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Cited by 27Lipid metabolism and disordersLipoproteins and Cardiovascular HealthGenomics and Rare Diseases

Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene

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Heidemann, Britt E., Koopal, Charlotte, Baass, Alexis, Defesche, Joep C., Zuurbier, Linda, Mulder, Monique T., Roeters van Lennep, Jeanine E., Riksen, Niels P. +3 more·2022·Clinical Genetics
DOI 10.1111/cge.14185PMC PMC9543580
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Abstract

Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol‐enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow‐up, and family counseling.

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  • The assessment of pathogenicity of rare APOE variants for FD has either not been performed or has not been fully presented in publications.

    “The assessment of the pathogenicity of these variants for FD has either not been performed or has not been fully presented in publications [30].”

    From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [30]

    The ‘Analysis of Genetic Variants in the APOE Gene’ section says new variants may be classified using general genetic principles rather than studies establishing a causal relationship with FD. The ‘Approaches to Establish a Causal Relation’ section recommends publishing comprehensive assessments. These passages support the concern that FD-specific assessment can be incomplete, but they do not establish that assessments of the variants in question were not performed or were not fully presented in publications; page numbers were unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • To date, only about 30 APOE variants associated with autosomal dominant FD have been reported.

    “To date, only about 30 APOE variants associated with autosomal dominant FD have been reported [29,30].”

    From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [30]

    The Introduction reports 23 APOE variants other than ε2ε2 associated with FD, rather than about 30. The Analysis of Genetic Variants section says these variants are often inherited dominantly, not that all 23 are associated with autosomal dominant FD. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Establishing the causal role of APOE variants to FD is complicated due to the multifactorial etiology of this disease.

    “Establishing the causal role of APOE variants to FD is complicated due to the multifactorial etiology of this disease [30].”

    From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [30]

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Cited by

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Authors
Heidemann, B. E., Koopal, C., Baass, A., Defesche, J. C., Zuurbier, L., Mulder, M. T., Roeters van Lennep, J. E., Riksen, N. P., Boot, C., Marais, A. D., & Visseren, F. L. J.
Affiliations
  • Utrecht University (NL)
  • Montreal Clinical Research Institute (CA)
  • Amsterdam University Medical Centers (NL)
  • Erasmus MC (NL)
  • Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands
  • Radboud University Medical Center (NL)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
  • University of Cape Town (ZA)
Corresponding author
Visseren, Frank L. J.
ORCID
Venue
Clinical Genetics
Publisher
Wiley
Published
2022-08-22
Volume
102
Issue
4
Pages
253-261
ISSN
  • 0009-9163 (ISSN-L)
  • 1399-0004
DOI
10.1111/cge.14185
PMC
PMC9543580
OpenAlex
W4283802206
Cited by
27
References
11
Citations by year
2026: 9 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 1
FWCI
0.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by-nc-nd)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
familial dysbetalipoproteinemia, APOE gene, APOE ε2 allele, genetic variants, remnant lipoproteins, cardiovascular risk, variant pathogenicity, family counseling, genotype-phenotype correlation
MeSH terms
Apolipoproteins E, Genotype, Humans, Hyperlipoproteinemia Type III, Phenotype

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