Expression of type III hyperlipoproteinemia in apolipoprotein E2 (Arg158 → Cys) homozygotes is associated with hyperinsulinemia
Open accessAbstract
Type III hyperlipoproteinemia (HLP) is mainly found in homozygous carriers of apolipoprotein E2 (apoE2, Arg158→Cys). Only a small percentage (<5%) of these apoE2 homozygotes develops hyperlipidemia, indicating that additional environmental and genetic factors contribute to the expression of type III HLP. In the present study, first, the prevalence of type III HLP among apoE2 homozygotes was estimated in a Dutch population sample of 8888 participants. Second, 68 normocholesterolemic and 162 hypercholesterolemic apoE2 homozygotes (type III HLP patients) were collected to investigate additional factors influencing type III HLP expression. In the Dutch population sample, apoE2 homozygosity occurred with a frequency of 0.6% (57 of 8888 individuals). Among the 57 E2/2 subjects, 10 type III HLP patients were identified (prevalence 18%). Comparison of normocholesterolemic E2/2 subjects and type III HLP patients showed that the latter had a significantly increased body mass index (25.6±4.0 versus 26.9±3.8 kg/m 2 , respectively; P =0.03) and prevalence of hyperinsulinemia (26% versus 63%, respectively; P <0.001). Multiple linear regression analysis demonstrated that most of the variability in type III HLP expression can be explained by fasting insulin levels (partial correlation coefficient ≈0.50, P <0.001). In contrast to men, apoE2 homozygous women aged ≥50 years had significantly higher plasma lipid levels than their counterparts aged <50 years. These data demonstrate that the expression of type III HLP in E2/2 subjects is elicited to a large extent by hyperinsulinemia. In addition, in female apoE2 homozygotes, the expression increases with age; this increase is most likely due to the loss of estrogen production.
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FD has a complex multifactorial phenotype caused by the interaction of APOE gene variants with additional factors such as overweight or obesity, insulin resistance, diabetes mellitus, and hypothyroidism.
“FD (OMIM #617347) has a complex multifactorial phenotype caused by the interaction of APOE gene variants with additional factors such as overweight or obesity [17,18,19], insulin resistance [17,18,20], diabetes mellitus [17,21], hypothyroidism, and so forth.”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [18]
The introduction says apoE2 homozygosity plus additional factors can produce type III hyperlipoproteinemia and names obesity, diabetes, and hypothyroidism as suggested influences. The discussion (p. 296) identifies hyperinsulinemia as an additional factor, but says insulin sensitivity was not directly measured; it suggests a role for insulin resistance rather than establishing that it causes the phenotype. (LLM, conf=0.84)
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Zannis, V. I., & Breslow, J. L. (1981) · Biochemistry · doi:10.1021/bi00507a059 · Cited by 563 · see citing works
Human Body Composition and the Epidemiology of Chronic Disease
Baumgartner, R. N., Heymsfield, S. B., & Roche, A. F. (1995) · Obesity Research · doi:10.1002/j.1550-8528.1995.tb00124.x · Cited by 413 · see citing works
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Research works printed but not linked: 1
- [1]1. Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH, Taylor JM. Apolipoprotein E: genetic variants provide insights into it structure and function. Curr Opin Lipidol. 1990;1:87–95.
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Prevalence of Dysbetalipoproteinemia in the UK Biobank According to Different Diagnostic Criteria
Paquette, M., Trinder, M., Guay, S.-P., Brunham, L. R., & Baass, A. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae259 · Cited by 19 · see citing works
Blokhina, A. V., Ershova, A. I., Kiseleva, A. V., Sotnikova, E. A., Zharikova, A. A., Zaicenoka, M., Vyatkin, Y. V., Ramensky, V. E., Kutsenko, V. A., Garbuzova, E. V., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312651 · Cited by 8 · see citing works
- Authors
- de Beer, F., Stalenhoef, A. F. H., Hoogerbrugge, N., Kastelein, J. J. P., Gevers Leuven, J. A., van Duijn, C. M., Havekes, L. M., & Smelt, A. H. M.
- Affiliations
- From the Department of General Internal Medicine (F.d.B., L.M.H., A.H.M.S.), Leiden University Medical Center, and TNO–Prevention and Health (F.d.B., J.A.G.L., L.M.H.), Gaubius Laboratory, Leiden, the Netherlands; the Department of Medicine (A.F.H.S.), Division of General Internal Medicine, University Hospital Nijmegen, Nijmegen, the Netherlands; the Department of Internal Medicine (N.H.), University Hospital Dijkzigt, and Department of Epidemiology and Biostatistics (C.M.v.D.), Erasmus University...
- Leiden University (NL)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2002-02
- Volume
- 22
- Issue
- 2
- Pages
- 294-299
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2145819586
- Cited by
- 74
- References
- 2
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 1 · 2012: 2
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- TNO Repository (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type III hyperlipoproteinemia, apolipoprotein E2, hyperinsulinemia, fasting insulin, hypercholesterolemia, prevalence, body mass index, sex differences, aging, estrogen loss, plasma lipids, genetic susceptibility
- MeSH terms
- Adult, Aging, Apolipoproteins E, Coronary Disease, Estrogens, Female, Gene Frequency, Homozygote, Humans, Hyperinsulinism, Hyperlipoproteinemia Type III, Male, Menopause, Middle Aged, Netherlands, Regression Analysis, Sex Factors, Gene Expression, Comorbidity, Prevalence, Peripheral Vascular Diseases, Age of Onset, Apolipoprotein E2
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