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APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

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Abou Khalil, Yara, Marmontel, Oriane, Ferrières, Jean, Paillard, François, Yelnik, Cécile, Carreau, Valérie, Charrière, Sybil, Bruckert, Eric +10 more·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23105792PMC PMC9145810
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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.

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  • APOE (c.44-1G>C) involves a mutation of the intron 2 acceptor site and apoE is not expressed from this allele.

    “APOE (c.44-1G>C) involves a mutation of the intron 2 acceptor site and apoE is not expressed from this allele, but no details were available other than that the case involved hypercholesterolemia.”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [40]

    Results §2.1 says c.44-1G>C destroys the intron 2 acceptor splice site. It predicts possible exon skipping or use of a cryptic splice site, but does not establish that apoE is not expressed from this allele; Discussion §3 likewise describes aberrant splicing as possible. Table 1 reports the carrier’s hyperlipidemia classification and lipid measurements. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • p.Leu46Pro has been described in patients with FH and familial combined hyperlipidemia.

    “Nevertheless, p.Leu46Pro has been described in patients with FH and familial combined hyperlipidemia [6,40].”

    From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [6]

  • Heterozygous APOE (c.44-1G>C) was recently discovered in the screening of hypercholesterolemic patients in a French cohort.

    “Heterozygous APOE (c.44-1G>C) was recently discovered in the screening of hypercholesterolemic patients in a French cohort40).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [40]

  • Ten novel APOE variants-APOE p.Thr11Ala, APOE p.Pro102Leu (Pro84Leu), APOE p.Arg137Cys (Arg119Cys), APOE p.Arg137His (Arg119His), APOE p.Leu155Phe (Leu137Phe), APOE p.Val179Ala (Val161Ala), APOE p.Val213Glu (Val195Glu), APOE p.Gly218Cys (Gly200Cys), APOE p.Glu249Lys (Glu231Lys), and APOE p.Glu252Lys (Glu234Lys)-were reported in a recent French cohort of ADH and CHL patients.

    “Finally, 10 novel APOE variants, namely, APOE p.Thr11Ala, APOE p.Pro102Leu (Pro84Leu), APOE p.Arg137Cys (Arg119Cys), APOE p.Arg137His (Arg119His), APOE p.Leu155Phe (Leu137Phe), APOE p.Val179Ala (Val161Ala), APOE p.Val213Glu (Val195Glu), APOE p.Gly218Cys (Gly200Cys), APOE p.Glu249Lys (Glu231Lys), and APOE p.Glu252Lys (Glu234Lys), were reported in a recent French cohort of ADH and CHL patients (”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [40]

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Authors
Abou Khalil, Y., Marmontel, O., Ferrières, J., Paillard, F., Yelnik, C., Carreau, V., Charrière, S., Bruckert, E., Gallo, A., Giral, P., Philippi, A., Bluteau, O., Boileau, C., Abifadel, M., Di-Filippo, M., Carrié, A., Rabès, J.-P., & Varret, M.
Affiliations
  • Laboratory for Vascular Translational Science (LVTS), Paris Cité University and Sorbonne Paris Nord University, INSERM, F-75018 Paris, France
  • Lyon 1 Université (FR)
  • Inserm (FR)
  • Centre Hospitalier Universitaire de Rennes (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Hospices Civils de Lyon (FR)
  • Department of Endocrinology and Prevention of Cardiovascular Disease, Institute of Cardio Metabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, F-75005 Paris, France
  • Centre National de la Recherche Scientifique (FR)
  • CarMen Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, F-69921 Oullins, France
Corresponding author
Varret, Mathilde
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-05-21
Volume
23
Issue
10
Pages
5792
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23105792
PMC
PMC9145810
OpenAlex
W4281249871
Cited by
21
References
8
Citations by year
2026: 5 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 1
FWCI
3.82
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • HAL (submittedVersion)
  • LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
Funders
  • CHOPIN (CHolesterol Personalized Innovation) (ANR-16-RHUS-0007)
  • National Research Agency (ANR-16-RHUS-0007)
  • INSERM (Institut National de la Santé et de la Recherche Médicale) (ANR-16-RHUS-0007)
  • Ministère de l’Education Nationale et de la Technologie (France) (ANR-16-RHUS-0007)
  • Nouvelle Société Francophone de l’Athérosclérose (France) (ANR-16-RHUS-0007)
  • Lebanese National Council for Scientific Research (CNRS-L) (ANR-16-RHUS-0007)
  • Council of Research of Saint-Joseph University of Beirut, Lebanon (ANR-16-RHUS-0007)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
primary hypercholesterolemia, familial combined hyperlipidemia, autosomal dominant hypercholesterolemia, LDL cholesterol, polygenic risk score, statin response, LDL receptor, PCSK9, apolipoprotein B, dyslipidemia, French cohort
MeSH terms
Proprotein Convertase 9, Apolipoproteins E, Humans, Hyperlipoproteinemia Type II, Cholesterol, LDL

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