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Cited by 8Lipid metabolism and disordersLipoproteins and Cardiovascular HealthGenomics and Rare Diseases

Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia

Open access
Blokhina, Anastasia V., Ershova, Alexandra I., Kiseleva, Anna V., Sotnikova, Evgeniia A., Zharikova, Anastasia A., Zaicenoka, Marija, Vyatkin, Yuri V., Ramensky, Vasily E. +8 more·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms252312651PMC PMC11641494
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Abstract

Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This study analyzed rare APOE variants in 4,720 Russian subjects and identified 24 variants, five causal for autosomal dominant familial dysbetalipoproteinemia (FD), including one novel frameshift. Carriers of pathogenic/likely pathogenic variants had higher triglycerides, and the expected population prevalence of causal variants was 0.27% (one in 619).

Key findings

  • Among 86 unrelated probands, 24 rare APOE variants were identified; 66.7% were unique, 83.3% were in exon 4, and 87.5% were missense.
  • Five variants were causal for autosomal dominant FD: p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87 (novel), p.Arg154Cys, and p.Glu230Lys.
  • Carriers of pathogenic/likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign/likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036).
  • In the ESSE-Ivanovo population sample (n = 1858), the expected prevalence of causal variants for autosomal dominant FD was 0.27% (one in 619; 95% CI 0.09–0.63); 12.8% of probands carried multiple rare variants.

Methods

  • Targeted (n = 4526) or exome (n = 194) sequencing data from 4,720 subjects were analyzed, including the ESSE-Ivanovo population sample (n = 1858), an FH sample (n = 557), and a Russian patient sample (n = 2305).
  • Rare non-synonymous APOE variants with MAF <0.5% in gnomAD were annotated and classified using ACMG/AMP2015 guidelines plus CADD; clinical comparison included 44 heterozygous carriers divided by pathogenicity.
  • Statistical analysis used R 4.3.2 with Mann–Whitney U, Kruskal–Wallis, Fisher’s exact tests, Holm–Bonferroni adjustment, and p < 0.05; prevalence was estimated in ESSE-Ivanovo.

Limitations

  • Stated: no lipoprotein ultracentrifugation or electrophoresis was used to confirm FD phenotype, and previously developed FD diagnostic algorithms including apoB could not be applied; cis/trans position of APOE variants was unavailable, so rare genotypes were presented only for common homozygous carriers and unclear genotypes were excluded from clinical comparison.
  • Evident: clinical comparison groups were small (n = 16 pathogenic/likely pathogenic, n = 13 uncertain significance, n = 15 benign/likely benign; total 44) and relied on retrospective data; no functional validation of the novel variants was performed in this study.

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

Integrity signals

Registry

Crossref · 10.3390/ijms252312651

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 58 cited sources checked · 10 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    FD has a complex multifactorial phenotype caused by the interaction of APOE gene variants with additional factors such as overweight or obesity, insulin resistance, diabetes mellitus, and hypothyroidism.

    “FD (OMIM #617347) has a complex multifactorial phenotype caused by the interaction of APOE gene variants with additional factors such as overweight or obesity [17,18,19], insulin resistance [17,18,20], diabetes mellitus [17,21], hypothyroidism, and so forth.”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [17] Smelt, 2004, Apolipoprotein E and familial dysbetalipoproteinemia: Clinical, biochemical, and genetic aspects, Semin. Vasc. Med. source
    • cites [18] Stalenhoef, 2002, Expression of type III hyperlipoproteinemia in apolipoprotein E2 (Arg158 → Cys) homozygotes is associated with hyperinsulinemia, Arterioscler. Thromb. Vasc. Biol. source

      The introduction says apoE2 homozygosity plus additional factors can produce type III hyperlipoproteinemia and names obesity, diabetes, and hypothyroidism as suggested influences. The discussion (p. 296) identifies hyperinsulinemia as an additional factor, but says insulin sensitivity was not directly measured; it suggests a role for insulin resistance rather than establishing that it causes the phenotype. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] Heidemann, 2021, Adiposity and the development of dyslipidemia in APOE ε2 homozygous subjects: A longitudinal analysis in two population-based cohorts, Atherosclerosis source

      The Introduction (page not provided) describes APOE ε2 predisposition together with adiposity and insulin resistance as possible contributors to the FD phenotype. The Discussion (page not provided) finds baseline adiposity associated with later FD-like dyslipidemia, but the type 2 diabetes association was not statistically significant; the paper does not establish the full causal interaction asserted. Hypothyroidism has no citation attached to it in the citing sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [20] Corsetti, 2018, Insulin resistance involvement in prevalence of familial dysbetalipoproteinemia in ε2ε2 subjects by Bayesian network modeling, Clin. Biochem. source
    • cites [21] Koopal, 2015, Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: A European cross-sectional study, Atherosclerosis source
  • Premisecitation

    To date, only about 30 APOE variants associated with autosomal dominant FD have been reported.

    “To date, only about 30 APOE variants associated with autosomal dominant FD have been reported [29,30].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [29] Abou, 2021, APOE gene variants in primary dyslipidemia, Atherosclerosis source
    • cites [30] Heidemann, 2022, Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene, Clin. Genet. source

      The Introduction reports 23 APOE variants other than ε2ε2 associated with FD, rather than about 30. The Analysis of Genetic Variants section says these variants are often inherited dominantly, not that all 23 are associated with autosomal dominant FD. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Elevated levels of cholesterol-enriched remnant lipoproteins contribute to the development of premature coronary and peripheral atherosclerosis.

    “As a result, elevated levels of cholesterol-enriched remnant lipoproteins contribute to the development of premature coronary [22,23,24] and peripheral [25,26] atherosclerosis.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [22] Varbo, 2015, Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population, Clin. Chem. source
    • cites [23] Quispe, 2021, Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: A primary prevention study, Eur. Heart. J. source
    • cites [24] Kexin, W., Yaodong, D., Wen, G., Rui, W., Jiaxin, Y., Xiaoli, L., Hua, S., and Hailong, G. (2021). Association of increased remnant cholesterol and the risk of coronary artery disease: A retrospective study. Front. Cardiovasc. Med., 8. source

      The Introduction identifies elevated remnant cholesterol as a risk factor for atherosclerosis, and the Discussion links it to CAD and describes a possible plaque-forming mechanism. The cited paper does not establish that this occurs prematurely, and its retrospective findings show an association rather than demonstrating causation. The peripheral claim is attached to different citations, so it is not assessed against this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [25] Karpe, 2001, Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides, J. Lipid Res. source

      The Discussion (page not provided) reports an association between remnant-like particle cholesterol and carotid intima-media thickness, a surrogate marker of early atherosclerosis. This supports a link to early carotid artery changes, but the study does not establish that elevated remnants cause peripheral atherosclerosis; its coronary discussion describes a previous study rather than a finding of this one. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [26] Wang, 2021, Association of remnant cholesterol with intra-and extra-cranial atherosclerosis in Chinese community population, Atheroscler. Plus source

      The Discussion (page unavailable) reports that higher remnant cholesterol was associated with intracranial and extracranial carotid atherosclerosis in asymptomatic Chinese adults. This lends some support to the cited peripheral-atherosclerosis point, but the paper does not establish premature or peripheral-limb disease. Its Limitations section explicitly says the cross-sectional design limits causal inference, so it does not establish that remnant lipoproteins contribute to disease development. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Based on previous research, the ε2ε1 genotype is considered likely pathogenic for FD.

    “Based on previous research data [32,33,34,35,36], we considered the ε2ε1 genotype as likely pathogenic for FD.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [32] Weisgraber, 1984, A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1, J. Clin. Investig. source

      The Introduction (page unavailable) links familial dysbetalipoproteinemia to apo E2, and the paper reports defective receptor binding by the E1 variant. The Discussion (page unavailable) mentions an E2/1 phenotype identified by other researchers, but this study characterizes an E3/1 subject and does not assess whether ε2ε1 is likely pathogenic for familial dysbetalipoproteinemia. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [33] Miller, 1995, Identification, molecular characterization, and cellular studies of an apolipoprotein E mutant (E1) in three unrelated families with hyperlipidemia, J. Clin. Endocrinol. Metab. source
    • cites [34] Richard, 1997, Compound heterozygote for both rare apolipoprotein E1 (Gly127-->Asp, Arg158-->Cys) and E3(Cys112-->Arg, Arg251-->Gly) alleles in a multigeneration pedigree with hyperlipoproteinaemia, Clin. Sci. source
    • cites [35] Wintjens, 2016, Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France, J. Lipid Res. source

      The APOE variants and structural analysis section (p. 487) discusses an E2E2 patient with mixed dyslipidemia, and Table 2 (p. 489) lists E2E2, but neither addresses ε2ε1. Searches for ε2ε1, E2E1, and the E1 isoform found no passage assessing whether ε2ε1 is likely pathogenic for FD. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [36] Limonova, A.S., Ershova, A.I., Meshkov, A.N., Kiseleva, A.V., Divashuk, M.G., Kutsenko, V.A., and Drapkina, O.M. (2021). Case Report: Hypertriglyceridemia and Premature Atherosclerosis in a Patient With Apolipoprotein E Gene ε2ε1 Genotype. Front. Cardiovasc. Med., 7. source
  • Findingown data

    Three carriers of the rare p.Gly145Asp variant had the ε2ε2 genotype, forming the rare ε2ε1 genotype.

    “In our study, three carriers of the rare p.Gly145Asp variant had the ε2ε2 (homozygous for the common p.Arg176Cys variant), forming the rare ε2ε1 genotype [32,33,34,35,36].”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [32] Weisgraber, 1984, A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1, J. Clin. Investig. source
    • cites [33] Miller, 1995, Identification, molecular characterization, and cellular studies of an apolipoprotein E mutant (E1) in three unrelated families with hyperlipidemia, J. Clin. Endocrinol. Metab. source
    • cites [34] Richard, 1997, Compound heterozygote for both rare apolipoprotein E1 (Gly127-->Asp, Arg158-->Cys) and E3(Cys112-->Arg, Arg251-->Gly) alleles in a multigeneration pedigree with hyperlipoproteinaemia, Clin. Sci. source
    • cites [35] Wintjens, 2016, Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France, J. Lipid Res. source

      The APOE variants and structural analysis section (p. 487) identifies a patient with p.(Gly145Asp) and the E2E2 genotype, supporting that association. It does not describe this combination as the rare ε2ε1 genotype. The citing sentence’s three carriers are explicitly from the citing authors’ own study, not a count attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [36] Limonova, A.S., Ershova, A.I., Meshkov, A.N., Kiseleva, A.V., Divashuk, M.G., Kutsenko, V.A., and Drapkina, O.M. (2021). Case Report: Hypertriglyceridemia and Premature Atherosclerosis in a Patient With Apolipoprotein E Gene ε2ε1 Genotype. Front. Cardiovasc. Med., 7. source
  • Classified as probably not a substantial claim. 21
  • May combine two claims. 23
  • The quote only partly states this claim. 2

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

    Premisecitation

    A set of 40 variants predicts TG levels in the population of the European part of Russia.

    “The weighted polygenic risk score (PRS) was calculated using the β-coefficients from the original article, which previously demonstrated significant associations with TG levels (40 variants predicting TG levels [67]) in the population of the European part of Russia.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [67] Khera, 2016, Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease, N. Engl. J. Med. source

      The Methods (Polygenic Risk Score; page unavailable) describe a score based on up to 50 variants associated with coronary artery disease, not 40 variants predicting triglyceride (TG) levels. The Methods (Study Populations; page unavailable) identify the study cohorts but no population in European Russia. The paper therefore describes a different score and outcome from those attributed to it. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent, genetically based lipid disorder.

    “Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder.”
    • Also stated in: § 1. Introduction · plain
      “familial dysbetalipoproteinemia (FD), which is also the most atherogenic and prevalent (from 0.2% to 2.7% [4,10,13,14]) hyperlipidemia”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [4] Paquette, M., Trinder, M., Guay, S.P., Brunham, L.R., and Baass, A. (2024). Prevalence of Dysbetalipoproteinemia in the UK Biobank According to Different Diagnostic Criteria. J. Clin. Endocrinol. Metab., dgae259. source
    • cites [10] Blokhina, A.V., Ershova, A.I., Kiseleva, A.V., Sotnikova, E.A., Zharikova, A.A., Zaicenoka, M., Vyatkin, Y.V., Ramensky, V.E., Kutsenko, V.A., and Shalnova, S.A. (2023). Applicability of Diagnostic Criteria and High Prevalence of Familial Dysbetalipoproteinemia in Russia: A Pilot Study. Int. J. Mol. Sci., 24. source
    • cites [13] Hopkins, 2009, Altered composition of triglyceride-rich lipoproteins and coronary artery disease in a large case–control study, Atherosclerosis source

      The Introduction and Results link type III hyperlipidemia (dysbetalipoproteinemia) to atherogenic remnants and substantially increased coronary artery disease risk; the Discussion also describes genetic variants associated with its manifestation. But the Discussion calls type III hyperlipidemia infrequent, contrary to the claim that it is prevalent. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [14] Pallazola, 2019, Modern prevalence of dysbetalipoproteinemia (Fredrickson-Levy-Lees type III hyperlipoproteinemia), Arch. Med. Sci. source

  • May combine two claims.

    Premisecitation

    The assessment of pathogenicity of rare APOE variants for FD has either not been performed or has not been fully presented in publications.

    “The assessment of the pathogenicity of these variants for FD has either not been performed or has not been fully presented in publications [30].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [30] Heidemann, 2022, Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene, Clin. Genet. source

      The ‘Analysis of Genetic Variants in the APOE Gene’ section says new variants may be classified using general genetic principles rather than studies establishing a causal relationship with FD. The ‘Approaches to Establish a Causal Relation’ section recommends publishing comprehensive assessments. These passages support the concern that FD-specific assessment can be incomplete, but they do not establish that assessments of the variants in question were not performed or were not fully presented in publications; page numbers were unavailable in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    p.Arg154Cys is located in the critical APOE domain and alters the amino acid residue in which another variant, p.Arg154Ser, was found to be likely pathogenic for FD.

    “This variant is located in the critical APOE domain [45,46] and alters the amino acid residue, in which another variant, p.Arg154Ser, was found to be likely pathogenic for FD [5,29,47].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [45] Feussner, 1996, Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia, Eur. J. Clin. Investig. source
    • cites [46] Walden, 1994, Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping, J. Clin. Endocrinol. Metab. source
    • cites [5] Bea, 2023, Contribution of APOE genetic variants to dyslipidemia, Arterioscler. Thromb. Vasc. Biol. source
    • cites [29] Abou, 2021, APOE gene variants in primary dyslipidemia, Atherosclerosis source
    • cites [47] Wardell, 1987, Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia, J. Clin. Investig. source

      The Results identify an APOE Arg136Ser variant, and the Discussion says it contributes significantly to hyperlipidemia in a patient with familial type III hyperlipoproteinemia. The paper does not use the p.Arg154Ser numbering or establish that it denotes the same residue, so our copy cannot fully verify that specific part of the claim. The critical-domain assertion is attached to other citations in the citing sentence. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The pathogenicity of APOE variants was analyzed based on ACMG/AMP2015 guidelines, combined with CADD and comprehensive literature data analysis.

    “Therefore, we analyzed the pathogenicity of APOE variants based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP2015) guidelines [43], combined with the modern predictive metric [44] and comprehensive literature data analysis.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [43] Richards, 2015, Standards and guidelines for 321 the interpretation of sequence variants: A joint consensus recommendation of the American 322 College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genet. Med. source
    • cites [44] Schubach, 2024, CADD v1.7: Using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions, Nucleic Acids Res. source
    • Rests on an assumption: The ACMG/AMP2015 criteria combined with CADD and literature are adequate to classify APOE variants for autosomal dominant FD despite the lack of FD-specific guidelines.

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

    Premisecitation

    p.Leu46Pro has been described in patients with FH and familial combined hyperlipidemia.

    “Nevertheless, p.Leu46Pro has been described in patients with FH and familial combined hyperlipidemia [6,40].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] Abou Khalil, Y., Marmontel, O., Ferrières, J., Paillard, F., Yelnik, C., Carreau, V., Charrière, S., Bruckert, E., Gallo, A., and Giral, P. (2022). APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int. J. Mol. Sci., 23. source
    • cites [40] Marmontel, 2023, Additive effect of APOE Rare Variants on the phenotype of familial hypercholesterolemia, Arterioscler. Thromb. Vasc. Biol. source

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

    Premisecitation

    The Apoε4-Freiberg genotype has been previously studied with Alzheimer's disease.

    “This genotype has been previously studied with Alzheimer’s disease [38,50].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [38] Rasmussen, 2020, APOE and dementia—Resequencing and genotyping in 105,597 individuals, Alzheimer’s Dement. source

      The Results (Individual rare APOE variants and risk of dementia; page unavailable) examine Leu46Pro in relation to Alzheimer’s disease, and the Discussion says it is linked to ε4 and had been studied previously. Our copy does not identify Leu46Pro as the Apoε4-Freiberg genotype, so it does not establish that the specifically named genotype was studied. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [50] Argyri, 2014, Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4, J. Biol. Chem. source

      The paper’s introduction (page unavailable) reports that apoE4 and its L28P variant have been studied in relation to late-onset Alzheimer’s disease. It identifies L28P as “apoE4 Pittsburgh”; our copy does not identify or discuss an Apoε4-Freiberg genotype, so it does not establish that the cited research concerned that specific genotype. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Previous studies have shown that a TG cutoff of ≥1.5 mmol/L is optimal for identifying carriers of the ε2ε2 genotype and FD.

    “Previous studies have shown that a TG cutoff of ≥1.5 mmol/L is optimal for identifying carriers of the ε2ε2 genotype and FD [10,51].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [10] Blokhina, A.V., Ershova, A.I., Kiseleva, A.V., Sotnikova, E.A., Zharikova, A.A., Zaicenoka, M., Vyatkin, Y.V., Ramensky, V.E., Kutsenko, V.A., and Shalnova, S.A. (2023). Applicability of Diagnostic Criteria and High Prevalence of Familial Dysbetalipoproteinemia in Russia: A Pilot Study. Int. J. Mol. Sci., 24. source

      Section 3.1 reports that a TG cutoff of ≥1.5 mmol/L had sufficiently high sensitivity and specificity for identifying ε2ε2 carriers, and says a previous study found it optimal for identifying people with FD. The paper does not establish that this cutoff is optimal for identifying ε2ε2 carriers; its FD recommendation also pairs the cutoff with the ε2ε2 haplotype. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [51] Varghese, 2021, Importance of the triglyceride level in identifying patients with a Type III Hyperlipoproteinemia phenotype using the ApoB algorithm, J. Clin. Lipidol. source

  • The quote only partly states this claim.

    Findingown data

    Carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of variants of uncertain significance (median 1.38 mmol/L, p = 0.036).

    “and variants of uncertain significance (median 1.38 mmol/L, p = 0.036).”
    • Also stated in: § 2.5. Clinical Features Depending on APOE Variants’ Pathogenicity · plain
      “and variants of uncertain significance (p = 0.036)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most common type among the identified rare APOE variants was missense (87.5%), while the rest were frameshifts.

    “The most common variant type was missense (87.5%), while the rest were frameshifts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The missense variant p.Arg154Cys is located in the critical APOE receptor binding site and was detected in ten subjects.

    “the missense variant p.Arg154Cys, located in the critical APOE receptor binding site, was detected in ten subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    p.Val254Glu and p.Arg269Gly were classified as benign.

    “p.Val254Glu and p.Arg269Gly were classified as benign.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    p.Leu46Pro was the most prevalent APOE variant (38.4% of all probands), predicted to be tolerated, and classified as likely benign.

    “p.Leu46Pro was the most prevalent APOE variant (38.4% of all probands), predicted to be tolerated, and classified as likely benign.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among carriers of rare APOE variants, ε3ε3 was the most prevalent genotype (56.9%), followed by ε3ε4 (23.2%), ε2ε3 (7.0%), ε2ε4 (4.7%), and ε4ε4 (4.7%); ε2ε2 prevalence was 3.5%.

    “Among carriers of rare APOE variants, ε3ε3 (56.9%) was the most prevalent genotype. This was followed by ε3ε4 (23.2%), ε2ε3 (7.0%), ε2ε4 (4.7%), and ε4ε4 (4.7%). The prevalence of the ε2ε2 genotype carriers was 3.5% (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Three carriers of p.Leu46Pro had the ε4ε4 genotype, forming the Apoε4-Freiberg genotype.

    “In addition, three carriers of p.Leu46Pro had the ε4ε4 (homozygous for the common p.Cys130Arg variant), forming the Apoε4-Freiberg [37] (Table A2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Orth, 1999, Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28→ Pro), on lipoproteins and the prevalence of coronary artery disease in whites, Arterioscler. Thromb. Vasc. Biol. source

  • May combine two claims.

    Findingown data

    In this study, p.Arg154Cys was detected only in carriers of the ε3ε3 genotype and was classified as likely pathogenic.

    “In our study, p.Arg154Cys was detected only in carriers of the ε3ε3 genotype and was classified as likely pathogenic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage of subjects taking lipid-lowering therapy (statins ± ezetimibe) was highest in carriers of pathogenic or likely pathogenic variants (56.3%), significantly different from carriers of variants of uncertain significance (7.7%, p = 0.024) but comparable to carriers of benign or likely benign variants (28.6%, p = 0.326).

    “the percentage of subjects taking lipid-lowering therapy (statins ± ezetimibe) was highest in carriers of pathogenic or likely pathogenic variants (56.3%), which was significantly different from carriers of variants of uncertain significance (7.7%, p = 0.024) but comparable to carriers of benign or likely benign variants (28.6%, p = 0.326).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    TC, LDL-C, HDL-C, and non-HDL-C levels in carriers of causal variants for FD were comparable to those in carriers of variants of uncertain significance and carriers of benign or likely benign variants.

    “Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) levels in carriers of causal variants for FD were comparable to those in carriers of variants of uncertain significance (p = 0.088, p = 0.598, p = 0.768, and p = 0.138, respectively)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All three carriers of the rare ε2ε1 genotype had a heterozygous p.Gly145Asp variant and a homozygous p.Arg176Cys variant.

    “It should be clarified that all these patients had a heterozygous p.Gly145Asp variant and a homozygous p.Arg176Cys variant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A carrier of p.Glu63ArgfsTer15 had only tendon xanthomas, and a carrier of p.Arg154Cys had eruptive xanthomas.

    “A carrier of p.Glu63ArgfsTer15 had only tendon xanthomas, and a carrier of p.Arg154Cys had the eruptive xanthomas.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In the ESSE-Ivanovo sample, high polygenic contribution corresponded to weighted PRS from −1.213 to −1.841, and low contribution to values from −2.037 to −2.820.

    “A high polygenic contribution was represented by a range of weighted PRS from (−1.213) to (−1.841) in the ESSE-Ivanovo sample. Values from (−2.037) to (−2.820) were set for a low contribution (Supplementary Figure S1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    There are insufficient data on the relationship between rare APOE variants and FD.

    “However, there are insufficient data on the relationship between rare APOE variants and FD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Frameshifts p.Glu63ArgfsTer15 and p.Gly145AlafsTer97 were predicted by CADD as deleterious and classified as pathogenic for autosomal dominant FD.

    “Thus, frameshifts p.Glu63ArgfsTer15 and p.Gly145AlafsTer97 were predicted by Combined Annotation Dependent Depletion (CADD) as deleterious and classified as pathogenic.”
    • Also stated in: § 3.1. Causality Between Rare APOE Variants and Autosomal Dominant FD · plain
      “when we applied the CADD metric in the current study, these frameshifts were reclassified as pathogenic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Among all identified APOE missense variants, p.Arg154Cys was predicted by CADD to be the most deleterious and was classified as likely pathogenic for FD.

    “Among all identified APOE missense variants, p.Arg154Cys was predicted by CADD to be the most deleterious and classified as likely pathogenic for FD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The total allele frequency of p.Val254Glu and p.Arg269Gly was greater than 0.01% in gnomAD, and the FD lipoprotein phenotype was not confirmed in proband and relatives in a previous study.

    “The total allele frequency of these variants was greater than 0.01% in gnomAD, and the FD lipoprotein phenotype was not confirmed in proband and relatives in a previous study [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Zhao, 1994, Lipoprotein profiles in a family with two mutants of apolipoprotein E: Possible association with hypertriglyceridaemia but not with dysbetalipoproteinaemia, Clin. Sci. source

  • May combine two claims.

    Premisecitation

    Walden et al. confirmed the FD phenotype by electrophoresis in heterozygous p.Arg154Ser and p.Arg176Cys carriers and showed in vitro that abnormal cell binding contributes to dysbetalipoproteinemia.

    “Walden et al. [46] confirmed the FD phenotype by electrophoresis in heterozygous p.Arg154Ser and p.Arg176Cys carriers and showed in vitro that abnormal cell binding contributes to dysbetalipoproteinemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Walden, 1994, Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping, J. Clin. Endocrinol. Metab. source

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

    Premisenone given

    There are no specific related guidelines for APOE variant classification or FD-specific classification.

    “To this point, we do not have specific related guidelines for APOE variant classification or FD-specific classification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Among patients with causal APOE variants in the Marmontel 2023 study, LDL-C levels were 46.0% higher in LDLR + APOE carriers than in LDLR carriers (mean 10.83 ± 3.45 versus 7.43 ± 1.59 mmol/L, p = 0.027), and premature atherosclerotic cardiovascular disease was more frequent (70.0% versus 30.0%, p = 0.026).

    “Among patients with causal APOE variants, LDL-C levels were 46.0% higher in LDLR + APOE carriers than in LDLR carriers (mean 10.83 ± 3.45 versus 7.43 ± 1.59 mmol/L, p = 0.027), and premature atherosclerotic cardiovascular disease was more frequent (70.0% versus 30.0%, p = 0.026).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Marmontel, 2023, Additive effect of APOE Rare Variants on the phenotype of familial hypercholesterolemia, Arterioscler. Thromb. Vasc. Biol. source

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

    Study design and conductnone given

    Written informed consent was obtained from each patient as part of their participation in these scientific projects.

    “Written informed consent was obtained from each patient as part of their participation in these scientific projects.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    FD has a complex multifactorial phenotype and a delayed onset.

    “It should be emphasized that FD has a complex multifactorial phenotype and a delayed onset.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was conducted in accordance with the Declaration of Helsinki and the National Standard of the Russian Federation "Good Clinical Practice (GCP)" GOST R52379-2005.

    “The study was conducted in accordance with the Declaration of Helsinki and the National Standard of the Russian Federation “Good Clinical Practice (GCP)” GOST R52379-2005 and was approved by the Independent Ethics Committee of the National Medical Research Center for Therapy and Preventive Medicine (protocol number 07-05/20 dated 26 November 2020).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    P-values from pairwise comparisons were adjusted using the Holm-Bonferroni method.

    “The p-values from pairwise comparisons were adjusted using the Holm–Bonferroni method.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Pretreatment non-HDL-C levels were also high in causal variant carriers, underscoring their high cardiovascular risk.

    “Moreover, pretreatment non-HDL-C levels were also high in causal variant carriers, underscoring their high cardiovascular risk.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    In all cases in the FH sample (n = 557), FH was diagnosed using the Dutch Lipid Clinic Network criteria.

    “In all cases (n = 557), FH was diagnosed using the Dutch Lipid Clinic Network criteria [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Civeira, 2004, Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia, Atherosclerosis source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The diagnosis of FD is complicated.

    “Therefore, the diagnosis of FD is complicated.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was approved by the Independent Ethics Committee of the National Medical Research Center for Therapy and Preventive Medicine (protocol number 07-05/20 dated 26 November 2020).

    “The study was conducted in accordance with the Declaration of Helsinki and the National Standard of the Russian Federation “Good Clinical Practice (GCP)” GOST R52379-2005 and was approved by the Independent Ethics Committee of the National Medical Research Center for Therapy and Preventive Medicine (protocol number 07-05/20 dated 26 November 2020).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The database containing clinical, biochemical, and genetic data was de-identified and encrypted to ensure confidentiality.

    “The database containing clinical, biochemical, and genetic data was de-identified and encrypted to ensure confidentiality.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The Clopper-Pearson exact method was used for the estimation of the 95% confidence interval.

    “The Clopper–Pearson exact method was used for the estimation of the 95% confidence interval.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The study did not use lipoprotein ultracentrifugation or electrophoresis to confirm the FD phenotype as part of the assessment of the pathogenicity of APOE variants.

    “First, we did not use lipoprotein ultracentrifugation or electrophoresis to confirm the FD phenotype as part of the assessment of the pathogenicity of APOE variants.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Patients with the unclear genotype were excluded from the clinical data comparison.

    “For the same reason, patients with the unclear genotype were excluded from the clinical data comparison.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The autosomal dominant FD phenotype was based on the cut-offs of lipoprotein ultracentrifugation, electrophoresis, or well-established biochemical algorithms from literature data when available for the APOE variant analyzed.

    “Instead, the autosomal dominant FD phenotype was based on the cut-offs of lipoprotein ultracentrifugation, electrophoresis, or well-established biochemical algorithms from literature data when available for the APOE variant analyzed.”
    Quote in the paperSubstantial claim
41 of 41

  • The paper relies on this without support.

    The ESSE-Ivanovo population sample is representative of similar regions of Russia for estimating the prevalence of causal APOE variants.

    “The Ivanovo region belongs to the European region of Russia and is representative of similar regions.”

  • The paper relies on this without support.

    Rare APOE variants associated with autosomal dominant FD are inherited in an autosomal dominant trait.

    “These variants are inherited in an autosomal dominant trait.”

  • The paper relies on this without support.

    The ACMG/AMP2015 criteria combined with CADD and literature are adequate to classify APOE variants for autosomal dominant FD despite the lack of FD-specific guidelines.

    “To this point, we do not have specific related guidelines for APOE variant classification or FD-specific classification. Therefore, we analyzed the pathogenicity of APOE variants based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP2015) guidelines [43], combined with the modern predictive metric [44] and comprehensive literature data”

  • The paper relies on this without support.

    The ESSE-Ivanovo population-based sample is representative of the general Russian population for estimating the prevalence of APOE variants.

    “The prevalence of identified rare APOE variants was investigated in the ESSE-Ivanovo population-based sample (n = 1858).”
4 of 4

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Prevalence does not match "one in 619"

    Major

    One in 619 is approximately 0.162%, not the reported 0.27%. The two figures give different estimates of the expected prevalence.

    Reported 0.27 · recomputed 0.161551

  • Incompatible reference amino acids at APOE position 200

    Minor

    The listed variant names identify the reference amino acid at position 200 as both Glu and Gly. Variants named against the same reference protein cannot have both reference residues at that position.

  • Reported 77.8% does not match seven of eleven carriers

    Minor

    The paper identifies seven APOE/LDLR double heterozygotes among eleven carriers of multiple rare variants. That is approximately 63.6% of all such cases, not 77.8%.

  • Multiple-variant carrier categories total 12, not 11

    Minor

    The listed categories contain 2 + 1 + 7 + 1 + 1 = 12 carriers, although the paper says there were eleven. The category counts therefore cannot all be correct as stated.

4 of 4

Cites

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Related

Authors
Blokhina, A. V., Ershova, A. I., Kiseleva, A. V., Sotnikova, E. A., Zharikova, A. A., Zaicenoka, M., Vyatkin, Y. V., Ramensky, V. E., Kutsenko, V. A., Garbuzova, E. V., Divashuk, M. G., Litinskaya, O. A., Pokrovskaya, M. S., Shalnova, S. A., Meshkov, A. N., & Drapkina, O. M.
Affiliations
  • National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia
  • Ministry of Health of the Russian Federation (RU)
  • Lomonosov Moscow State University (RU)
  • Novosibirsk State University (RU)
  • All-Russian Research Institute of Agricultural Biotechnology Russian Academy of Agricultural Sciences (RU)
  • Pirogov Russian National Research Medical University (RU)
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-11-25
Volume
25
Issue
23
Pages
12651
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms252312651
PMC
PMC11641494
OpenAlex
W4404696066
Semantic Scholar
651e8022f5a9852c9e00019ecb6b0352297bb680
Cited by
8
References
74
Citations by year
2026: 4 · 2025: 3 · 2024: 1
FWCI
2.41
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
familial dysbetalipoproteinemia, rare variants, variant pathogenicity, variant prevalence, triglyceride levels, lipid metabolism disorders
MeSH terms
Adolescent, Adult, Aged, Apolipoproteins E, Child, Female, Humans, Hyperlipoproteinemia Type III, Male, Middle Aged, Mutation, Triglycerides, Genetic Variation, Prevalence, Genetic Predisposition to Disease, Young Adult

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.

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Statistics and arithmetic are recomputed, not judged.

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