Apolipoprotein E and atherosclerosis: insight from animal and human studies

Davignon, Jean; Cohn, Jeffrey S.; Mabile, Laurence; Bernier, Lise

doi:10.1016/s0009-8981(99)00097-2

Cited by 193 publications

(146 citation statements)

References 163 publications

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“…The SNP at site 3937 in combination with the SNP at site 4075 code for changes in residues 112 and 158 of the 299 amino acid ApoE protein. Lower circulating levels of the ApoE protein are associated with the C allele at SNP 3937 compared to the T allele (Davignon et al 1999).…”

Section: Location and Function Of Interacting Variable Sitesmentioning

confidence: 97%

“…This result is not unexpected because most genetic and environmental agents only have an influence in the presence of a particular environment or genetic background (Holdrege, 1996;Lewontin, 2000). Many studies have established that age, gender, smoking and alcohol consumption modify the influence of variation in the APOE gene on interindividual variation in measures of lipid metabolism (Zerba et al 1996;Jarvik et al 1997;Davignon et al 1999;Lussier-Cacan et al 2002). The age specific distribution of plasma ApoE, and the association of plasma lipid and apolipoprotein traits with variation in the APOE gene have all been shown to be dependent upon gender (Reilly et al 1991;Cobb et al 1992;Jarvik et al 1997).…”

Section: Context Dependencymentioning

confidence: 99%

“…Interindividual variability in circulating levels of the ApoE protein has been associated with each of these variants (Artiga et al 1998;Davignon et al 1999). Within our own study, differences between those individuals who are heterozygous at SNP 832 versus those who are homozygous for either the C or T allele at SNP 832 only occurs in the presence of those individuals who are homozygous for the C allele at SNP 3937.…”

Section: Location and Function Of Interacting Variable Sitesmentioning

confidence: 99%

See 2 more Smart Citations

Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

Hamon

Stengård

Clark

et al. 2004

Annals of Human Genetics

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SummaryWe analyzed 13 single nucleotide polymorphisms (SNPs) within the apolipoprotein E (APOE) gene, to identify pairs of SNPs that interact in a non-additive manner to influence genotypic mean levels of the ApoE protein in blood. An overparameterized general linear model of two-SNP genotype means was applied to data from 456 female and 398 male unrelated European Americans from Rochester, MN, USA. We found statistically significant evidence for non-additivity between SNPs within the male sample, but not within the female sample. We observed nine pairs of SNPs with evidence of non-additivity at the α = 0.05 level of statistical significance within the male sample, when approximately three were expected by chance. Five of the nine pairs involved three SNPs (560, 624 and 1163) that did not have a statistically significant influence when considered separately in a single-site analysis. Three of the nine pairs involving four SNPs (832, 1998, 3937 and 4951) showed significant evidence for non-additivity in at least one of two other male samples from Jackson, MS, USA and North Karelia, Finland. Although all four of these SNPs had a statistically significant influence in Rochester when considered separately, only SNP 3937 gave a significant result in the other male samples. The four SNPs are located in the promoter, intronic and exonic regions, and 3' to the polyadenylation signal in the APOE gene. Our study suggests that analyses that only consider SNPs located in exons and ignore contexts such as those indexed by gender and population, and disregard non-additivity of SNP effects, may inappropriately model the contribution of a gene to the genetic architecture of a trait that has a complex multifactorial etiology.

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Section: Location and Function Of Interacting Variable Sitesmentioning

confidence: 97%

Section: Context Dependencymentioning

confidence: 99%

Section: Location and Function Of Interacting Variable Sitesmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

Hamon

Stengård

Clark

et al. 2004

Annals of Human Genetics

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“…ApoE2 (Cys-112, Cys-158) displays defective binding and is associated with type III hyperlipoproteinemia (11). ApoE4 (Arg-112, Arg-158) is associated with a higher risk of heart disease (12,13) and is the major genetic risk factor for sporadic AD (13)(14)(15)(16).…”

mentioning

confidence: 99%

Inhibition of Apolipoprotein E-Related Neurotoxicity by Glycosaminoglycans and Their Oligosaccharides

et al. 2002

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Apolipoprotein E (apoE) has been genetically linked to late-onset Alzheimer's disease (AD). The role of this lipid-transport protein in AD remains to be established. One hypothesis is that apoE, particularly the apoE4 isoform, may have neurotoxic effects as demonstrated using apoE-related synthetic peptides and the N-terminal fragment of apoE. ApoE is a heparan-sulfate binding protein, and apoE peptide neurotoxicity can be blocked by heparin and prevented by degrading heparan sulfate or inhibiting its biosynthesis. The possibility that heparin inhibition of toxicity is mediated by a specific oligosaccharide sequence was investigated using a bioassay to determine the inhibition of apoE peptide toxicity by glycosaminoglycans and purified glycosaminoglycan oligosaccharides. Studies on modified heparins showed that the presence of N-sulfo groups and either 2-or 6-O sulfo groups were required for inhibition of toxicity. Heparin oligosaccharides with eight or more saccharide residues with seven O-sulfo groups and four N-sulfo groups exhibited potent inhibition. Larger oligosaccharides, and heparin and heparan sulfate polymers, afforded comparable, or somewhat better, protective effects but also caused clumping and detachment of cells when administrated alone.Alzheimer's disease (AD) 1 remains the most common form of dementia, with four million Americans currently suffering from it and an estimated 22 million people throughout the world who will be afflicted by 2025. There are no current effective treatments for AD, and the cause of this illness remains unknown despite the tremendous increase in information regarding genetic linkages to the disease. The pathological hallmarks of AD include the accumulation of extracellular plaques containing amyloid and other proteins, the presence of intracellular neurofibrillary tangles, whose effect on neuronal function is not yet known, and the loss of nerve cells and synaptic connections within the areas of the brain responsible for learning and memory. Mutations in three known genes, the amyloid protein precursor and presenilin 1 and 2, nearly always cause the disease (1). These mutations, however, account only for a very small percentage (5-10%) of AD cases. A fourth genetic factor is apolipoprotein E (apoE). Unlike the three other genes, the apoE4 gene is a susceptibility locus accounting for approximately 40-70% of the cases of late-onset AD (2).ApoE is a 299-residue lipid-associated protein that binds and transports cholesterol-rich lipoproteins for internalization via receptors of the low-density lipoprotein (LDL) receptor family (3). In addition, apoE has other putative functions that do not seem to involve lipid transport (4). ApoE plays an important role in maintaining central nervous system functions (4, 5), and recent studies have suggested that apoE is a major risk factor in a number of diseases (6). The N-terminal domain (1-191) is composed of four amphipathic R-helices arranged in an antiparallel fashion and connected by loop regions (7). It contains the lo...

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“…Human apoE has been reported to have allele-specific effects on reverse cholesterol transport, platelet aggregation, immune response, and oxidative processes that are likely to affect the overall pathological vascularization and wound healing potential ascribed to modulation of lipoprotein metabolism (Davignon et al, 1999;Mahley, 1988). The E4 allele that is associated with higher low-density lipoprotein cholesterol is considered pro-atherogenic (Davignon et al, 1999;Mahley, 1988;Song et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

Bhattacharjee

Neumann

Foster

et al. 2008

Experimental Eye Research

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The isoform-specific role of human apolipoprotein E (apoE) has been assessed in a mouse model of ocular herpes. Female, age-matched transgenic mice knocked-in for the human allele apoE3 or apoE4 and their parent C57Bl/6 mice were inoculated corneally with HSV-1 strain KOS. Ocular HSV-1 pathogenesis was monitored through viral replication and clinical progression of stromal opacity and neovascularization by slit-lamp examination. Establishment of latency was determined by analysis of HSV-1 DNA (copy number) by specific real-time PCR in the cornea, trigeminal ganglia (TG), and brain. Representative groups of transgenic mice were sacrificed for the analysis of gene expression of vascular endothelial growth factor (VEGF) by reverse-transcription PCR, and apoE expression by Western blot analysis. At 6 days post-infection (P.I.), the ocular infectious HSV-1 titer was significantly higher (p < 0.05) in apoE4 mice compared with apoE3 and C57Bl/6 mice. Corneal neovascularization in apoE4 mice was significantly higher (p < 0.05) than apoE3 and C57Bl/6 mice. The onset of corneal opacity in apoE4 mice was accelerated during days 9--11 P.I.; however, no significant difference in severity was seen on P.I. days 15 and beyond. At 28 days P.I., infected mice of all genotypes had no significant differences in copy numbers (range 0--15) of HSV-1 DNA in their corneas, indicating that HSV-1 DNA copy numbers in cornea are independent of apoE isoform regulation. At 28 days P.I., both apoE4 and C57Bl/6 mice had a significantly higher (p = 0.001) number of copies of HSV-1 DNA in TG compared with apoE3. ApoE4 mice also had significantly higher (p = 0.001) copies of HSV-1 DNA in their TGs compared with C57Bl/6 mice. In brain, both apoE4 and C57Bl/6 mice had significantly higher numbers (p ≤ 0.03) of copies of HSV-1 DNA compared with apoE3 mice. However, the number of HSV-1 DNA copies in the brain of C57Bl/6 mice was not significantly different than that of apoE4 (p = 0.1). Comparative molecular analysis between apoE3 and apoE4 mice on selected days between 7 and 28 P.I., inclusive, revealed that the corneas of apoE4 mice expressed VEGF. None of the corneas in the apoE3 mice expressed VEGF Corresponding author: James M. Hill, Ph.D., LSU Eye Center, 2020 Gravier Street, Suite B, New Orleans, LA 70112, USA, Telephone: (504) 568 2274, Fax: (504) 568 2385, E-mail: jhill@lsuhsc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Western blot analysis showed proteolytic cleavage of the apoE protein in the corneas of the apoE4 mice. Through days 14 to 28 P.I., a ~29 kDa C-terminal truncated apoE f...

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Apolipoprotein E and atherosclerosis: insight from animal and human studies

Cited by 193 publications

References 163 publications

Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

Inhibition of Apolipoprotein E-Related Neurotoxicity by Glycosaminoglycans and Their Oligosaccharides

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

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