Hyperlipoproteinemia Type 3: The Forgotten Phenotype

Hopkins, Paul N.; Brinton, Eliot A.; Nanjee, M. Nazeem

doi:10.1007/s11883-014-0440-2

Cited by 74 publications

(49 citation statements)

References 113 publications

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“…Future studies should examine mice with heterozygous genotypes, as this condition is much more common in humans. Third, type-3 hyperlipoproteinemia occurs in only 10% of human APOE2/2 individuals but is present in 100% of the APOE2 mice (87)(88)(89). Whether this hyperlipoproteinemia may contribute to the microbiome phenotype reported here is unclear.…”

Section: Discussionmentioning

confidence: 84%

Murine Gut Microbiome Association With APOE Alleles

et al. 2020

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Background: Since APOE alleles represent the most impactful genetic risk factors for Alzheimer's disease (AD), their differential mechanism(s) of action are under intense scrutiny. APOE4 is robustly associated with increased AD risk compared to the neutral APOE3 and protective APOE2. APOE alleles have also been associated with differential inflammation and gastrointestinal recovery after insult in human and murine studies, leading us to hypothesize that APOE alleles impact the gut microbiome. Methods: To assess this hypothesis, we compared 16S ribosomal RNA gene amplicon-based microbiome profiles in a cohort of mice that were homozygous for APOE2, APOE3, or APOE4, and included both males and females as well as carriers and non-carriers of five familial AD (5xFAD) mutations. Fecal samples were analyzed from mice at 4 and 6 months of age. APOE genotype, as well as sex and 5xFAD status, was then tested for influence on alpha diversity (Shannon H index) and beta diversity (principal coordinate analyses and PERMANOVA). A Random Forest analysis was used to identify features that predicted APOE, sex and 5xFAD status. Results: The richness and evenness (alpha diversity) of the fecal microbiome was not robustly associated with APOE genotype, 5xFAD status or sex. In contrast, microbial community composition (beta-diversity) was consistently and strongly associated with APOE genotype. The association between beta-diversity and sex or 5xFAD status was less consistent and more modest. Comparison of the differences underlying APOE effects showed that the relative abundance of multiple bacterial taxa was significantly different as a function of APOE genotype. Conclusions: The structure of the gut microbiome was strongly and significantly associated with APOE alleles in this murine model. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on AD-relevant phenotypes in murine models, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby APOE genotype impacts AD.

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Section: Discussionmentioning

confidence: 84%

Murine Gut Microbiome Association With APOE Alleles

et al. 2020

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“…Two missense SNPs (rs7412, rs429358) define three isoforms named E2, E3, and E4, the two mutant isoforms E2 and E4 presenting markedly different physiological functions ( 51 ). E2 presents only ∼1% of the LDLR binding affinity compared with E3 and E4 ( 51 ) and results in impaired removal of VLDL particles ( 53 ). Coincidence of homozygous APOE2 and conditions causing high VLDL, such as obesity, led to hyperlipoproteinemia type III ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms

Mack

Coassin

Rueedi

et al. 2017

Journal of Lipid Research

134

153

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High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10−30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10−10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population’s mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.

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“…Abnormal apoB48 and apoB100 remnant lipoprotein particles may also be present. A dramatic delay in clearance of partially hydrolyzed VLDL and chylomicron particles by the liver exaggerates core lipid exchanges, which result in increased numbers of cholesterol-enriched remnant particles (17,18). In classical type III hyperlipoproteinemia, abnormal apoB48 remnant particles plus abnormal VLDL apoB100 remnant particles are present in concentrations 30-50 times or more the concentration of normal remnant particles (11,12,19).…”

Section: Abnormal Remnant Particlesmentioning

confidence: 99%

Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding

Sniderman

Couture

Martin

et al. 2018

Journal of Lipid Research

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Triglycerides are the conventional tool to measure VLDLs, whereas LDL cholesterol (LDL-C) is the conventional tool to measure LDLs. Multiple epidemiological studies, including a series of genetically based analyses, have demonstrated that cardiovascular risk is related to triglycerides independently of LDL-C, and this has led to a series of new therapeutic agents designed specifically to reduce plasma triglycerides. The triglyceride hypothesis posits that increased levels of triglycerides increase cardiovascular risk and decreasing plasma triglycerides decreases cardiovascular risk. In this work, we will examine the validity of the triglyceride hypothesis by detailing the biological complexities associated with hypertriglyceridemia, the genetic epidemiological evidence in favor of hypertriglyceridemia, the evidence from the fibrate randomized clinical trials relating triglycerides and clinical outcomes, and the completeness of the evidence from the initial studies of novel mutations and the therapeutic agents based on these mutations that lower triglycerides. Because of the multiple metabolic links between VLDL and LDL, we will try to demonstrate that measuring triglycerides and LDL-C alone are inadequate to document the lipoprotein profile. We will try to demonstrate that apoB must be measured, as well as triglycerides and cholesterol, to have an accurate estimate of lipoprotein status.

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Hyperlipoproteinemia Type 3: The Forgotten Phenotype

Cited by 74 publications

References 113 publications

Murine Gut Microbiome Association With APOE Alleles

Murine Gut Microbiome Association With APOE Alleles

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms

Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding

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