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

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
DOI 10.1172/jci112704PMC PMC423806
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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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci112704

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Homozygotes had accumulations of apoB-48 and apoA-IV in VLDL, IDL, and LDL.

    “accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipo- proteins.”
    • Also stated in: § Lipoprotein analysis. · hedged
      “These data indicate lack ofapoE and accumulation of apoB-48 and apoA-IV in the VLDL, IDL, and LDL density fractions of subjects with homozygous apoE deficiency.”
    Quote in the paperSubstantial claim
  • Findingown data

    Obligate heterozygotes (n = 10) had mean plasma apoE concentrations that were 42% of normal.

    “mean plasma apoE concentrations that were 42% of normal.”
    Quote in the paperSubstantial claim
  • Findingown data

    Obligate heterozygotes (n = 10) generally had normal plasma lipids.

    “Obligate heterozygotes (n = 10) generally had normal plasma lipids”
    Quote in the paperSubstantial claim
  • Findingown data

    Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL).

    “Homozygotes (n = 4) had marked increases in cho- lesterol-rich very low density lipoproteins (VLDL) and inter- mediate density lipoproteins (IDL)”
    Quote in the paperSubstantial claim
  • Findingown data

    The homozygous proband had an extremely low apoE synthesis rate compared to normals.

    “as well as an extremely low apoE synthesis rate as com- pared to normals.”
    Quote in the paperSubstantial claim
    • 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.
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 26
  • The quote only partly states this claim. 7

  • May combine two claims.

    Findingown data

    The four homozygotes sampled had significant hyperlipidemia associated with elevations in both VLDL and LDL cholesterol (including IDL and LDL) and a marked elevation in the VLDL cholesterol/plasma triglyceride ratio.

    “The four homozygotes sampled had significant hyperlipidemia associated with elevations in both VLDL and LDL cholesterol (includes both IDL and LDL), and a marked elevation in the VLDL cho- lesterol/plasma triglyceride ratio.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The reported kindred has premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia associated with familial apolipoprotein E deficiency.

    “A unique kindred with premature cardiovascular disease, tubo- eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Sibling 7 was a non-smoker and was not hypertensive.

    “She was a non- smoker and was not hypertensive.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Sibling 7 was noted to have significant hypercholesterolemia at age 58 yr, and was placed on a cholesterol-lowering diet, which caused a decrease in the size of her xanthomas.

    “She was noted to have significant hypercholesterolemia at age 58 yr, and was placed on a cholesterol-low- ering diet, which caused a decrease in the size of her xanthomas.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sibling 2 had a history of tubo-eruptive xanthomas since her 30s and was noted to be hypercholesterolemic at age 42 yr.

    “One sister (sibling 2) of the proband had a history of tubo-eruptive xanthomas since her 30s.She was noted to be hypercholesterolemic at age 42 yr”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Nine offspring of sibling 7 were healthy and free of xanthomas.

    “Nine offspring were healthy and free of xanthomas.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    With clofibrate administered at a dosage of 1 g p.o. twice daily, sibling 2 had mean reductions of 27, 50, 61, and 17% in her plasma cholesterol, triglyceride, VLDL cholesterol, and LDL cholesterol, while her HDL cholesterol increased by 59%.

    “With clofibrate administered at a dosage of 1 g p.o. twice daily she had mean reductions of 27, 50, 61, and 17% in her plasma cholesterol, triglyceride, VLDL cholesterol, and LDL cholesterol, while her HDL cholesterol increased by 59%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Sibling 7 has not as yet been treated with cholesterol-lowering medication.

    “She has not as yet been treated with cholesterol-lowering medication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A 3-wk course of ethinyl estradiol 0.1 mg p.o. daily caused increases in the proband's plasma triglyceride and HDL cholesterol of 148 and 25% and decreases in total cholesterol, VLDL cholesterol, and LDL cholesterol of 11, 13, and 18%, respectively.

    “A 3-wk course of ethinyl estradiol 0.1 rmg p.o. daily caused increases in plasma triglyceride and HDL cholesterol of 148 and 25% and decreases in total cholesterol, VLDL cholesterol, and LDL cholesterol of 11, 13, and 18%, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Physical examination of the proband was unremarkable except for small tubo-eruptive xanthomas on the elbows and knees, and arcus senilis.

    “Physical examination was unremarkable except for small tubo-eruptive xanthomas on the el- bows and knees, and arcus senilis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Sibling 1 was first noted to have xanthomas in his 20s, was documented to have type III HLP at age 34 yr, and was subsequently placed on a low saturated fat, low cholesterol diet, as well as clofibrate 500 mg p.o., twice daily.

    “A younger brother (sibling 1) was first noted to have xanthomas in his 20s, was documented to have type III HLP at age 34 yr, and was subsequently placed on a low saturated fat, low cholesterol diet, as well as clofibrate 500 mg p.o., twice daily.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Obligate heterozygotes had mean plasma lipid and lipoprotein cholesterol values within the 5th-95th percentile of the normal non-White population except for two offspring of sibling 1 of the proband, who had slightly elevated VLDL cholesterol levels.

    “Obligate heterozygotes (offspring of homozy- gotes) had mean plasma lipid and lipoprotein cholesterol values within the 5th-95th percentile of the normal non-White pop-”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    The proband's father died at age 62 yr of a myocardial infarction and coronary artery disease documented at autopsy; he had a history of angina for the previous 12 yr, a history of cigarette smoking, and a long history of xanthomas on his ears, scalp, elbows, and knees.

    “The proband's father died at age 62 yr of a myocardial infarction and coronary artery disease documented at autopsy.He had a history of angina for the previous 12 yr, a history of cigarette smoking, and a long history of xanthomas on his ears, scalp, elbows, and knees.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Despite these dramatic reductions, sibling 1's VLDL cholesterol was still elevated above the 95th percentile of normal at 83 mg/dl.

    “Despite these dramatic reductions, his VLDL cho- lesterol was still elevated above the 95th percentile of normal at 83 mg/ dl.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Clofibrate administration (1 g p.o., three times daily) in the proband resulted in decreases in total cholesterol, triglyceride, and VLDL cholesterol of 7, 34, and 29%, and increases in HDL cholesterol of 66% as compared with values on diet only.

    “Clofibrate administration (1 g p.o., three times daily) resulted in decreases in total cholesterol, triglyceride, and VLDL cholesterol of 7, 34, and 29%, and increases in HDL cholesterol of 66% as compared with values on diet only.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Findingown data

    Despite these effects, sibling 2's VLDL cholesterol remained elevated at 76 mg/dl.

    “Despite these effects her VLDL cholesterol remained elevated at 76 mg/dl.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Coronary angiography at age 60 in the proband revealed an 80% narrowing of the first diagonal branch of the left anterior descending coronary artery; other coronary arteries had no detectable narrowing.

    “Coronary an- giography at age 60 yr revealed an 80% narrowing of the first diagonal branch of the left anterior descending coronary artery; other coronary arteries had no detectable narrowing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband was a 60-year-old Black female with a 10-year history of small tubo-eruptive xanthomas on her elbows and knees, a 5-yr history of hypertension, a history of intermittent cigarette smoking, and a 3-yr history of chest pain consistent with angina pectoris.

    “The proband for the apoE-deficient kindred was a 60- year-old Black female of 161 cm height, 69.8 kg, with a 10-year history of small tubo-eruptive xanthomas on her elbows and knees, a 5-yr history of hypertension, a history of intermittent cigarette smoking, and a 3-yr history of chest pain consistent with angina pectoris.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Long-acting nicotinic acid (1 g p.o., twice daily) in sibling 1 resulted in a further decrease in VLDL cholesterol of 27%, with no change in HDL cholesterol.

    “This therapy resulted in a further decrease in VLDL cholesterol of 27%, with no change in HDL cholesterol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sibling 7 was 68 yr of age with a history of mild exertional chest pain for the past several years, and a long history of tubo-eruptive xanthomas on her elbows and knees.

    “The proband's oldest sister (sibling 7) was 68 yr of age with a history ofmild exertional chest pain for the past several years, and a long history of tubo-eruptive xanthomas on her elbows and knees.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Plasma concentrations of vitamins A and E and plasma fatty acid composition in the proband were within normal limits.

    “Plasma concentra- tions of vitamins A and E as measured by high pressure liquid chro- matography, and plasma fatty acid composition as determined by gas liquid chromatography were within normal limits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The addition of nicotinic acid 1 g p.o., three times daily to the proband's regimen resulted in further decreases in total cholesterol, VLDL cholesterol and LDL cholesterol of 23, 35, and 26%, respectively, with an increase in HDL cholesterol of 10%, and little effect on triglycerides.

    “The addition of nicotinic acid 1 g p.o., three times daily to this regimen resulted in further decreases in total cholesterol, VLDL cholesterol and LDL cholesterol of 23, 35, and 26%, respectively, with an increase in HDL cholesterol of 10%, and little effect on triglyc- erides.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The proband's mother was alive and well, except for arthritis, at age 87 yr.

    “The proband's mother was alive and well, except for arthritis, at age 87 yr.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The proband's mother and a paternal uncle both had hyperlipidemia.

    “In addition, the proband's mother and a paternal uncle both had hyperlipidemia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The proband had no corneal opacification, lymphadenopathy, or hepatosplenomegaly.

    “No corneal opacification, lymphad- enopathy, or hepatosplenomegaly was noted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    At age 46 yr, sibling 1 suffered a mild stroke resulting in temporary right hemiparesis.

    “At age 46 yr he suffered a mild stroke resulting in temporary right hemiparesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Analytical ultracentrifugation of the proband's plasma indicated a significant increase in VLDL and IDL and no clear LDL peak.

    “Analytical ultracentrifugation ofthe proband's plasma in- dicated a significant increase in VLDL and IDL and no clear LDL peak”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    VLDL particles from the proband were extremely heterogeneous in size as indicated by the large standard deviation; this heterogeneity was confirmed by scanning of gradient gels that demonstrated the presence of at least four components.

    “VLDL particles were extremely heterogeneous in size as indicated by the large standard deviation; this heterogeneity was confirmed by scanning of gra- dient gels that demonstrated the presence of at least four com- ponents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean particle diameters (nm±SD) based on electron microscopy were: VLDL, 36.5±11.5; IDL, 31.0±3.9; LDL, 26.9±4.2; HDL2b, 10.5±1.3; and HDL2a+3, 8.3±1.7.

    “mean particle diameters (nm±SD) based on electron microscopy were: VLDL, 36.5±11.5;IDL, 3 1.0±3.9;LDL, 26.9±4.2;HDL2b, 10.5±1.3; and HDL2a+3, 8.3±1.7.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    About 50% of the offspring of the proband's parents were homozygotes, and no homozygotes were found among the offspring of the proband or any of her homozygous siblings.

    “About 50% of the offspring of the proband's parents were homozygotes, and no homozygotes have been found among the offspring ofthe proband or any ofher homozygous siblings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Premature CAD and stroke events were evident among homozygotes, but were not strikingly premature.

    “Premature CAD and stroke events were evident among homozygotes, but were not strikingly premature.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    No increases in LDL (d, 1.019-1.063 g/ml) constituents were noted in three homozygotes.

    “No increases in LDL (d, 1.019- 1.063 g/ml) constituents were noted.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Consistent results were obtained in all three homozygotes tested for lack of apoE and accumulation of apoB-48 and apoA-IV.

    “Consistent results were obtained in all three homo- zygotes tested.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gradient gel electrophoresis and electron microscopy data on lipoproteins isolated from the proband indicate the presence of small, dense VLDL, and heterogeneous populations within IDL and LDL.

    “Gradient gel electrophoresis and electron microscopy data on lipoproteins isolated from the proband indicate the presence of small, dense VLDL, and heterogeneous populations within IDL and LDL.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Apolipoprotein quantitation indicated elevations of apolipoproteins A-I, A-II, and C-II in plasma in homozygotes.

    “Apolipoprotein quantitation indicated elevations of apoli- poproteins A-I, A-II, and C-II in plasma”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Type III HLP has been associated with abnormalities of apolipoprotein E.

    “Type III HLP has been associated with abnormalities of apolipoprotein (apo) E (5)(6)(7)(8)(9)(10)(11)(12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (5)(6)(7)(8)(9)(10)(11)(12)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Type III HLP patients generally present in adulthood, often develop premature coronary artery disease and peripheral vascular disease, and may have palmar and tubo-eruptive xanthomas.

    “Type III HLP patients generally present in adulthood, often develop premature coronary artery disease and peripheral vascular disease, and may have palmar and tubo- eruptive xanthomas (1-3).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Type III HLP lipoproteins are cholesterol rich and migrate to an abnormal beta position on electrophoresis.

    “These lipoproteins in type III HLP are cholesterol rich, and migrate to an abnormal beta position on electrophoresis (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ApoE is a glycoprotein of 34,000 kD that serves as a constituent of plasma triglyceride-rich lipoproteins and HDL.

    “ApoE is a glycoprotein of 34,000 kD, which serves as a con- stituent ofplasma triglyceride-rich lipoproteins and high density lipoproteins (HDL) (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human apoE is a polymorphic protein having three major isoforms separated by isoelectric focusing (apoE2, E3, and E4).

    “Human apoE is a polymorphic protein having three major isoforms separated by isoelectric focusing (apoE2, E3, and E4) (5,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Type III HLP is characterized by elevations of both plasma cholesterol and triglyceride due to an increase in chylomicron remnants, VLDL, and IDL.

    “Type III hyperlipoproteinemia (HLP)' is an uncommon lipid disorder characterized by elevations of both plasma cholesterol and triglyceride due to an increase in chylomicron remnants, very low density lipoproteins (VLDL), and intermediate density lipoproteins (IDL) (1)(2)(3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (1)(2)(3)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The apoE4 allele has been associated with elevated LDL cholesterol levels in plasma.

    “More recently, the apoE4 allele has been associated with elevated LDL choles- terol levels in plasma (14)(15)(16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (14)(15)(16)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Type III HLP has been associated with apoE2 homozygosity, various rare mutations of apoE, and apoE deficiency.

    “Type III HLP has been associated with apoE2 homozygosity, various rare mutations of apoE, and apoE deficiency (5)(6)(7)(8)(9)(10)(11)(12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (5)(6)(7)(8)(9)(10)(11)(12)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ApoE3 is the most common isoform present in the general population, may be associated with normal plasma lipids, and has been proposed to be the normal allele.

    “ApoE3 is the most common isoform present in the general population, may be associated with normal plasma lipids, and has been proposed to be the normal allele (5,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Each known polymorphic form of apoE is coded by a separate allele, and those alleles are inherited in a codominant fashion at a single genetic locus.

    “Each of the known polymorphic forms of apoE is coded by a separate allele, and those alleles are inherited in a codominant fashion at a single genetic locus (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An increased prevalence of the apoE4 phenotype has been observed in patients with type V hyperlipoproteinemia.

    “An increased prevalence ofthe apoE4 phenotype has been observed in patients with type V hyperlipoproteinemia (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    The proband's mother and paternal uncle are probably also heterozygotes.

    “These subjects are probably also heterozygotes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All blood samples were obtained while subjects had been off lipid-lowering medication for at least 3 wk and while on an ad lib. diet, except for homozygous siblings 1, 2, and 7, whose blood samples were examined while on an outpatient low saturated fat, low cholesterol diet.

    “All blood samples were obtained while subjects had been off lipid lowering medication for at least 3 wk and while on an ad lib.diet, except for homozygous siblings 1, 2, and 7, whose blood samples were examined while on an outpatient low saturated fat, low cholesterol diet.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ApoE4 differs from apoE3 by an arginine for cysteine substitution at residue 112, while apoE2 differs from apoE3 by a cysteine for arginine substitution at residue 158.

    “The primary amino acid sequence of apoE has been reported, and it has been shown that apoE4 differs from apoE3 by an arginine for cysteine substitution at residue 112, while apoE2 differs from apoE3 by a cysteine for arginine substitution at residue 158 (7,8).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The proband's father was most likely a homozygote because he had xanthomas.

    “It is most likely that the proband's father was a homozygote since he had xanthomas”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The aging process and/or menopause may affect the expression of the hyperlipidemia in heterozygotes and homozygotes.

    “The aging process and/or menopause may affect the expression of the hyperlipidemia in heterozygotes and ho- mozygotes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The apoE gene was present in homozygotes, and no restriction fragment length polymorphism was noted.

    “The apoE gene was present in homozygotes, and no restriction fragment length polymorphism was noted (45, 46).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [45]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [46]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Recent data indicate only trace amounts of apoE mRNA in macrophages from homozygotes compared with normal macrophages, and an additional abnormal apoE mRNA band was observed.

    “Recent data examining apoE messenger (m)RNA levels in macrophages from homo- zygotes indicate only trace amounts of mRNA to be present as compared with normal macrophages, and an additional abnormal apoE mRNA band was also observed (45).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Remnant lipoprotein particles containing apoB-48 and apoA-IV, found in the proband's plasma but lacking in normal fasting plasma, may enhance the uptake of apoE.

    “These data suggest that remnant lipoprotein particles containing apo- lipoproteins such as apoB-48 and apoA-IV, found in the pro- band's plasma but lacking in normal fasting plasma, may en- hance the uptake of apoE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Familial apoE deficiency is a rare autosomal recessive condition associated with type III hyperlipoproteinemia and markedly decreased apoE production.

    “The combined data are consistent with the concepts that familial apoE deficiency is a rare autosomal recessive condition associated with type III hyperlipoproteinemia and markedly de- creased apoE production”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    ApoB-48 and/or apoA-IV may also play a role in the uptake of triglyceride-rich lipoproteins.

    “Moreover, apoB-48 and/or apoA-IV may also play a role in the uptake of triglyceride-rich lipoproteins, since apoE was catabolized at a significantly greater fractional catabolic rate on lipoproteins isolated from the proband than on normal li- poproteins when studied in normal subjects.”
    Quote in the paperNot a substantial claim
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

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Insufficient levels of apoE also lead to hypertriglyceridemia, because less apoE protein is present to serve as ligands for the LDL receptor and LRP, as clinically illustrated by familial apoE deficiency.

    “Interestingly, insufficient levels of apoE also lead to hypertriglyceridemia, because less apoE protein is present to serve as ligands for the LDL receptor and LRP, clinically illustrated by familial apoE deficiency [9,26,27].”

    From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [26]

    The Lipoprotein analysis section reports increased VLDL and IDL triglycerides in homozygotes with familial apoE deficiency. The paper also suggests that apoE is essential for receptor-mediated clearance of triglyceride-rich remnants, but the passages do not identify both the LDL receptor and LRP as the receptors responsible. Its finding is specific to homozygous deficiency; heterozygotes generally had normal plasma lipids. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes.

    “Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes27, 29-40).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [32]

    The Lipoprotein analysis section reports four homozygotes in the studied kindred, and Table III lists eight obligate heterozygotes. It does not establish the claimed total of 11 cases or the seven-case breakdown; the paper also says the precise gene-level defect remained to be elucidated, so it cannot substantiate the qualifier about reported mutation sites. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G) and APOE deficiency (Glu79fsTer98) with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas.

    “Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G)32, 33) and APOE deficiency (Glu79fsTer98)34) with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas (Table 1).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [32]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Mutations in apoE that diminish binding of apoE-containing lipoproteins to the LDL receptor are associated with high plasma cholesterol levels and cause premature atherosclerosis in humans and experimental animals.

    “In vivo and in vitro studies have shown that mutations in apoE that diminish binding of apoE-containing lipoproteins to the LDL receptor are associated with high plasma cholesterol levels and cause premature atherosclerosis in humans and experimental animals ( 1-3, 7, 8 ).”

    From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [2]

    The Discussion (page unavailable) reports elevated cholesterol and premature cardiovascular events in members of the human apoE-deficient kindred, while noting that other risk factors may have contributed and that the events were not strikingly premature. The paper attributes the defect to markedly decreased apoE production, not a demonstrated mutation that diminishes LDL-receptor binding; it provides no experimental-animal finding for this claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The characteristics of the APOE polymorphism suggest a qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism.

    “The characteristics of the APOE polymorphism thus suggest a qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism [26,27].”

    From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [26]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • LDL composition percentages do not total 100%

    Minor

    The four percentages reported for homozygotes' LDL add to 93.4%, although the table describes them as percentages of total lipoprotein by weight.

    Reported 100 · recomputed 93.4

  • Sibling 4's VLDL cholesterol-to-triglyceride ratio is incorrect

    Minor

    Table I defines this ratio as VLDL cholesterol divided by plasma triglyceride. For sibling 4, 28 divided by 217 is 0.13, not 0.24.

    Reported 0.24 · recomputed 0.129032

2 of 2

Cites

Flagged first, then by citations

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.

Cited by

Sorted by citations

Related

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)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1986-11-01
Volume
78
Issue
5
Pages
1206-1219
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci112704
PMC
PMC423806
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 › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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