Primary
hypercholesterolemia is characterized by elevated
LDL-cholesterol (
LDL-C) levels isolated in
autosomal dominant hypercholesterolemia (ADH) or associated with elevated
triglyceride levels in
familial combined hyperlipidemia (FCHL). Rare
APOE variants are known in ADH and FCHL. We explored the
APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9,
APOB, and
APOE revealed 76 carriers of a rare
APOE variant, with no mutation in LDLR, PCSK9, or
APOB. Among the 31
APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with
dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower
polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between
LDL-C levels and wPRS, suggesting a major effect of
APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an
APOE variant respond better to
statins than carriers of a LDLR mutation. Altogether, we show that the
APOE variants account for a significant contribution to ADH and FCHL.