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Cited by 100Lipid metabolism and disordersLipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and Lipoproteins

Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree.

Open access
de Knijff, P, van den Maagdenberg, A M, Stalenhoef, A F, Leuven, J A, Demacker, P N, Kuyt, L P, Frants, R R, Havekes, L M·1991·Journal of Clinical Investigation
DOI 10.1172/jci115349
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Abstract

By the careful screening of familial dysbetalipoproteinemic (FD) patients, five probands showing heterozygosity for the APOE*3-Leiden allele were found. Genealogical studies revealed that these probands share common ancestry in the 17th century. In a group of 128 family members, spanning three generations, 37 additional heterozygous APOE*3-Leiden gene carriers were detected. Although with a variable degree of severity, all carriers exhibited characteristics of FD such as (a) elevated levels of cholesterol in the very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fractions, (b) elevated ratios of cholesterol levels in these density fractions over total plasma levels of triglycerides, and (c) strongly increased plasma levels of apolipoprotein E (apoE). Multiple linear regression analysis revealed that most of the variability in expression of FD in APOE*3-Leiden allele carriers can be explained by age. Body mass index showed a less significant influence on the expression of FD. Gender had no effect on the expression in E*3-Leiden allele carriers, nor did it influence the age of onset of FD. In the group of APOE*3-Leiden allele carriers, we found that the E*2 allele enhances the expression of FD, whereas the E*4 allele had the opposite effect. Isoelectric focusing of plasma and of isolated VLDL, IDL, and high density lipoprotein density fractions showed that in E*3-Leiden allele carriers the apoE3-Leiden variant largely predominates over its normal apoE counterpart, especially in the VLDL and IDL density fractions. We conclude that in APOE*3-Leiden allele carriers FD is dominantly inherited with a high rate of penetrance, i.e., the presence of normally functioning apoE molecules in the plasma does not prevent the age-related expression of this disease.

AI snapshot

Written from the paper’s full text.

TL;DR

In an extended Dutch multigeneration pedigree, heterozygosity for APOE*3-Leiden was invariably associated with familial dysbetalipoproteinemia (FD), with dominant inheritance and high penetrance. Age was the main modifier of FD expression, while BMI had a weaker effect and gender had no effect.

Key findings

  • Among 128 family members from five probands, 42 carried APOE*3-Leiden; after excluding probands, 37 carriers and 86 noncarriers were compared. All carriers showed β-migrating VLDL, and carriers had higher mean plasma triglycerides (2.24 vs. 1.48 mmol/liter), cholesterol (7.14 vs. 5.44 mmol/liter), VLDL-cholesterol (1.65 vs. 0.48 mmol/liter), IDL-cholesterol (1.41 vs. 0.24 mmol/liter), and apoE (22.76 vs. 5.31 mg/100 ml).
  • The VLDL-cholesterol/plasma triglyceride ratio was 0.67 in carriers vs. 0.30 in noncarriers, and the (VLDL + IDL)-cholesterol/plasma triglyceride ratio was 1.26 vs. 0.49.
  • Multiple regression in carriers showed age had the strongest influence on the (VLDL + IDL)-cholesterol/triglyceride ratio (partial r = 0.71, P < 0.0001), IDL-cholesterol (r = 0.69, P = 0.0001), and apoE (r = 0.50, P = 0.0029); BMI had an additional weaker effect, and gender had no effect.
  • The accompanying APOE allele modified expression: E*2 enhanced FD, whereas E*4 had the opposite effect; apoE3-Leiden largely predominated over normal apoE in VLDL and IDL fractions.

Methods

  • Five independently ascertained Dutch FD probands heterozygous for APOE*3-Leiden were studied with genealogical records and family sampling; blood was collected from the five probands and 123 relatives.
  • Lipids and lipoproteins were measured by ultracentrifugation and enzymatic kits; apoE was quantified by ELISA, phenotyped by isoelectric focusing/immunoblotting, and genotyped by PCR, allele-specific oligonucleotide hybridization, and HhaI restriction digestion.
  • Statistical comparisons used nonparametric tests (Kruskal-Wallis or Mann-Whitney), χ² for gender distribution, Spearman correlation, and multiple linear regression on log-transformed data; the five probands were excluded from calculations to avoid ascertainment bias.

Limitations

  • The paper states that the E2E3-Leiden and E4E3-Leiden subgroups were small (four and three individuals, respectively) and that results could be biased because all E4E3-Leiden individuals came from one generation of a single kindred, and three of four E2E3-Leiden individuals came from one generation of another kindred.
  • Evident from the text: the study is cross-sectional and family-based, so it cannot establish longitudinal onset or causality, and the pedigree-specific findings may not generalize to other populations.

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

Integrity signals

Registry

Crossref · 10.1172/jci115349

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 79 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    All probands showed only partial modification with cysteamine, indicating heterozygosity for apoE3-Leiden.

    “All probands showed only partial modification with cysteamine, indicating heterozygosity for apoE3-Leiden (21 ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21]

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

  • Findingown data

    Regarding ratio of (VLDL+IDL)-cholesterol to plasma triglycerides, range of overlap between both groups was much smaller.

    “Regarding the ratio of (VLDL + IDL)-cholesterol to plasma triglycerides, the range of overlap between both groups was much smaller (see Appendix).”
    Quote in the paperNot a substantial claim
  • Findingnone given

    Later, four other, apparently unrelated probands with FD and heterozygosity for apoE3-Leiden have been found in lipid clinics in Nijmegen and Leiden.

    “Later, four other, apparently unrelated probands with FD and heterozygosity for apoE3-Leiden have been found in lipid clinics in Nijmegen and Leiden.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Both in carriers and noncarriers, there is a strong linear correlation between age and BMI (Spearman's correlation coefficients of 0.61 and 0.66 for carriers and noncarriers, respectively; P<0.001).

    “Both in the group of carriers and in the group of noncarriers, we found a strong linear correlation between age and BMI (Spearman's correlation coefficients of0.61 and 0.66 for carriers and noncarriers, respectively; P < 0.001, results not shown), indicating that BMI is strongly influenced by age.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In this paper, four additional, apparently unrelated patients with FD carrying APOE*3-Leiden allele in heterozygous form were ascertained.

    “In this paper, four additional, apparently unrelated patients with FD carrying the APOE*3-Leiden allele in a heterozygous form were ascertained.”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • Classified as probably not a substantial claim. 29
  • The quote only partly states this claim. 5

  • May combine two claims.

    Findingown data

    All carriers display high plasma apoE concentrations (>11 mg/100 ml); only one individual in noncarriers showed apoE level above 11 mg/100 ml.

    “All carriers display high plasma apoE concentrations(> 11 mg/ 100 ml) (see Appendix).Only one individual in the group of noncarriers showed an apoE level above 11 mg/100 ml (see Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Agarose electrophoresis of VLDL revealed that all carriers showed beta-migrating VLDL particles, whereas beta-VLDL could not be detected in any noncarriers.

    “Agarose electrophoresis ofVLDL (d < 1.006 g/ml) revealed that all carriers showed /3-migrating VLDL particles, whereas /3-VLDL could not be detected in any of the noncarriers (results not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although five probands were ascertained independently in two different lipid clinics, they had relatives living in the same area of The Netherlands.

    “Although the five probands were ascertained independently in two different lipid clinics (Leiden and Nijmegen), we learned that they had relatives living in the same area of The Netherlands.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In both age classes (<45 and >=45 yr), no significant difference in levels of any plasma lipid and lipoprotein parameter measured was found between male and female APOE*3-Leiden allele carriers, indicating no influence of gender on age of onset of FD.

    “In both age classes no significant difference in levels of any plasma lipid and lipoprotein parameter measured was found between males and females (Table V), indicating that in the group of APOE•3-Leiden allele carriers there is no influence of gender on the age of onsetofFD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    All individuals with FD found in this study are heterozygous for APOE*3-Leiden allele and thus heterozygous for a common APOE allele as well.

    “All individuals with FD found in this study are heterozygous for the APOE•3-Leiden allele and thus, they are heterozygous for a common APOE allele as well.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In group of carriers, there is a strong influence of age on ratio (VLDL+IDL)-cholesterol/plasma triglycerides and an even more pronounced effect on plasma IDL-cholesterol and plasma apoE concentration.

    “In the group of carriers we found a strong influence of age on the ratio (VLDL + IDL)-cholesterol/plasma triglycerides and an even more pronounced effect on plasma IDL-cholesterol and plasma apoE concentration (Fig. 6 A, B, and C, respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In APOE*3-Leiden allele carriers, development of FD is strongly correlated with age as is BMI.

    “We found that in APOE*3-Leiden allele carriers the development ofFD is strongly correlated with age (Fig. 6, A-C) as is BMI (Fig. 6 D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Since apoE3-Leiden mutation adds 21 bp to 72-bp HhaI fragment normally found in individuals with APOE*4 allele, resulting 93-bp HhaI fragment is typical for APOE*3-Leiden allele.

    “Since the apoE3-Leiden mutation adds 21 bp to the 72-bp HhaI fragment that is normally found in individuals with the APOE*4 allele, the resulting 93-bp Hhal fragment is typical for the APOE*3-Leiden allele (Figs. 1 and 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The grandfather and grandmother of proband CV were related, giving possibility of homozygosity for E3-Leiden variant in parental generation of this proband; the mother of proband CV was heterozygous for this variant.

    “It was found that the grandfather and grandmother of proband CV were related, giving the possibility of homozygosity for the E3-Leiden variant in the parental generation of this proband; the mother of proband CV, however, was heterozygous for this variant.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In the region southeast of The Hague, there is no high degree of consanguinity.

    “We learned that in this region there is no high degree of consanguinity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Multiple regression analysis revealed that there was a weak effect of BMI on expression of FD in addition to highly significant effect of age.

    “Multiple regression analysis revealed that there was a weak effect ofBMI on the expression ofFD in addition to the highly significant effect of age (Table IV).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In carriers, ratio VLDL-cholesterol to plasma triglycerides and plasma level of IDL-cholesterol was much higher than in noncarrier group (mean values 0.67 vs. 0.30 and 1.41 vs. 0.24, respectively).

    “In the carriers, the ratio VLDL-cholesterol to plasma triglycerides and the plasma level of IDL-cholesterol was much higher than in the noncarrier group (mean values 0.67 vs. 0.30 and 1.41 vs. 0.24, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although E3-Leiden heterozygotes resembles E2(Arg158-Cys) homozygotes with respect to effect of age on expression of FD, in E*3-Leiden allele carriers there is no influence of gender on expression and on age of onset of FD.

    “Although the E3-Leiden heterozygotes resembles the E2(Argl 58 -Cys) homozygotes with respect to the effect of age on the expression ofFD, we found that in E*3-Leiden allele carriers there is, strikingly, no influence of gender on the expression and on age of onset of FD (Table V).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In group of APOE*3-Leiden allele carriers, E*2 allele enhances expression of FD (reflected by higher lipid and lipoprotein levels), whereas E*4 allele showed opposite effect.

    “The results presented in Table VI show that, in the group of APOE•3-Leiden allele carriers, the E•2 allele enhances the expression ofFD (which is reflected by the higher lipid and lipoprotein levels), whereas the E•4 allele showed the opposite effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no significant differences between group of APOE*3-Leiden allele carriers and noncarriers with respect to BMI (P=0.656; NS), age (P=0.778; NS) and gender distribution (chi2=1.020; P=0.315; NS).

    “As indicated in Table II, there were no significant differences between the group of APOE*3-Leiden allele carriers and the group of noncarriers with respect to BMI (P = 0.656; NS), age (P = 0.778; NS)andgenderdistribution (x 2 = l.020;P=0.315; NS).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four probands (GW, AB, JB, and JE) have apoE3E3-Leiden phenotype whereas original proband CV exhibits apoE2E3-Leiden phenotype.

    “As shown in Fig. 2, four probands (GW, AB, JB, and JE) have the apoE3E3-Leiden phenotype whereas the original proband CV exhibits the apoE2E3-Leiden phenotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Three apoE3-Leiden probands show signs and symptoms typical for FD; the remaining two probands had clinical signs only.

    “Three apoE3-Leiden probands show the signs and symptoms typical for FD.The remaining two probands had the clinical signs only.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    As well as five probands, 123 family members were studied; after apoE phenotyping and genotyping, 37 additional individuals were found to be heterozygous for APOE*3-Leiden allele.

    “As well as the five probands, 123 family members were studied (Appendix and Fig. 5).After apoE phenotyping and genotyping, performed as described above for the probands, 37 additional individuals were found to be heterozygous for the APOE*3-Leiden allele (solid symbols in Fig. 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In group of carriers, age has a strong influence on ratio (VLDL+IDL)-cholesterol/plasma triglycerides, IDL-cholesterol, and plasma apoE concentration; BMI showed an additional influence on expression of FD; gender had no effect.

    “It is clear that in the group of carriers, age has a strong influence on these parameters.BMI showed an additional influence on the expression ofFD in this group, whereas gender had no effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The predominance of apoE3-Leiden is most pronounced in the VLDL and IDL density fractions, except when apoE4 is the normal variant.

    “nance is most pronounced in the VLDL and IDL density frac-”
    • Also stated in: § Discussion · plain
      “except in the case of apoE4 as the normal variant.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    The APOE*2(Arg158-Cys) allele as second allele in apoE3-Leiden subjects enhances the expression of FD.

    “apoE3-Leiden subjects enhances the expression ofFD”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Approximately 75% of total plasma apoE consists of apoE3-Leiden.

    “showed that ~ 75% of the total plasma apoE”
    • Also stated in: § Discussion · plain
      “consists of apoE3-Leiden (results not shown)”
    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.

    Findingnone given

    Dominantly inherited forms of FD display high rates of penetrance.

    “FD display high rates of penetrance, making early diagnosis in”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The vast majority of FD patients are homozygous for the apoE2(Arg158-Cys) variant.

    “The vast majority of FD patients are homozygous for the apoE2(Arg158 -Cys) variant (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

      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

    Recently, DNA and protein sequence analysis revealed that molecular basis of apoE3-Leiden is due to partial gene duplication leading to in-frame insertion of 21 nucleotides forming tandem repeat of codons 120-126 or 121-127.

    “Recently, DNA and protein sequence analysis revealed that the molecular basis of apoE3-Leiden is due to a partial gene duplication leading to an in-frame insertion of 21 nucleotides forming a tandem repeat of the codons 120-126 or 121-127 (23,24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23]

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

    • cites [24]

      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

    In Caucasian populations, homozygosity for apoE2(Arg158-Cys) occurs with a frequency of 1%, whereas the frequency of FD is about 1:2,500.

    “In Caucasian populations homozygosity for apoE2(Argl58 -Cys) occurs with a frequency of 1 %, whereas the frequency of FD is about 1 :2,500 ( 1 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Previously, the authors reported on a patient with FD exhibiting heterozygosity for a rare apoE variant focusing at E3 position, lacking cysteine residues, designated apoE3-Leiden.

    “Previously, we have reported on a patient with FD exhibiting heterozygosity for a rare apoE variant focusing at the E3 position, lacking cysteine residues, and designated as apoE3-Leiden (20,21).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20]

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

    • cites [21]

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

  • May combine two claims.

    Premisecitation

    The insertion leads to a tandem repeat of codons 120-126 or 121-127.

    “the insertion leads to a tandem repeat of codons 120-126 or 121-127 (23,24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23]

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

    • cites [24]

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

  • May combine two claims.

    Interpretationown data

    From our data it is clear that there is a strong association between presence of APOE*3-Leiden allele and development of FD, although there is considerable variability in expression.

    “From our data it is clear that there is a strong association between the presence of the APOE*3-Leiden allele and the development of FD, although there is a considerable variability in the expression of FD”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In addition to rare variants described above, apoE variants E2(Arg145-Cys) and E2-Christchurch(Arg136-Ser) are also reported to be associated with development of FD.

    “In addition to the rare variants described above, the apoE variants E2(Argl45 -Cys) (8,34,35) and E2-Christchurch(Argl36 -Ser) (35,36) are also reported to be associated with the development ofFD.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [8]

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

    • cites [34]

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

    • cites [35]

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

    • cites [36]

      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

    This effect is consistent with previous data obtained by Weintraub et al.

    “This effect is consistent with previous data obtained by Weintraub et al. (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33]

      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

    One of these (AB) was previously reported as apoE3-Nijmegen.

    “One of these (AB) was previously reported as apoE3-Nijmegen (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

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

  • May combine two claims.

    Premisecitation

    The initial proband (CV) is a Caucasian male previously described as FD patient with heterozygosity for apoE3-Leiden variant.

    “The initial proband (CV) is a Caucasian male who was previously described as a FD patient with heterozygosity for the apoE3-Leiden variant (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20]

      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).

    Study design and conductreasoning

    Multiple regression analysis to determine independent effects of age, BMI, and gender was performed on logarithmic transformed data in order to avoid non-Gaussian distribution of dependent variables.

    “Multiple regression analysis to determine the independent effects of age, BMI, and gender was performed on logarithmic transformed data in order to avoid non-Gaussian distribution of the dependent variables.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In individuals with homozygosity for E2(Arg158-Cys) variant, a marked difference in onset of expression of FD exists between males and females owing to difference in hormonal status; in males FD normally expressed between 30 and 40 yr, whereas in females FD expressed after menopause.

    “In case of individuals with homozygosity for the E2 (Argl58 -Cys) variant, a marked difference in the onset of expression of FD exists between males and females owing to the difference in hormonal status ( 1 ).In males the FD is normally expressed between 30 and 40 yr of age, whereas in females FD is expressed after the menopause.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1]

      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

    In subjects with homozygosity for apoE2(Arg158-Cys), FD only rarely develops (1-4%) and is commonly assumed to be highly influenced by additional factors such as age, BMI, nutritional status and gender.

    “In subjects with homozygosity for apoE2(Argl58 -Cys) FD only rarely develops (1-4%) and is commonly assumed to be highly influenced by additional factors such as age, BMI, nutritional status and gender (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1]

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

  • May combine two claims.

    Premisereasoning

    The seven-amino acids insert introduces one extra negatively charged glutamyl residue when compared with common apoE4(Cys112-Arg) variant and thus leads to focusing on apoE3 position.

    “The seven-amino acids insert introduces one extra negatively charged glutamyl residue when compared with the common apoE4(Cysl 12 -Arg) variant and thus leads to a focusing on the apoE3 position.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Patients with FD are characterized by elevated plasma cholesterol and triglycerides levels owing to the presence of beta-migrating chylomicron and VLDL remnants enriched in cholesterol and apolipoprotein E.

    “Patients with FD are characterized by elevated plasma cholesterol and triglycerides levels owing to the presence of tJ-migrating chylomicron and very low density lipoprotein (VLDL) remnants enriched in cholesterol and apolipoprotein E (apoE) (2--4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 2--4

      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.

    Study design and conductown data

    The relatively high number of FD subjects ascertained in this study (37 individuals in addition to five probands), together with absence of significant differences between apoE3-Leiden carriers and noncarriers with respect to age, BMI, and gender distribution, gave unique opportunity to estimate possible association of expression of FD with these factors by means of statistical analysis.

    “The relatively high number of FD subjects ascertained in this study (37 individuals in addition to the five probands), together with the absence of significant differences between the apoE3-Leiden carriers and noncarriers with respect to age, BMI, and gender distribution (Table II), gave us the unique opportunity to estimate the possible association of the expression of FD with these factors by me”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In previous studies, the authors have shown that dominant expression of FD also occurs in family of an FD patient who has apoE3-Leiden mutation.

    “In previous studies (20,21) we have shown that dominant expression of FD also occurs in the family of an FD patient who has the apoE3-Leiden mutation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20]

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

    • cites [21]

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

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    In order to avoid the possibility of ascertainment bias, the five probands were omitted from all calculations.

    “In order to avoid the possibility of ascertainment bias, the five probands were omitted from all calculations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Irrespective of common accompanying second allele in E*3-Leiden allele carriers, FD is dominantly inherited, i.e., presence of normally functioning apoE molecules does not prevent expression of FD in these subjects.

    “Irrespective of the common accompanying second allele in the E•3-Leiden allele carriers, FD is dominantly inherited, i.e., the presence of normally functioning apoE molecules does not prevent the expression of FD in these subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE plays a central role in receptor-mediated endocytosis of chylomicron and VLDL remnants, functioning as a high-affinity ligand for hepatic lipoprotein receptors.

    “ApoE, one of tlie major protein constituents of chylom1cron and VLDL remnants, plays a central role in the receptormediated endocytosis of these particles functioning as a highaffinity ligand for hepatic lipoprotein receptors (5,6).”
    Quote in the paperSubstantial 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

    FD has been reported earlier in association with heterozygosity for E3(Cys112-Arg; Arg142-Cys), E2(Lys146-Gln), and E1-Harrisburg(Lys146-Glu).

    “FD has been reported earlier in association with heterozygosity for E3(Cysl 12 -Arg; Argl42 -Cys), E2(Lysl46 -Gin), and El-Harrisburg(Lysl46 -Glu) (13)(14)(15)(16)(17)(18)(19).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [13]

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

    • cites [14]

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

    • cites [15]

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

    • cites [16]

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

    • cites [17]

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

    • cites [18]

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

    • cites [19]

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

  • May combine two claims.

    Study design and conductown data

    There could be some bias of results since all E4E3-Leiden individuals come from one generation in a single kindred, and three of four individuals with E2E3-Leiden phenotype come from one generation of another kindred.

    “In addition, there could be some bias of the results since all E4E3-Leiden individuals come from one generation in a single kindred, and three of the four individuals with the E2E3-Leiden phenotype come from one generation of another kindred (see Fig. 5 and Appendix).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both apoE3(Cys112-Arg; Arg142-Cys) and apoE1-Harrisburg(Lys146-Glu) have been reported in one family each, whereas apoE2(Lys146-Gln) has been studied in three apparently unrelated kindreds.

    “Both apoE3(Cysl 12 -Arg; Argl42 -Cys) and apoEl-Harrisburg(Lysl46 -Glu) have been reported in one family each (13, 14, 18), whereas apoE2(Lysl46 -Gin) has been studied in three apparently unrelated kindreds ( 17).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13]

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

    • cites [14]

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

    • cites [18]

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

    • cites [17]

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

  • May combine two claims.

    Premisecitation

    DNA and protein sequencing analyses revealed that APOE*3-Leiden allele was identical to APOE*4(Cys112-Arg) allele, but included an in-frame repeat of 21 nucleotides in exon 4.

    “Recently, DNA and protein sequencing analyses revealed that the APOE*3-Leiden allele was identical to the APOE*4(Cysl 12 -Arg) allele, but included an in-frame repeat of 21 nucleotides (coding for seven amino acids) in exon 4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23]

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

    • cites [24]

      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

    Familial dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism predisposing to premature coronary and/or peripheral vascular disease.

    “Familial dysbetalipoproteinemia (FD) 1 is a genetic disorder of the lipoprotein metabolism.predisposing to premature coro-nary and/or peripheral vascular disease (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

      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

    Approximately 50% of FD patients show lipid deposits like palmar streaks and tuberous xanthomas.

    “Approximately 50% of the patients show lipid deposits like palmar streaks and tuberous xanthomas ( 1 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

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

  • May combine two claims.

    Premisereasoning

    Family studies have confirmed that heterozygosity for these rare variants is associated with development of FD despite presence of a 'normal' APOE allele, indicating that with these variants FD is dominantly inherited with a high degree of penetrance.

    “Family studies have confirmed that heterozygosity for these rare variants is associated with the development ofFD despite the presence of a”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Only a small percentage of E2E2 individuals will develop FD.

    “Thus, only a small percentage of these E2E2 individuals will develop FD (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

      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.

    Study design and conductreasoning

    Since the studied population involves family members (not randomly selected individuals), and most measured parameters showed non-Gaussian distributions, differences in these parameters between groups were calculated using nonparametric ANOVA (Kruskal-Wallis) or Mann-Whitney test.

    “Since the studied population involves family members (not randomly selected individuals), and most of the measured parameters showed non-Gaussian distributions, differences in these parameters between groups were ~culated using either the nonparametric analysis of variance (ANOVA) test of Kruskal-Wallis (in the case of more than two groups) or the Mann-Whitney test (in the case of two groups).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Cysteamine treatment enabled distinction of 'normal' apoE from apoE3-Leiden since apoE3-Leiden contains no cysteine residues.

    “The cysteamine treatment enabled us to distinguish”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21]

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

  • May combine two claims.

    Interpretationreasoning

    Thus, for these variants FD is inherited in a dominant fashion with a high penetrance.

    “Thus, for these variants FD is inherited in a dominant fashion with a high penetrance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Subsequently, his first-degree relatives were studied and five more gene carriers were found, all exhibiting FD.

    “Subsequently, his first-degree relatives members were studied and five more gene carriers were found, all exhibiting FD (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21]

      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

    A number of studies conducted by Mahley and co-workers strongly suggest that conformation of 130-150 alpha-helical region of apoE, putative receptor-binding domain, can be easily modulated, leading to change in receptor- (truncated).

    “A number of studies conducted by Mahley and co-workers (10,(37)(38)(39)(40) strongly suggest that the conformation of the 130-150 a-helical region of apoE, the putative receptor-binding domain, can be easily modulated, leading to a change in receptor-”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [10]

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

    • cites [37]

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

    • cites [38]

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

    • cites [39]

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

    • cites [40]

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

  • The quote only partly states this claim.

    Interpretationreasoning

    Only when exacerbating factors are present does the receptor-binding activity of β-VLDL decrease and eventually result in the development of FD.

    “Only when exacerbating factors are present, does the receptor-binding activity of P-VLDL decrease and, eventually, will result in the development of FD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These binding-defective apoE mutants are associated with dominantly inherited FD; heterozygous subjects display FD irrespective of the presence of normal apoE molecules.

    “that are associated with dominantly inherited FD, i.e., the subjects who are heterozygous for these variant alleles display FD, irrespective of the presence of normal apoE molecules.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    An increase in receptor-binding activity of apoE2(Arg158-Cys) can be obtained in vitro by cleavage with thrombin or by cysteamine treatment.

    “For instance, an increase in receptor-binding activity ofapoE2(Argl58 -Cys) can be obtained in vitro by cleavage with thrombin (38) or by cysteamine treatment (a reagent that converts cysteine to a positively charged lysine analogue) (10,38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38]

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

    • cites [10]

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Loss of any positively charged amino acid residue within the putative α-helical segment affects the binding of apoE by reducing the ionic interaction.

    “Mahley et al. ( 41) suggest that loss of any positively charged amino acid residue within the putative a-helical segment affects the binding of apoE by reducing the ionic interaction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41]

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

  • May combine two claims.

    Interpretationreasoning

    The seven-amino-acid insertion in apoE3-Leiden changes the structure of the entire protein such that the carboxyl-terminal domain prevents the receptor-binding region from interacting with the LDL receptor, thereby interfering with binding activity.

    “This suggests that, owing to the insertion of seven amino acids, close to the receptor-binding domain, and constituting nearly two turns of the a-helix, the structure of the entire protein is changed in such a way that the carboxyl-terminal domain irreversibly prevents the receptor-binding region of apoE to interact with the LDL receptor, and as a consequence, interferes with the binding activity”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Both normal and mutant apoE molecules are present on each chylomicron and VLDL remnant particle.

    “it may be expected that both normal and mutant apoE molecules are present on each particle.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Chylomicron and VLDL remnants possess several apoE molecules per particle.

  • May combine two claims.

    Premisenone given

    ApoE3-Leiden, E3(Cys112-Arg; Arg142-Cys), E2(Lys146-Gln), and E1-Harrisburg(Lys146-Glu) are binding-defective apoE mutants.

    “ApoE3-Leiden, described in this paper, as well as the E3(Cysl 12 -Arg; Argl42 -Cys), E2(Lys146 -Gin), and EI-Harrisburg(Lysl46 -Glu), represent binding-defective apoE mutants”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Early diagnosis in these families is feasible.

    “these families feasible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE4 distributes preferentially to VLDL, which is ascribed to arginine at residue 112.

    “ApoE4 distributes preferentially to VLDL (44), which should”
    • Also stated in: § Discussion · plain
      “be ascribed to the arginine at residue 112 (45).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44]

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

    • cites [45]

      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

    Upon cleavage with thrombin, the 22-kD fragment of apoE3-Leiden possesses nearly normal binding activity.

    “Recently it was found that upon cleavage with thrombin, the 22-kD fragment of apoE3-Leiden possesses a nearly normal binding activity (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23]

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

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Premisecitation

    Plasma levels of apoE may become rate-limiting in the clearance of remnant lipoproteins.

    “There is some evidence that plasma levels of apoF may become rate-limiting in the clearance of remnant lipoproteins (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43]

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

  • May combine two claims.

    Interpretationreasoning

    FD has a recessive mode of inheritance in case of the common E2(Arg158-Cys) variant and a dominantly inherited form in case of rare apoE mutants.

    “with a recessive mode of in”
    • Also stated in: § Discussion · plain
      “heritance in case of the common E2(Argl 58 -Cys) variant”
    • Also stated in: § Discussion · plain
      “with a dominantly inherited form in case of rare apoE”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The basic amino acid residues in the predicted α-helical receptor-binding domain of apoE (residues 130-150) provide direct ionic interaction with the LDL receptor.

    “It is suggested that the basic amino acid residues in this particular domain provide direct ionic interaction with the LDL receptor ( 42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42]

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

  • May combine two claims.

    Premisereasoning

    The conformation of apoE2(Arg158-Cys) is sensitive to its environment and the cysteine at residue 158 has a secondary, rather than a direct, effect on receptor-binding activity.

    “Their results suggest that the conformation of apoE2(Argl 58 -Cys) is sensitive to its environment and that the cysteine at residue 158 has a secondary, rather than a direct, effect on receptorbinding activity.”
    Quote in the paperSubstantial claim
70 of 70

  • The paper relies on this without support.

    Chylomicron and VLDL remnants possess several apoE molecules per particle.

    “In that chylomicron and VLDL remnants possess several apoE molecules per particle”
1 of 1

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?

  • Both apoE Leiden and another apoE variant that shows preferential in vitro association with VLDL are found in much higher concentrations compared with normal apoE in affected subjects' VLDL, at a ratio of 4:1 or higher in the former and 3:1 in the latter.

    “In contrast, both apoE Leiden and another apoE variant that shows a preferential in vitro association with VLDL (22) are found in much higher concentrations compared with normal apoE in affected subjects' VLDL, at a ratio of 4:1 or higher in the former instance (12) and 3:1 in the latter instance (22).”

    From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [12]

    The citation to this paper is attached to the apoE3-Leiden finding, not the other variant’s 3:1 ratio. The ‘Effect of the second APOE allele’ section says apoE3-Leiden makes up the majority of apoE in affected subjects’ VLDL, but the passages found do not establish the claimed ratio of 4:1 or higher. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • Subjects heterozygous for the apoE Leiden mutation show a predominance of the variant apoE over the wild-type protein in total plasma, but especially in the VLDL fraction (4:1 ratio or higher).

    “Interestingly, subjects heterozygous for the apoE Leiden mutation show a predominance of the variant apoE over the wild-type protein in total plasma, but especially in the VLDL fraction (4:1 ratio or higher) (6, 11, 12)”

    From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [12]

    The Discussion (page unavailable) says apoE3-Leiden largely predominates over normal apoE in plasma. The ‘Effect of the second APOE allele’ section (page unavailable) says it makes up the majority of apoE in VLDL and IDL, but gives no 4:1 ratio; it also notes that the fraction-by-fraction pattern differs when the second allele is E4. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Other rare apoE variants such as apoE3-Leiden and apoE2(Lys1463 Gln) can also cause dysbetalipoproteinemia.

    “Other rare apoE variants such as apoE3-Leiden and apoE2(Lys1463 Gln) can also cause dysbetalipoproteinemia (122, 123).”

    From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [123]

  • ApoE Leiden is associated with dominant transmission of type III hyperlipoproteinemia.

    “All subjects carrying the apoE Leiden mutation are heterozygotes, but all demonstrate type III hlp, although to varying degrees (12).”

    From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [12]

  • ApoE Leiden is a rare variant of human apolipoprotein E.

    “ApoE Leiden, one of the most thoroughly studied of the rare apoE variants (6, 11, 12)”

    From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [12]

Self-check

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

  • E3E3-L subgroup cholesterol means do not add up

    Minor

    In Table VI, the E3E3-L mean VLDL-cholesterol of 1.58 plus mean IDL-cholesterol of 1.39 equals 2.97 mmol/liter, not the reported combined-fraction mean of 2.85 mmol/liter. Rounding cannot explain the difference.

    Reported 2.85 · recomputed 2.97

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. I. Mahley, R. W., and s. c. Rall. 1989. Type ill hyperlipoproteinemia (dysbe- talipoproteinemia): the role of apolipoprotein E in normal and abnormal lipopro- tein metabolism. In The Metabolic Basis oflnherited Disease. 6th edition. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill Book Co., Inc., New York. 1195-1213.
  2. Havel, R. J., Y.-C. Chao, E. E. Windler, L. Kotite, and L. S.S. Guo. 1980. lsoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogene- sis offamilial dysbetalipoproteinemia. Proc. Natl. Acad. Sci. USA. 77:4349-4353.

Cited by

Sorted by citations

Related

Authors
de Knijff, P., van den Maagdenberg, A. M., Stalenhoef, A. F., Leuven, J. A., Demacker, P. N., Kuyt, L. P., Frants, R. R., & Havekes, L. M.
Affiliations
  • Netherlands Organisation for Applied Scientific Research (NL)
  • Leiden University (NL)
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1991-08-01
Volume
88
Issue
2
Pages
643-655
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci115349
OpenAlex
W2119332560
Semantic Scholar
142204b0a1a095b50c34d56ca0cf115b25b0ebfd
Cited by
100
References
40
Citations by year
2026: 1 · 2025: 4 · 2024: 1 · 2022: 3 · 2020: 1 · 2019: 1 · 2018: 1 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 3
FWCI
8.06
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed (publishedVersion)
  • TNO Repository (submittedVersion)
  • Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
familial dysbetalipoproteinemia, APOE gene, heterozygous carriers, VLDL cholesterol, penetrance, dominant inheritance, body mass index
MeSH terms
Adolescent, Adult, Age Factors, Aged, Alleles, Apolipoproteins E, Body Weight, Cholesterol, Female, Heterozygote, Genetic Carrier Screening, Humans, Hyperlipoproteinemia Type III, Lipoproteins, Male, Middle Aged, Pedigree, Sex Factors, Cholesterol, VLDL, Apolipoprotein E3

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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