Cited by 313Lipid metabolism and disordersLipoproteins and Cardiovascular HealthCholesterol and Lipid Metabolism

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index; none of the 34 sources its claims cite is checked for support yet.

Familial apolipoprotein E deficiency.

Open access
Schaefer, E J, Gregg, R E, Ghiselli, G, Forte, T M, Ordovas, J M, Zech, L A, Brewer, H B·1986·Journal of Clinical Investigation

Abstract

A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.

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Written from the paper’s full text.

TL;DR

This paper characterizes the first reported kindred with familial apolipoprotein E deficiency, showing that homozygotes develop type III hyperlipoproteinemia with xanthomas and premature cardiovascular disease. It concludes that apoE deficiency is an autosomal recessive condition with markedly decreased apoE production and that apoE is essential for normal catabolism of triglyceride-rich lipoprotein remnants.

Key findings

  • Four homozygotes had severe type III hyperlipoproteinemia: mean plasma cholesterol 529±74 mg/dl, triglyceride 221±62 mg/dl, VLDL cholesterol 243±97 mg/dl, LDL cholesterol 230±41 mg/dl, HDL cholesterol 51±16 mg/dl, and VLDL cholesterol/plasma triglyceride ratio 1.09±0.18, all significantly different from normal (P < 0.01).
  • Homozygotes had only trace plasma apoE (mean 0.016±0.003 mg/dl, 0.3% of normal), while obligate heterozygotes (n = 10) had mean apoE concentrations 42.1% of normal (P < 0.01).
  • In the proband, VLDL apoB-100 residence time was 7.8 times greater than normal and VLDL apoB-48 residence time was 44 times greater than normal; calculated apoE synthesis rate was only 0.15% of that observed in normal females.
  • Lipid-lowering therapy was effective: clofibrate produced mean reductions in VLDL cholesterol of 53% of baseline and increases in HDL cholesterol of 75% of baseline (P < 0.01).

Methods

  • Clinical, genetic, biochemical, and metabolic characterization of a single kindred with familial apoE deficiency, including four homozygotes, ten obligate heterozygotes, and normal controls.
  • Lipoprotein analysis used ultracentrifugation, paper and agarose electrophoresis, analytical ultracentrifugation, electron microscopy, gradient gel electrophoresis, and apolipoprotein quantitation by radial immunodiffusion, radioimmunoassay, enzyme-linked immunoassay, and electroimmunoassay.
  • Metabolic studies in the proband and normal subjects used radioiodinated apoE3 and VLDL tracers, with kinetic analysis by SAAM to calculate residence times and synthesis rates.

Limitations

  • Stated: whether apoE deficiency alone is sufficient to cause type III hyperlipoproteinemia or whether an additional genetic factor is present in this kindred is uncertain; kinetic data are valid only if the proband synthesizes structurally normal apoE; the apolipoprotein control group was Caucasian while study subjects were Black; consanguinity could not be documented but is possible.
  • Evident from the text: findings come from a single small kindred (four homozygotes, ten obligate heterozygotes), limiting generalizability; the paper also notes that the precise defect at the gene level remained to be elucidated.

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Integrity signals

Registry

Crossref · 10.1172/jci112704

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

87 Own result · 22 Sources not found · 20 Own interpretation · 5 No basis given · 2 Own method

  • It may state two separate claims as one. 42
  • Probably not a substantial claim. 26
  • The quote only partly states this claim. 7
56 of 56
  • The authors state this as an assumption.

    The metabolic studies were conducted under steady state conditions, so that the synthesis rate could be calculated from plasma concentration, plasma volume, residence time, and body weight.

    “Under steady state conditions: synthesis rate (mg/kg d) = [(plasma concentration, mg/dl) (plasma volume, dl)] + [(residence time, days) (body wt, kg)].”
  • The authors state this as an assumption.

    The proband synthesizes apoE that is structurally normal.

    “The kinetic data therefore are valid only if the proband syn- thesizes apoE that is structurally normal.”
2 of 2

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Citations

Cites

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Research works printed but not linked: 2

  1. Gregg, R. E., D. Wilson, E. Rubalcaba, R. Ronan, and H. B. Brewer, Jr. Immunoquantitation of apolipoprotein E. In Proceedings of the Workshop on Apolipoprotein Quantitation. K. Lippel, editor. DHHS, NIH Publ. No. 83-1266: 383-401.
  2. McConathy, W. J., P. Alaupovic, and J. D. Fesmire. 1982. Various applications of electroimmunoassay for plasma apolipoproteins. In Pro- ceedings of the Workshop in Apolipoprotein Quantification. K. Lippel, editor. NIH Publication No. 83-1266: 276-282.

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Metadata

Authors
Schaefer, E. J., Gregg, R. E., Ghiselli, G., Forte, T. M., Ordovas, J. M., Zech, L. A., & Brewer, H. B.
Affiliations
  • Tufts University (US)
  • Houston Methodist (US)
Venue
Journal of Clinical Investigation
Published
1986-11-01
Volume
78
Issue
5
Pages
1206-1219
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2169149496
Cited by
313
References
48
Citations by year
2026: 3 · 2025: 8 · 2024: 3 · 2023: 5 · 2021: 3 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 13 · 2013: 2 · 2012: 9
FWCI
6.59
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Oklahoma Medical Research Foundation
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein E deficiency, type III hyperlipoproteinemia, familial hypertriglyceridemia, premature cardiovascular disease, VLDL, intermediate density lipoprotein, apolipoprotein B-48, apolipoprotein A-IV, nicotinic acid, clofibrate, triglyceride-rich lipoproteins, heterozygotes, homozygotes
MeSH terms
Adolescent, Adult, Aged, Apolipoproteins E, Child, Cholesterol, Female, Homozygote, Humans, Hyperlipoproteinemia Type III, Lipoproteins, Male, Middle Aged, Pedigree, Phospholipids, Reference Values, Skin Diseases, Triglycerides, Xanthomatosis

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