Metabolic characterisation of a rare genetic variation within APOC3 and its lipoprotein lipase independent effects

Background: Plasma triglyceride levels (TG) have been implicated in atherosclerosis and coronary heart disease (CHD). 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 TG, very-low density lipoprotein (VLDL) and high density lipoprotein (HDL) levels, as well as risk of CHD. We aimed to characterise 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 two European population cohorts. We analysed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL independent effects. 142 metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported TG and HDL associations, the variant was also associated with VLDL and HDL composition measures, other cholesterol measures and fatty acids. Comparison of the APOC3 and LPL associations revealed that measures of medium and very large VLDL composition could not be predicted by the action of APOC3 through LPL.

Conclusions: We characterised 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 TG metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.