Adiposity and the development of dyslipidemia in APOE ε2 homozygous subjects: A longitudinal analysis in two population-based cohorts
Open accessAbstract
BACKGROUND AND AIMS: Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE ε2 allele, but genetic predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hit - notably adiposity or insulin resistance - is required, but the association between these risk factors and development of FD has not been studied prospectively. METHODS: For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE ε2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemia - likely to be FD - was defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated. RESULTS: Eleven of the 69 ε2ε2 subjects (16%) developed dyslipidemia - likely FD - during follow-up. Age-, sex- and cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04-1.39), waist circumference (OR 1.26 95%CI 1.01-1.61) and presence of non-TG metabolic syndrome (OR 4.39; 95%CI 1.04-18.4) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia. CONCLUSIONS: Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE ε2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD.
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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 [19]
The Introduction (page not provided) describes APOE ε2 predisposition together with adiposity and insulin resistance as possible contributors to the FD phenotype. The Discussion (page not provided) finds baseline adiposity associated with later FD-like dyslipidemia, but the type 2 diabetes association was not statistically significant; the paper does not establish the full causal interaction asserted. Hypothyroidism has no citation attached to it in the citing sentence. (LLM, conf=0.86)
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Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease
Marais, A. D. (2019) · Pathology · doi:10.1016/j.pathol.2018.11.002 · Cited by 382 · see citing works
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- F.J. Wolters, Q. Yang, M.L. Biggs, J. Jakobsdottir, S. Li, D.S. Evans, et al., The impact of APOE genotype on survival: results of 38,537 participants from six population-based cohorts (E2-CHARGE), PloS One (2019) 14 (7):e0219668.
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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
- Heidemann, B. E., Wolters, F. J., Kavousi, M., Gruppen, E. G., Dullaart, R. P., Marais, A. D., Visseren, F. L., & Koopal, C.
- Affiliations
- Utrecht University (NL)
- Erasmus MC (NL)
- University Medical Center Groningen (NL)
- University of Cape Town (ZA)
- Corresponding author
- Visseren, Frank LJ.
- ORCID
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 325
- Pages
- 57-62
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W3142570895
- Cited by
- 21
- References
- 1
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 5
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Atherosclerosis (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, cc-by-nc-nd)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by-nc-nd)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Nierstichting
- 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
- familial dysbetalipoproteinemia, dyslipidemia, adiposity, body mass index, waist circumference, metabolic syndrome, type 2 diabetes, remnant lipoproteins, triglycerides, cardiovascular risk, PREVEND cohort, Rotterdam Study
- MeSH terms
- Cross-Sectional Studies, Diabetes Mellitus, Type 2, Humans, Prospective Studies, Adiposity, Dyslipidemias, Apolipoprotein E2
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