Abstract 17697: Plasma Levels of Angiopoietin-Like Proteins 3 and 4 are Associated with Lipid and Metabolic Factors but are not Independent Predictors of Coronary Artery Calcification

Abstract

Background: The angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) gene loci are significantly associated with plasma lipid phenotypes. Both ANGPTL3 and 4 inhibit lipoprotein lipase and ANGPTL3 also inhibits endothelial lipase. We investigated the association of plasma ANGPTL3 and 4 levels with lipid, metabolic, and inflammatory parameters and coronary artery calcification.

Methods: Plasma ANGPTL3 and 4 levels were measured in 1773 subjects from three separate studies: 1) asymptomatic adults with family history of premature coronary artery disease; 2) type 2 diabetic subjects without coronary artery disease; and 3) healthy subjects with one or more metabolic syndrome risk factors.

Results: In all three studies, subjects with ANGPTL3 levels in the highest quartile had significantly higher LDL-C levels than the lowest quartile, ranging from a mean difference of 7.1 mg/dL to 24.3 mg/dL higher (all with p<0.01). ANGPTL3 levels were not associated with fasting TG levels. Among diabetic subjects, HDL-C levels were 7.7 mg/dL higher (95% CI: 5.3-10.2 mg/dL, p<0.0001) in the highest ANGPTL3 quartile compared to the lowest quartile group. In contrast, subjects with ANGPTL4 levels in the highest quartile had significantly lower HDL-C levels than in the lowest quartile, most prominently in the T2DM cohort (4.6 mg/dL lower, 95% CI: -2.0 to -7.2 mg/dL, p<0.0001). ANGPTL4 levels were strongly associated with triglycerides (p=0.03), waist circumference, hsCRP and IL-6 (all p<0.0001). ANGPTL4 concentrations were strongly associated with metabolic syndrome (odds ratio: 1.98, 95% CI: 1.24-3.18, p=0.005). No significant association was seen between levels of ANGPTL3 and 4 and coronary artery calcium score upon Tobit regression analysis.

Conclusions: ANGPTL3 levels are strongly positively associated with LDL-C levels. ANGPTL4 levels are strongly associated positively with fasting TG levels and negatively with HDL-C levels, and overall with the metabolic syndrome. These findings extend the previous genetic findings and suggest that plasma ANGPTL3 and ANGPTL4 may represent biomarkers and mediators of metabolic and cardiovascular disease.