Abstract 18248: Apolipoprotein E Gene Mutations in Subjects with Mixed Hyperlipoproteinemia and a Clinical Diagnosis of Familial Combined Hyperlipidemia
Introduction Familial combined hyperlipidemia (FCH) is characterized by elevated levels of total cholesterol (TC) and triglycerides (TG), vertical transmission of a variable hyperlipidemic phenotype, and high risk of premature cardiovascular disease. FCH is the most common cause of primary mixed hyperlipoproteinemia (MHLP). An APOE E2/E2 genotype in the presence of MHLP is diagnostic of familial dysbetalipoproteinemia. However, rare dominant mutations in APOE, which go undetected with the usual genotyping procedure, may also cause dysbetalipoproteinemia. Uncovering such rare APOE variants may change the diagnosis from FCH to dysbetalipoproteinemia.
Objectives To identify APOE mutations associated with dominant MHLP and to establish their frequency in subjects with a clinical diagnosis of FCH.
Methods We examined 472 unrelated subjects with dominant MHLP and a clinical diagnosis of FCH and 264 unrelated normolipidemic subjects (control group). Clinical and analytical determinations were done in all of them. Screening of LDLR and APOB gene mutations was performed with Lipochip, version 4 (Progenika, Derio, Spain). Entire APOE gene (4 exons and intron-flanking sequences) was sequenced.
Results In the MHLP group, 10 subjects had the E2/E2 genotype, and then, were diagnosed as dysbetalipoproteinemia. Twenty three subjects were carriers of a functional mutation in the LDLR gene. In the left 439 subjects with MHLP, two rare functional APOE variants, R136S and DeltaL149, were identified. Nine subjects (2.0%) were carriers of the R136S mutation and 6 subjects (1.4%) were carriers of the DeltaL149 mutation. In the control group, no rare APOE mutation was identified. Subjects with R136S mutation had higher VLDL-cholesterol/TG ratio and lower apoB/TC ratio, similar to those of E2/E2 subjects, suggesting a diagnosis of dysbetalipoproteinemia. However, subjects carrying the DeltaL149 mutation did not show this pattern, being their VLDL-cholesterol/TG and apoB/TC ratios similar to those of E3/E3 subjects.
Conclusion Rare mutations in the APOE gene, R136S and DeltaL149, were identified in subjects with mixed hyperlipoproteinemia and a clinical diagnosis of FCH, indicating that the APOE gene contributes to this phenotype.
- © 2011 by American Heart Association, Inc.