevant to diabetes and cardiometabolic risk beyond LDL-C regulation.