APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

Int J Mol Sci. 2022 May 21;23(10):5792. doi: 10.3390/ijms23105792.

Abstract

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.

Keywords: ADH; APOE gene; FCHL; apolipoprotein E; hypercholesterolemia; mutation; variant.

MeSH terms

  • Apolipoproteins E* / genetics
  • Apolipoproteins E* / metabolism
  • Cholesterol, LDL / genetics
  • Cholesterol, LDL / metabolism
  • Humans
  • Hyperlipoproteinemia Type II* / genetics
  • Hyperlipoproteinemia Type II* / metabolism
  • Proprotein Convertase 9* / genetics
  • Proprotein Convertase 9* / metabolism

Substances

  • ApoE protein, human
  • Apolipoproteins E
  • Cholesterol, LDL
  • Proprotein Convertase 9

Grants and funding

This work was supported by grants from the national project CHOPIN (CHolesterol Personalized Innovation) granted by the National Research Agency (ANR-16-RHUS-0007), INSERM (Institut National de la Santé et de la Recherche Médicale). YAK was supported by a grant from Ministère de l’Education Nationale et de la Technologie (France), a grant from Nouvelle Société Francophone de l’Athérosclérose (France), and grants from the Lebanese National Council for Scientific Research (CNRS-L) and the Council of Research of Saint-Joseph University of Beirut, Lebanon.