Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia



      Rare mutations in the APOE gene, undetectable with the usual genotyping technique, are responsible for dominant familial dysbetalipoproteinemia (FD) and therefore could be easily misclassified as familial combined hyperlipidemia (FCHL). We aimed to identify APOE mutations associated with dominant combined hyperlipoproteinemia and to establish their frequency in subjects with a clinical diagnosis of FCHL.

      Methods and results

      In 279 unrelated subjects with FCHL in whom a functional LDLR mutation was excluded, sequencing of the entire APOE gene detected 9 carriers of a rare mutation: 5 subjects (1.8%) with the R136S mutation (arginine at residue 136 changed to serine) and 4 subjects (1.4%) with the p.Leu149del mutation, a 3-bp inframe deletion that results in the loss of leucine at position 149. Both genetic defects were detected with similar frequency (2.5% and 1.3%, respectively) in an independent group of 160 FCHL subjects from other locations in Spain. Family studies demonstrated cosegregation of these APOE mutations with hyperlipoproteinemia. R136S carriers showed dysbetalipoproteinemia, while the lipid phenotype of p.Leu149del carriers was IIa or IIb.


      Rare APOE mutations are responsible for approximately 3.5% of FCHL cases in our population. APOE R136S and p.Leu149del induce autosomal dominant FD and a phenotype indistinguishable from FCHL, respectively.


      • Rare APOE mutations are responsible for approximately 3.5% of FCHL cases in our population.
      • APOE R136S mutation induces autosomal dominant familial dysbetalipoproteinemia.
      • APOE p.Leu149del induces a phenotype indistinguishable from familial combined hyperlipidemia.


      FH (familial hypercholesterolemia), FD (familial dysbetalipoproteinemia), FCHL (familial combined hyperlipidemia), CVD (cardiovascular disease), Apo (apolipoprotein), LDL (low-density lipoprotein), VLDL (very low-density lipoprotein), IDL (intermediate-density lipoprotein), HDL (high-density lipoprotein), IR (interquartile ranges)


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