Dataset Information

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431?239 Patients.

ABSTRACT: OBJECTIVE:Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. APOE genotypes have different affinities for the low-density lipoprotein (LDL) receptor and LDL-related protein-1, with ?2 having the weakest binding to LDL receptor at <2% relative to ?3 and ?4. APPROACH AND RESULTS: APOE genotypes (?2/?2, ?2/?3, ?2/?4, ?3/?3, ?3/?4, and ?4/?4), Lp(a) mass, directly measured Lp(a)-cholesterol levels, and a variety of apoB-related lipoproteins were measured in 431?239 patients. The prevalence of APOE traits were ?2: 7.35%, ?3: 77.56%, and ?4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in ?4/?4 compared with ?2/?2 genotypes and increased significantly according to APOE genotype: ?2/?2: 23.4 (29.2), ?2/?3: 31.3 (38.0), ?2/?4: 32.8 (38.5), ?3/?3: 33.2 (39.1), ?3/?4: 35.5 (41.6), and ?4/?4: 38.5 (44.1) mg/dL (P<0.0001). LDL-cholesterol, apoB, Lp(a)-cholesterol, LDL-cholesterol corrected for Lp(a)-cholesterol content, LDL-particle number, and small, dense LDL also had similar patterns. Patients with LDL-cholesterol ?250 mg/dL, who are more likely to have LDL receptor mutations and reduced affinity for apoB, had higher Lp(a) levels across all apoE isoforms, but particularly in patients with ?2 alleles, compared with LDL <250 mg/dL. The lowest Lp(a) mass levels were present in patients with ?2 isoforms and lowest LDL-cholesterol. CONCLUSIONS:APOE genotypes strongly influence Lp(a) and apoB-related lipoprotein levels. This suggests that differences in affinity of apoE proteins for lipoprotein clearance receptors may affect Lp(a) catabolism, suggesting a competition between Lp(a) and apoE protein for similar receptors.

SUBMITTER: Moriarty PM

PROVIDER: S-EPMC5323356 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Lipoprotein(a) Mass Levels Increase Significantly According to <i>APOE</i> Genotype: An Analysis of 431 239 Patients.

Moriarty Patrick M PM Varvel Stephen A SA Gordts Philip L S M PL McConnell Joseph P JP Tsimikas Sotirios S

Arteriosclerosis, thrombosis, and vascular biology 20170105 3

<h4>Objective</h4>Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. <i>APOE</i> genotypes have different affinities for the low-density lipoprotein (LDL) receptor and LDL-related protein-1, with ε2 having the weakest binding to LDL receptor at <2% relative to ε3 and ε4. APPROACH AND RESULTS: <i>APOE</i> genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4), Lp(a) mass, directly measured ...[more]

PMID: 28062489

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Project description:BackgroundLipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease that is most commonly caused by mutations in ApoE Kyoto (p.R43C) and ApoE Sendai (p.R163P). Differences in phenotype among the various ApoE mutations have been suggested, but the pathogenic role of ApoE Kyoto has not been validated in an animal model. This study intended to establish an ApoE Kyoto murine model and to further compare the pathologic differences between ApoE Kyoto and ApoE Sendai.MethodMale ApoE-deficient mice, 3 months of age, were divided into five groups, including the AD-ApoE Sendai, AD-ApoE Kyoto, AD-ApoE3, AD-eGFP, and ApoE (-/-) groups. The first four groups received recombinant adenovirus that contained the entire coding regions of the human ApoE Sendai and ApoE Kyoto, apoE3, and eGFP genes, respectively. Fasting blood and urine samples were collected at multiple time points. Lipid profiles and urine albumin-creatinine ratio were measured. Renal and aortic histopathologic alterations were analyzed.ResultsAfter virus injection, plasma human ApoE was detected and rapidly reached the maximum level at 4-6 days in the AD-ApoE Kyoto and AD-ApoE Sendai groups (17.4 ± 3.1 µg/mL vs.: 22.2 ± 4.5 µg/mL, respectively) and at 2 days in the AD-ApoE3 group (38.4 µg/mL). The serum total cholesterol decreased by 63%, 65%, and 73% in the AD-ApoE Kyoto, AD-ApoE Sendai and AD-ApoE3 groups, respectively. There were no significant changes in serum triglyceride and urinary albumin-creatinine ratio among the five groups. Typical lipoprotein thrombi with positive ApoE staining were detected in the AD-ApoE Kyoto and AD-ApoE Sendai groups. The Oil-red O-positive glomerular area tended to be higher in the AD-ApoE Kyoto group (9.2%) than in the AD-ApoE Sendai (3.9%), AD-ApoE3 (4.8%), AD-eGFP (2.9%), and ApoE (-/-) (3.6%) groups. The atherosclerotic plaque area in the aorta was lower in the group injected with various ApoE mutations than in the group without injection of ApoE mutation.ConclusionsIn this animal study, we first established an ApoE Kyoto mutation murine model and confirmed its pathogenic role in LPG. Our results suggested that LPG may be more severe with the ApoE Kyoto than with the ApoE Sendai.

Dataset Information

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431?239 Patients.

Publications

Lipoprotein(a) Mass Levels Increase Significantly According to <i>APOE</i> Genotype: An Analysis of 431 239 Patients.

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