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Cited by 89Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

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

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Moriarty, Patrick M., Varvel, Stephen A., Gordts, Philip L.S.M., McConnell, Joseph P., Tsimikas, Sotirios·2017·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.116.308704PMC PMC5323356
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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 ε2 having the weakest binding to LDL receptor at <2% relative to ε3 and ε4. Approach and Results—: APOE genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4), 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 ε2: 7.35%, ε3: 77.56%, and ε4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in ε4/ε4 compared with ε2/ε2 genotypes and increased significantly according to APOE genotype: ε2/ε2: 23.4 (29.2), ε2/ε3: 31.3 (38.0), ε2/ε4: 32.8 (38.5), ε3/ε3: 33.2 (39.1), ε3/ε4: 35.5 (41.6), and ε4/ε4: 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 ε2 alleles, compared with LDL <250 mg/dL. The lowest Lp(a) mass levels were present in patients with ε2 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.

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  • Lp(a) levels are driven largely by hepatic apo(a) synthesis and isoform biology, so PCSK9 inhibition only partially enhances Lp(a) removal.

    “Its levels are driven largely by hepatic apo(a) synthesis and isoform biology, so PCSK9 inhibition, despite markedly increasing LDL receptor recycling, only partially enhances Lp(a) removal [28].”

    From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [28]

    The Introduction (page unavailable) says Lp(a) levels are primarily determined by LPA variation, including kringle IV2 repeats, and describes hepatocyte apo(a) production. The Discussion (page unavailable) considers LDL-receptor clearance and PCSK9 but reports conflicting mechanisms and says the receptor’s contribution cannot be quantified. It does not establish that PCSK9 inhibition only partially enhances Lp(a) removal despite markedly increasing LDL-receptor recycling. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Moriarty, P. M., Varvel, S. A., Gordts, P. L. S. M., McConnell, J. P., & Tsimikas, S.
Affiliations
University of California San Diego (US)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-03
Volume
37
Issue
3
Pages
580-588
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.116.308704
PMC
PMC5323356
OpenAlex
W2570683458
Cited by
89
References
7
Citations by year
2026: 7 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 15 · 2017: 9
FWCI
12.89
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL106579, R01HL078610, P01HL055798, R01HL119828, R01HL124174, P01HL088093)
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
lipoprotein(a), APOE genotype, apolipoprotein E isoforms, LDL cholesterol, small dense LDL, LDL particle number, hypercholesterolemia, LDL receptor mutations, lipoprotein catabolism
MeSH terms
Adult, Aged, Apolipoproteins E, Female, Gene Frequency, Genotype, Humans, Cholesterol, LDL, Male, Middle Aged, Phenotype, Biomarkers, Lipoprotein(a), Apolipoprotein B-100, Genetic Association Studies

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