Contribution of APOE Genetic Variants to Dyslipidemia
Abstract
Background: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. Methods: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. Results: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. Conclusions: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE . However, more investigation is required to elucidate the significance of rarer variants of apoE.
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p.Arg154Cys is located in the critical APOE domain and alters the amino acid residue in which another variant, p.Arg154Ser, was found to be likely pathogenic for FD.
“This variant is located in the critical APOE domain [45,46] and alters the amino acid residue, in which another variant, p.Arg154Ser, was found to be likely pathogenic for FD [5,29,47].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [5]
APOE (c.237-33C>G) is a mutation adjacent to the splicing branchpoints of intron 3, which might impair splicing.
“Another example of an APOE variant, APOE (c.237-33C>G), recently reported in Spain, is a mutation adjacent to the splicing branchpoints of intron 3, which might impair splicing44).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
APOE (c.237-33C>G) was found to be in linkage disequilibrium with APOE2 (Arg158Cys) and only two of the four reported cases, where the other allele was also E2, had type III HLP, while the other two had CHL.
“However, it was found to be in linkage disequilibrium with APOE2 (Arg158Cys) and only two of the four reported cases, where the other allele was also E2, had type III HLP, while the other two had CHL.”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
APOE p.Arg121Trp (Arg103Trp) and APOE p.Arg165Trp (Arg147Trp) have recently been reported to cause type III HLP, but only in one case each, and it was not known whether they were dominant.
“APOE p.Arg121Trp (Arg103Trp) and APOE p.Arg165Trp (Arg147Trp) have also recently been reported to cause type III HLP, but only in one case each, and it was not known whether they were dominant44).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
A case of APOE p.Pro220Leu (Pro202Leu) with CHL was reported.
“while a case of APOE p.Pro220Leu (Pro202Leu) with CHL was also reported44).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
APOE p.Gly191Cys (Gly173Cys), APOE1 Barden (Arg180Cys), and APOE p.Pro220Leu (Pro202Leu) were shown to be located in the hinge region.
“APOE p.Gly191Cys (Gly173Cys), APOE1 Barden (Arg180Cys), and APOE p.Pro220Leu (Pro202Leu) were shown to be located in the hinge region44, 119).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
A case of an APOE p.Met82Ile (Met64Ile) heterozygote showed hypertriglyceridemia.
“In addition, a case of an APOE p.Met82Ile (Met64Ile) heterozygote showed hypertriglyceridemia44).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
A case exhibiting APOE p.Gly191Cys (Gly173Cys) heterozygosity showed isolated hypercholesterolemia.
“Moreover, a case exhibiting APOE p.Gly191Cys (Gly173Cys) heterozygosity showed isolated hypercholesterolemia44).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
APOE p.Arg108Trip (Arg90Trp) and APOE p.Tyr136His (Tyr118His) heterozygotes were detected in a normolipidemic group.
“APOE p.Arg108Trip (Arg90Trp) and APOE p.Tyr136His (Tyr118His) heterozygotes were detected in a normolipidemic group (Table 5)44).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [44]
APOE variants contribute to lipid disorders.
“APOE variants contribute to lipid disorders 58 ; like APOE2, APOE3Ch may promote hyperlipidemia due to reduced receptor binding but also limit uptake of oxidized lipoproteins, protecting against lipid overload and oxidative stress. 7”
Cites
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
The Metabolic and Molecular Bases of Inherited Disease
Scriver, R. C. (1995) · Medical Entomology and Zoology · Cited by 12,101 · see citing works
The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2020) · Nature · doi:10.1038/s41586-020-2308-7 · Cited by 9,434 · see citing works
An integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711 · see citing works
ClinVar: public archive of interpretations of clinically relevant variants
Landrum, M. J., Lee, J. M., Benson, M., Brown, G., Chao, C., Chitipiralla, S., Gu, B., Hart, J., Hoffman, D., Hoover, J., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1222 · Cited by 2,758 · see citing works
Improved Splice Site Detection in Genie
Reese, M. G., Eeckman, F. H., Kulp, D., & Haussler, D. H. (1997) · Journal of Computational Biology · doi:10.1089/cmb.1997.4.311 · Cited by 1,578 · see citing works
SIFT missense predictions for genomes
Vaser, R., Adusumalli, S., Leng, S. N., Sikic, M., & Ng, P. C. (2016) · Nature Protocols · doi:10.1038/nprot.2015.123 · Cited by 1,510 · see citing works
Jones, P. H., Davidson, M. H., Stein, E. A., Bays, H. E., McKenney, J. M., Miller, E., Cain, V. A., & Blasetto, J. W. (2003) · The American Journal of Cardiology · doi:10.1016/s0002-9149(03)00530-7 · Cited by 1,392 · see citing works
PredictSNP: Robust and Accurate Consensus Classifier for Prediction of Disease-Related Mutations
Bendl, J. M., Štourač, J., Šalanda, O., Pavelka, A., Wieben, E. D., Zendulka, J., Brezovský, J., & Damborský, J. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003440 · Cited by 850 · see citing works
Exome-wide association study of plasma lipids in >300,000 individuals
Charge Diabetes Working Group, Liu, D. J., Program, V. M. V., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X. Q., Mahajan, A., Saleheen, D., Emdin, C. A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3977 · Cited by 537 · see citing works
Mahley, R. W., Huang, Y., & Rall, S. C. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32417-2 · Cited by 447 · see citing works
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
Schneider, W. J., Kovanen, P. T., Brown, M. S., Goldstein, J. L., Utermann, G., Weber, W., Havel, R. J., Kotite, L., Kane, J. P., Innerarity, T. L., et al. (1981) · Journal of Clinical Investigation · doi:10.1172/jci110330 · Cited by 310 · see citing works
Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions
Chen, J., Li, Q., & Wang, J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106420108 · Cited by 283 · see citing works
Femoral and Carotid Subclinical Atherosclerosis Association With Risk Factors and Coronary Calcium
Laclaustra, M., Casasnovas, J. A., Fernández‐Ortíz, A., Fuster, V., León-Latre, M., Jiménez‐Borreguero, L. J., Pocovı́, M., Hurtado-Roca, Y., Ordovás, J. M., Jarauta, E., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.12.056 · Cited by 245 · see citing works
Self-citationFutema, M., Shah, S., Cooper, J. A., Li, K., Whittall, R. A., Sharifi, M., Goldberg, O., Drogari, E., Mollaki, V., Wiegman, A., et al. (2015) · Clinical Chemistry · doi:10.1373/clinchem.2014.231365 · Cited by 213 · see citing works
Hegele, R. A., Borén, J., Ginsberg, H. N., Arca, M., Averna, M., Binder, C. J., Calabresi, L., Chapman, M. J., Cuchel, M., von Eckardstein, A., et al. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30264-5 · Cited by 204 · see citing works
Liposcale: a novel advanced lipoprotein test based on 2D diffusion-ordered 1H NMR spectroscopy
Mallol, R., Amigó, N., Rodriguez, M. A., Heras, M., Vinaixa, M., Plana, N., Rock, E., Ribalta, J., Yanes, Ó., Masana, L., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.d050120 · Cited by 199 · see citing works
APOE gene variants in primary dyslipidemia
Khalil, Y. A., Rabès, J.-P., Boileau, C., & Varret, M. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.007 · Cited by 170 · see citing works
Vedhachalam, C., Narayanaswami, V., Neto, N., Forte, T. M., Phillips, M. C., Lund‐Katz, S., & Bielicki, J. K. (2007) · Biochemistry · doi:10.1021/bi602407r · Cited by 106 · see citing works
Cenarro, A., Etxebarria, A., de Castro-Orós, I., Stef, M., Bea, A. M., Palacios, L., Mateo-Gallego, R., Benito-Vicente, A., Ostolaza, H., Tejedor, T., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3874 · Cited by 100 · see citing works
Self-citationA mechanism-based operational definition and classification of hypercholesterolemia
Civeira, F., Arca, M., Cenarro, A., & Hegele, R. A. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.09.006 · Cited by 99 · see citing works
Self-citationVLDL Induces Adipocyte Differentiation in ApoE-Dependent Manner
Chiba, T., Nakazawa, T., Yui, K., Kaneko, E., & Shimokado, K. (2003) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000085040.58340.36 · Cited by 78 · see citing works
Solanas-Barca, M., de Castro-Orós, I., Mateo-Gallego, R., Cofán, M., Plana, N., Puzo, J., Burillo, E., Martín-Fuentes, P., Ros, E., Masana, L., et al. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.03.011 · Cited by 74 · see citing works
Self-citationde Villiers, W. J. S., van der Westhuyzen, D. R., Coetzee, G. A., Henderson, H. E., & Marais, A. D. (1997) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.17.5.865 · Cited by 41 · see citing works
Faivre, L., Saugier-Veber, P., Pais de Barros, J.-P., Verges, B., Couret, B., Lorcerie, B., Thauvin, C., Charbonnier, F., Huet, F., Gambert, P., et al. (2005) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201480 · Cited by 34 · see citing works
Hoffer, M. J. V., Niththyananthan, S., Naoumova, R. P., Kibirige, M. S., Frants, R. R., Havekes, L. M., & Thompson, G. R. (1996) · Atherosclerosis · doi:10.1016/0021-9150(96)05819-4 · Cited by 32 · see citing works
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., et al. (2022) · Clinical Genetics · doi:10.1111/cge.14185 · Cited by 27 · see citing works
Puig-Jové, C., Julve, J., Castelblanco, E., Julián, M. T., Amigó, N., Andersen, H. U., Ahluwalia, T. S., Rossing, P. R., Mauricio, D., Jensen, M. T., et al. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01652-z · Cited by 26 · see citing works
Bea, A. M., Cenarro, A., Marco-Bened, V., Laclaustra, M., Martn, C., Ibarretxe, D., Pint, X., Arrobas, T., Vials, C., Civeira, F., et al. (2023) · Clinical Chemistry · doi:10.1093/clinchem/hvac213 · Cited by 21 · see citing works
Self-citationLarrea, A., Benito‐Vicente, A., Fernández-Higuero, J. Á., Jebari‐Benslaiman, S., Galicia-García, U., Uribe, K. B., Cenarro, A., Ostolaza, H., Civeira, F., Arrasate, S., et al. (2021) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2021.08.009 · Cited by 19 · see citing works
Self-citationAdvanced lipoprotein profile in individuals with normal and impaired glucose metabolism
Puig-Jové, C., Castelblanco, E., Falguera, M., Hernández, M., Soldevila, B., Julián, M. T., Teis, A., Julve, J., Barranco-Altirriba, M., Franch‐Nadal, J., et al. (2021) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2021.02.006 · Cited by 11 · see citing works
Pieri, K., Trichia, E., Neville, M. J., Taylor, H., Bennett, D., Karpe, F., & Koivula, R. W. (2022) · International Journal of Cardiology · doi:10.1016/j.ijcard.2022.11.024 · Cited by 9 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- National Library of Medicine. Reference SNP (rs) Report: rs1050106163. https://www.ncbi.nlm.nih.gov/snp/rs1050106163
Cited by
Sorted by citations
Current insights into apolipoprotein E and the immune response in Alzheimer's disease
Lin, P. B., & Holtzman, D. M. (2024) · Immunological Reviews · doi:10.1111/imr.13414 · Cited by 19 · see citing works
Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
Matsunaga, A., & Saito, T. (2025) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.65393 · Cited by 14 · 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
Pineda‐Lopez, L., Aguillon, D., Villar‐Vesga, J., Valderrama‐Carmona, P., Guerrero, A., Upreti, A., Arevalo‐Alquichire, S., Correa, L., Mendez‐Castellanos, K., Castaño, D., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71148 · Cited by 4 · see citing works
- Authors
- Bea, A. M., Larrea-Sebal, A., Marco-Benedi, V., Uribe, K. B., Galicia-Garcia, U., Lamiquiz-Moneo, I., Laclaustra, M., Moreno-Franco, B., Fernandez-Corredoira, P., Olmos, S., Civeira, F., Martin, C., & Cenarro, A.
- Affiliations
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Biofisika Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Spain (A.L.-S., C.M.).
- Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).
- University of the Basque Country (ES)
- Department of Biochemistry and Molecular Biology, UPV/EHU, University of the Basque Country, Bilbao, Spain (K.B.U., U.G.-G., C.M.).
- Universidad de Zaragoza (ES)
- Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.).
- Corresponding author
- Civeira, Fernando
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2023-06
- Volume
- 43
- Issue
- 6
- Pages
- 1066-1077
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W4365443132
- Semantic Scholar
- 38f997a1e8925168c99f0863d5ea570c43e26cb7
- Cited by
- 40
- References
- 34
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 12 · 2023: 2
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- European Commission (318977)
- Ministerio de Economía y Competitividad
- Gobierno de Aragón
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares
- Instituto de Salud Carlos III
- European Regional Development Fund
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- dyslipidemia, dysbetalipoproteinemia, familial hypercholesterolemia, mixed dyslipidemia, APOE2, APOE ε4, LDL receptor, lipoprotein particle size
- MeSH terms
- Apolipoproteins E, Humans, Hypercholesterolemia, Hyperlipidemias, Hyperlipoproteinemia Type III, Receptors, LDL, Apolipoprotein E3, Apolipoprotein E2
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