189 - Characterization of seven novel ApoE pathogenic variants causing primary hyperlipemia (ID 298)
Abstract
Background and Aims
Autosomal dominant hypercholesterolemias (ADH) are monogenic disorders characterized by high plasma levels of low-density lipoprotein cholesterol and high risk of premature cardiovascular disease. In 80%-60% of primary hyperlipemia (PH) cases, it is caused by mutations in LDLR, ApoB and PCSK9 genes. However, in up to 20-40% of PH cases, a causative mutation in candidate genes is not found. Recently, it has been described that APOE p.(Leu167del) variant produces PH, constituting a new cause of ADH. In this work, we have assessed the pathogenicity of seven novel APOE variants found in hypercholesterolemic patients.
Methods
Affinity for LDLR was determined by ELISA and the effect of APOE variants on VLDL uptake was determined by flow cytometry in HepG2 cells incubated with DiI labelled VLDL. In addition, competition assays between LDL and VLDL for LDLR were performed to study the mechanism of action of the variants.
Results
We determined that the 7 APOE variants are pathogenic. While five of them showed less affinity than E3/E3 VLDL controls and a reduced VLDL uptake, two variants increased the affinity for the LDLR and show an enhanced VLDL uptake which leads to a downregulation of the LDLR.
Conclusions
Here we found 7 novel APOE pathogenic variants causing PH by different mechanism of action which highlights the contribution of this gene on the incidence of the disease.
