Apo E variants in patients with type III hyperlipoproteinemia
Abstract
Type III hyperlipoproteinemia (HLP III) is characterized by the reduced catabolism and accumulation of chylomicron and very low density lipoprotein (VLDL) remnants. Most HLP III patients are homozygous for the apolipoprotein E2 (Cys112, Cys158) allele; however, several other mutations at this gene locus have been associated with this HLP. In order to assess the presence of rare apo E variants in our population, we have examined apo E phenotypes by isoelectric focusing (IEF) and genotypes by restriction enzyme analysis of polymerase chain reaction (PCR) amplified DNA in 15 patients with HLP III. Lack of concordance between these two methods was observed in 11 subjects (73.3%). DNA sequencing analysis of the receptor binding domain of the apo E gene in the 11 HLP III patients with discrepancies demonstrated the presence of six carriers of the epsilon 3(Arg136-->Ser) allele and three carriers of the epsilon 2(Gly127-->Asp) allele. Five HLP III patients were apo E2/E2 using IEF, but only 2 of them were epsilon 2 homozygous using PCR. Two patients were E3/E3 homozygous with normal DNA sequence in the low density lipoprotein receptor binding domain of apo E. In conclusion, our results show that a number of different apo E genotypes are associated with HLP III in this population. More specifically, mutations at positions 127 and 136 might be frequent in Spain and occur in patients with HLP III.
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More than 90% of affected individuals with familial type III HLP are APOE2 homozygotes, with the remainder having rare APOE variants, including those causing apoE deficiency or compound heterozygotes of APOE variants and APOE2.
“In fact, more than 90% of affected individuals are APOE2 homozygotes, with the remainder having rare APOE variants, including those causing apoE deficiency or compound heterozygotes of APOE variants and APOE2 23, 25-28).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [26]
The Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys).
“The Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys)26, 38, 56, 57).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [26]
Rare APOE variants associated with dominant type III HLPs include APOE2 Heidelberg (Arg136Cys), APOE2 Christchurch (Arg136Ser), APOE2 (Arg142Cys), APOE2 (Arg142Leu), APOE2 (Lys146Gln), and APOE1 Harrisburg (Lys146Glu).
“Rare APOE variants associated with dominant type III HLPs include single-nucleotide substitutions at APOE2 Heidelberg (Arg136Cys)47), APOE2 Christchurch (Arg136Ser)26, 48), APOE2 (Arg142Cys)49, 50), APOE2 (Arg142Leu)51), APOE2 (Lys146Gln)45), and APOE1 Harrisburg (Lys146Glu)52, 53) (Table 2, Fig.5).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [26]
The Gly127Asp variant is not causative of a dominantly inherited familial type III HLP and is not directly related to receptor binding, but may be one of the factors that cause hyperlipidemia in association with the ε2 allele.
“This variant is not causative of a dominantly inherited familial type III HLP and is not directly related to receptor binding, but may be one of the factors that cause hyperlipidemia in association with the ε2 allele26, 58).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [26]
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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
Large animal models of cardiovascular disease
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Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
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- Authors
- Civeira, F., Pocoví, M., Cenarro, A., Casao, E., Vilella, E., Joven, J., González, J., Garcia-Otín, A. L., & Ordovás, J.
- Affiliations
- Hospital Royo Villanova (ES)
- Universidad de Zaragoza (ES)
- Hospital Universitari Sant Joan de Reus (ES)
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 1996-12
- Volume
- 127
- Issue
- 2
- Pages
- 273-282
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W2020737544
- Cited by
- 48
- References
- 11
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 6 · 2012: 4
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Atherosclerosis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- type III hyperlipoproteinemia, apolipoprotein E, apolipoprotein E2, apolipoprotein E3, genotype-phenotype discordance, receptor-binding domain mutations, chylomicron remnants, VLDL remnants, Spanish population
- MeSH terms
- Adolescent, Adult, Aged, Apolipoproteins E, DNA, Female, Genotype, Humans, Hyperlipoproteinemia Type III, Isoelectric Focusing, Male, Middle Aged, Phenotype, Spain, DNA Probes, Prevalence, Polymerase Chain Reaction
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