Metabolic Characterization of a Rare Genetic Variation Within APOC3 and Its Lipoprotein Lipase-Independent Effects

Abstract

Background: Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low-density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures.

Methods and results: A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low-density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low-density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL.

Conclusions: We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.

Keywords: LPL; VLDL; association studies; genetics; lipids; metabolism; triglycerides.

Figure 1.

APOC3(rs138326449) associations with selected metabolic measures in plasma in ALSPAC young participants and BWHHS–ALSPAC mothers in Beta/SE units. The variant is associated predominately with very low–density lipoprotein (VLDL) and high-density lipoprotein (HDL) concentration and composition, as well as particle size, cholesterol measures, and fatty acids. Multiple associations per particle are represented by a single entry. Information on the transformation used is also provided. Estimates and confidence intervals were scaled by the standard error of each measurement. Plot of the association of all 225 measured metabolites is given in Figure I in the Data Supplement. A detailed list of effect sizes and P values for all measures is given Table I in the Data Supplement. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; BWHHS, the British Women Heart Health Study; HDL, high-density lipoprotein; and IDL, intermediate-density lipoproteins.

Figure 2.

APOC3(rs138326449) and LPL(rs12678919) correlation of their respective associations with metabolic measures in plasma. The observed effects of LPL(rs12678919) are similar to those seen with APOC3(rs138326449). The black line is the line of perfect fit, whereas the blue line is the correlation between the 2 metabolic profiles of the 2 singe nucleotide polymorphism (SNPs) with slope equal to 0.87 for the ASPAC young participants. Estimates and confidence intervals were scaled by the standard error of each measurement. A detailed list of the association measures for all metabolites and the LPL(rs12678919) is given in Table II in the Data Supplement and plotted in Figure II in the Data Supplement. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; and BWHHS, the British Women Heart Health Study.

Figure 3.

Expected and observed APOC3–metabolites associations for the subset of metabolites with a lipoprotein lipase (LPL)–independent effect. The coefficients and confidence interval (CIs) are scaled by the SE of the observed effect. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; BWHHS, the British Women Heart Health Study; and VLDL, very low–density lipoprotein.