Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features

The Cys112Arg and Arg158Cys SNPs appear to be in almost perfect linkage disequilibrium.

“The Cys112Arg and Arg158Cys SNPs appear to be in almost perfect linkage disequilibrium (Fig.3), and the combination of arginine at position 112 and cysteine at position 158, which may define the apoE1, also called apoE3r isoform, is extremely rare15).”

• cites [15] 15) Belloy ME, Napolioni V and Greicius MD: A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward. Neuron, 2019; 101: 820-838 sourceDisputed

  In “A Brief History of APOE in Human Genetics,” the paper says rs429358 and rs7412 are in almost perfect linkage equilibrium, not linkage disequilibrium. It does support the citing sentence’s separate statement that the arginine-112/cysteine-158 combination is extremely rare. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In one family, only two of the five carriers of the APOE2 allele showed type III HLP.

“In one family, only two of the five carriers of the APOE2 allele showed type III HLP.”

• cites [39] 39) Leren TP, Strom TB and Berge KE: Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene. Mol Genet Metab Rep, 2016; 9: 67-70 sourceDisputed

  In Results and discussion (Family T0657), the five people are carriers of the p.Thr5* mutation, not five carriers of an APOE2 allele. Only two had an APOE2 allele, and both showed a Type III hyperlipoproteinemia phenotype; the other three were APOE4 homozygotes. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

The LDL receptor-binding affinity of apoE is more than 20-fold greater than that of apoB100.

“The LDL receptor-binding affinity of apoE was reported to be more than 20-fold greater than that of apoB100 5).”

• cites [5] 5) Mahley RW: Apolipoprotein E: Remarkable Protein Sheds Light on Cardiovascular and Neurological Diseases. Clin Chem, 2017; 63: 14-20 sourceSupported

ApoE is a ligand that can bind to many LDL receptor-related receptors and cell surface heparan sulfate proteoglycans (HSPGs), in addition to the LDL receptor.

“While apoB100 can bind only to the LDL receptor, apoE is a ligand that can bind to many LDL receptor-related receptors and cell surface heparan sulfate proteoglycans (HSPGs), in addition to the LDL receptor4).”

• cites [4] 4) Mahley RW, Weisgraber KH and Huang Y: Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res, 2009; 50 Suppl: S183-188 sourceSupported

The combination of arginine at position 112 and cysteine at position 158, which may define the apoE1, also called apoE3r isoform, is extremely rare.

“The Cys112Arg and Arg158Cys SNPs appear to be in almost perfect linkage disequilibrium (Fig.3), and the combination of arginine at position 112 and cysteine at position 158, which may define the apoE1, also called apoE3r isoform, is extremely rare15).”

• cites [15] 15) Belloy ME, Napolioni V and Greicius MD: A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward. Neuron, 2019; 101: 820-838 sourceSupported

ApoE is a multifunctional protein synthesized and secreted by numerous tissues throughout the body.

“ApoE is a multifunctional protein synthesized and secreted by numerous tissues throughout the body, but hepatocytes contribute to approximately 75% of the apoE peripheral blood pool4).”

• cites [4] 4) Mahley RW, Weisgraber KH and Huang Y: Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res, 2009; 50 Suppl: S183-188 sourceSupported

In vessels, apoE on VLDL and chylomicron particles competitively inhibits triglyceride degradation processing by lipoprotein lipase (LPL) promoted by apoC-II and apoA-V.

“Meanwhile, in vessels, apoE on VLDL and chylomicron particles competitively inhibits triglyceride degradation processing by lipoprotein lipase (LPL) promoted by apoC-II and apoA-V20).”

• cites [20] 20) Rensen PC and van Berkel TJ: Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem, 1996; 271: 14791-14799 sourcePartly supported

  The ‘Effect of ApoE on LPL Activity in Vitro’ section (page unavailable) reports that apoE inhibited LPL-mediated triglyceride hydrolysis in chylomicron-like emulsions even when apoC-II was present. The Discussion (page unavailable) describes supporting experiments in rats, but the paper does not establish competitive inhibition by apoE on native VLDL and chylomicrons, or address apoA-V’s role in promoting lipolysis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

ApoE binds a wide range of cellular receptors, including LDLR, LRP1, LRP2, LRP8, and VLDLR, which mediate the cellular uptake of apoE-containing lipoprotein particles.

“ApoE binds a wide range of cellular receptors, including the LDL receptor (LDLR), the LDL receptor-related proteins (LRP) LRP1, LRP2, and LRP8, and the very low-density-lipoprotein receptor (VLDLR), which mediate the cellular uptake of the apoE-containing lipoprotein particles6).”

• cites [6] 6) Martinez-Martinez AB, Torres-Perez E, Devanney N, Del Moral R, Johnson LA and Arbones-Mainar JM: Beyond the CNS: The many peripheral roles of APOE. Neurobiol Dis, 2020; 138: 104809 sourcePartly supported

  The ‘Lipid transport and metabolism’ section (page unavailable) says APOE promotes lipoprotein-particle internalization through LDL-receptor-family receptors, and the ‘Liver’ section describes APOE binding to LDLR. Our copy does not identify LRP1, LRP2, LRP8 and VLDLR as the specific receptors mediating that uptake, so it supports the mechanism but not the full receptor list. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

APOE Groningen (Glu96fsTer50) was identified as a mutation in which a G was inserted in codon 95 or 96 of the APOE3 allele.

“APOE Groningen (Glu96fsTer50) was identified as a mutation in which a G was inserted in codon 95 or 96 (95AAG96GAG>95AAG96GGA-G) of the APOE3 allele41).”

• cites [41] 41) Dijck-Brouwer DA, van Doormaal JJ, Kema IP, Brugman AM, Kingma AW and Muskiet FA: Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem, 2005; 42: 264-268 sourceSupported

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

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

• cites [27] 27) Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H and Marz W: Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat, 1998; 11: 417-423 sourceNot checked — no full text of the source
• cites [29] 29) Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchke P, Jais JP, French Research Network on ADH, Abifadel M, Kathiresan S, Leren TP, Rabes JP, Boileau C and Varret M: Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat, 2013; 34: 83-87 sourceCould not verify

  The Abstract describes an APOE mutation in a family with autosomal dominant hypercholesterolemia, but does not give a count of APOE-deficiency cases or classify 11 cases by zygosity. Searches for APOE deficiency, homozygotes, and compound heterozygotes found no passage supporting the four-versus-seven breakdown. Page numbers are unavailable in our copy. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [30] 30) Mabuchi H, Itoh H, Takeda M, Kajinami K, Wakasugi T, Koizumi J, Takeda R and Asagami C: A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism, 1989; 38: 115-119 sourceNot checked — no full text of the source
• cites [31] 31) Kurosaka D, Teramoto T, Matsushima T, Yokoyama T, Yamada A, Aikawa T, Miyamoto Y and Kurokawa K: Apolipoprotein E deficiency with a depressed mRNA of normal size. Atherosclerosis, 1991; 88: 15-20 sourceNot checked — no full text of the source
• cites [32] 32) Schaefer EJ, Gregg RE, Ghiselli G, Forte TM, Ordovas JM, Zech LA and Brewer HB, Jr.: Familial apolipoprotein E deficiency. J Clin Invest, 1986; 78: 1206-1219 sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [33] 33) Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G and Zannis VI: The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene. J Biol Chem, 1987; 262: 2310-2315 sourceNot checked — no full text of the source
• cites [34] 34) Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Duncan JL, Miller BL, Kane JP, Kwok PY and Malloy MJ: Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol, 2014; 71: 1228-1236 sourcePartly supported

  The Results (Exome Sequencing Results; page unavailable) identify one patient with APOE deficiency caused by a homozygous mutation. The paper does not report a tally of 11 cases or establish the claimed split of four homozygotes and seven compound heterozygotes or heterozygotes. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [35] 35) Feussner G, Dobmeyer J, Grone HJ, Lohmer S and Wohlfeil S: A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet, 1996; 58: 281-291 sourceNot checked — no full text of the source
• cites [36] 36) Lohse P, Brewer HB, 3rd, Meng MS, Skarlatos SI, LaRosa JC and Brewer HB, Jr.: Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res, 1992; 33: 1583-1590 sourceNot checked — no full text of the source
• cites [37] 37) Feussner G, Funke H, Weng W, Assmann G, Lackner KJ and Ziegler R: Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/’null’ genotype. Eur J Clin Invest, 1992; 22: 599-608 sourceNot checked — no full text of the source

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

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

• cites [32] 32) Schaefer EJ, Gregg RE, Ghiselli G, Forte TM, Ordovas JM, Zech LA and Brewer HB, Jr.: Familial apolipoprotein E deficiency. J Clin Invest, 1986; 78: 1206-1219 sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [33] 33) Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G and Zannis VI: The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene. J Biol Chem, 1987; 262: 2310-2315 sourceNot checked — no full text of the source
• cites [34] 34) Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Duncan JL, Miller BL, Kane JP, Kwok PY and Malloy MJ: Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol, 2014; 71: 1228-1236 sourcePartly supported

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

  Experimental — accuracy not yet measured

ApoE4, which is abundant on VLDL and chylomicrons, tends to inhibit triglyceride degradation by LPL more readily than apoE2 or apoE3.

“Therefore, apoE4, which is abundant on VLDL and chylomicrons, tends to inhibit triglyceride degradation by LPL more readily than apoE2 or apoE3 21).”

• cites [21] 21) Huang Y, Liu XQ, Rall SC, Jr., Taylor JM, von Eckardstein A, Assmann G and Mahley RW: Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem, 1998; 273: 26388-26393 sourcePartly supported

  The Results report that apoE3-enriched VLDL inhibits LPL-mediated lipolysis and note a similar effect for apoE2-enriched VLDL. They do not establish that apoE4 inhibits lipolysis more readily than either isoform, or that apoE4 is abundant on both VLDL and chylomicrons. The Results’ comparison of all three isoforms concerns VLDL production, not LPL-mediated lipolysis. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Heterozygous APOE (c.44-1G>C) was recently discovered in the screening of hypercholesterolemic patients in a French cohort.

“Heterozygous APOE (c.44-1G>C) was recently discovered in the screening of hypercholesterolemic patients in a French cohort40).”

• cites [40] 40) Abou Khalil Y, Marmontel O, Ferrieres J, Paillard F, Yelnik C, Carreau V, Charriere S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrie A, Rabes JP and Varret M: APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci, 2022; 23: sourceSupported

Heterozygous APOE (p.Thr5*) was found in two families in a screening of a hypercholesterolemic, hypertriglyceridemic population in Norway.

“Heterozygous APOE (p.Thr5*) was found in two families in a screening of a hypercholesterolemic, hypertriglyceridemic population in Norway39).”

• cites [39] 39) Leren TP, Strom TB and Berge KE: Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene. Mol Genet Metab Rep, 2016; 9: 67-70 sourcePartly supported

  The Results and discussion (Identification of mutation p.Thr5*) report that screening 844 hypercholesterolemic subjects found two p.Thr5* heterozygotes from two families; both also had hypertriglyceridemia. The Materials and methods (Subjects) describe the screened group as referred for hypercholesterolemia testing, not as a population selected for both conditions. The paper places the families in southern Norway. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

APOE Groningen (Glu96fsTer50) was detected in the analysis of a type III HLP case.

“APOE Groningen (Glu96fsTer50) was detected in the analysis of a type III HLP case.”

• cites [41] 41) Dijck-Brouwer DA, van Doormaal JJ, Kema IP, Brugman AM, Kingma AW and Muskiet FA: Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem, 2005; 42: 264-268 sourceSupported

APOE (p.Thr5*) does not express apoE because the fifth position of the signal peptide is a stop codon.

“APOE (p.Thr5*) does not express apoE because the fifth position of the signal peptide is a stop codon.”

• cites [39] 39) Leren TP, Strom TB and Berge KE: Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene. Mol Genet Metab Rep, 2016; 9: 67-70 sourcePartly supported

  The Results and discussion section (‘Identification of mutation p.Thr5*’; page unavailable) says codon 5 is in the signal peptide and that the mutation is expected to prevent APOE synthesis. The claim states this predicted effect as a certainty. The paper also reports measurable serum apoE in heterozygous carriers, so ‘does not express apoE’ should not be read as saying carriers have no apoE at all. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

APOE (Arg145Cys) homozygote was also found in a cohort of autosomal dominant hypercholesterolemia (ADH) patients in France.

“APOE (Arg145Cys) homozygote was also found in a cohort of autosomal dominant hypercholesterolemia (ADH) patients in France57).”

• cites [57] 57) Wintjens R, Bozon D, Belabbas K, F MB, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M and Dufernez F: Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J Lipid Res, 2016; 57: 482-491 sourcePartly supported

  The Patients section describes a French ADH cohort, and Table 2 and the discussion (p. 489) report a patient homozygous for an APOE variant. The paper names that variant p.(Arg163Cys), not Arg145Cys; our copy does not establish whether those labels are equivalent. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Some APOE3 Kochi (Arg145His) carriers have also been reported to have normal lipid levels or hypertriglyceridemia.

“Some APOE3 Kochi (Arg145His) carriers have also been reported to have normal lipid levels or hypertriglyceridemia.”

• cites [61] 61) Suehiro T, Yoshida K, Yamano T and Ohno F: Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi). Jpn J Med, 1990; 29: 587-594 sourceSupported
• cites [62] 62) Hidaka H, Tozuka M, Hidaka E, Yamauchi K, Ota H, Honda T and Katsuyama T: Characterization of an apolipoprotein E3 variant (Arg 145-->His) associated with mild hypertriglyceridemia. Ann Clin Lab Sci, 2001; 31: 163-170Not checked — no full text of the source

Some rare APOE variants that cause familial type III HLP were found to exhibit a dominant mode of inheritance.

“Some of these rare APOE variants that cause familial type III HLP were found to exhibit a dominant mode of inheritance45, 46).”

• cites [45] 45) Smit M, de Knijff P, van der Kooij-Meijs E, Groenendijk C, van den Maagdenberg AM, Gevers Leuven JA, Stalenhoef AF, Stuyt PM, Frants RR and Havekes LM: Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146----gln) variant results in a dominant mode of inheritance. J Lipid Res, 1990; 31: 45-53 sourceSupported
• cites [46] 46) Khalil YA, Rabes JP, Boileau C and Varret M: APOE gene variants in primary dyslipidemia. Atherosclerosis, 2021; 328: 11-22 sourceNot checked — no full text of the source

Five variants in helix 4 that were not in the LDL receptor binding site-APOE Kanto (Asp151dupAsp), APOE Las Vegas (Ala152Asp), APOE Chengdu (Leu155Pro), APOE1 (156_173del), and APOE Osaka/Kurashiki (Arg158Pro)-were reported to cause LPG.

“Five variants in helix 4 that were not in the LDL receptor binding site were identified (Fig.5), but were reported to cause LPG, namely, APOE Kanto (Asp151dupAsp)70, 80), APOE Las Vegas (Ala152Asp)81), APOE Chengdu (Leu155Pro)82), APOE1 (156_173del)83), and APOE Osaka/Kurashiki (Arg158Pro)84, 85).”

• cites [70] 70) Matsunaga A and Saito T: Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia. Clin Exp Nephrol, 2014; 18: 220-224 sourceNot checked — no full text of the source
• cites [80] 80) Yokochi A, Matsunaga A, Kanemoto K, Tominaga N, Uda S and Saito T: Lipoprotein glomerulopathy with a novel apolipoprotein E variant, APOE Kanto (Asp 151dup). CEN Case Rep, 2024; sourceSupported
• cites [81] 81) Bomback AS, Song H, D’Agati VD, Cohen SD, Neal A, Appel GB and Rovin BH: A new apolipoprotein E mutation, apoE Las Vegas, in a European-American with lipoprotein glomerulopathy. Nephrol Dial Transplant, 2010; 25: 3442-3446 sourceNot checked — no full text of the source
• cites [82] 82) Wu H, Yang Y and Hu Z: The Novel Apolipoprotein E Mutation ApoE Chengdu (c.518T>C, p.L173P) in a Chinese Patient with Lipoprotein Glomerulopathy. J Atheroscler Thromb, 2018; 25: 733-740 sourcePartly supported

  The DNA Sequence Analysis section identifies apoE Chengdu in a patient with LPG, and the Discussion places it near, rather than within, the LDL receptor-binding region. However, our copy calls the variant p.L173P, not Leu155Pro, and does not identify its location as helix 4. It does not establish the claim's exact residue numbering or helix designation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

APOE (Arg145Cys) heterozygotes in Africa-derived populations were associated with higher triglyceride levels.

“while APOE (Arg145Cys) heterozygotes in Africa-derived populations were associated with higher triglyceride levels64).”

• cites [64] 64) Abou Ziki MD, Strulovici-Barel Y, Hackett NR, Rodriguez-Flores JL, Mezey JG, Salit J, Radisch S, Hollmann C, Chouchane L, Malek J, Zirie MA, Jayyuosi A, Gotto AM, Jr. and Crystal RG: Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations. Am J Cardiol, 2014; 113: 302-308 sourceSupported

Rare APOE variants associated with dominant type III HLPs include APOE2 Heidelberg (Arg136Cys), APOE2 Christchurch (Arg136Ser), APOE2 (Arg142Cys), APOE2 (Arg142Leu), APOE2 (Lys146Gln), and APOE1 Harrisburg (Lys146Glu).

“Rare APOE variants associated with dominant type III HLPs include single-nucleotide substitutions at APOE2 Heidelberg (Arg136Cys)47), APOE2 Christchurch (Arg136Ser)26, 48), APOE2 (Arg142Cys)49, 50), APOE2 (Arg142Leu)51), APOE2 (Lys146Gln)45), and APOE1 Harrisburg (Lys146Glu)52, 53) (Table 2, Fig.5).”

• cites [47] 47) Feussner G, Albanese M, Mann WA, Valencia A and Schuster H: Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia. Eur J Clin Invest, 1996; 26: 13-23 sourceNot checked — no full text of the source
• cites [26] 26) Civeira F, Pocovi M, Cenarro A, Casao E, Vilella E, Joven J, Gonzalez J, Garcia-Otin AL and Ordovas JM: Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis, 1996; 127: 273-282 sourceNot checked — no full text of the source
• cites [48] 48) Wardell MR, Brennan SO, Janus ED, Fraser R and Carrell RW: Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J Clin Invest, 1987; 80: 483-490 sourcePartly supported

  The Abstract and Discussion (page unavailable) identify APOE2-Christchurch as the Arg136Ser variant in a patient with type III hyperlipoproteinemia. The paper does not establish that Christchurch causes dominant type III disease: the patient also carried another APOE2 variant, and the Results report that his daughter inherited Christchurch but had no symptoms of type III hyperlipoproteinemia. This citation is attached to Christchurch, not to the other variants in the list. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [49] 49) Horie Y, Fazio S, Westerlund JR, Weisgraber KH and Rall SC, Jr.: The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J Biol Chem, 1992; 267: 1962-1968 sourceNot checked — no full text of the source
• cites [50] 50) Havel RJ, Kotite L, Kane JP, Tun P and Bersot T: Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest, 1983; 72: 379-387 sourcePartly supported

  The clinical-features and discussion passages describe familial dysbetalipoproteinemia across three generations and suggest that an abnormal apo E may be involved. They do not identify an APOE2 Lys146Gln substitution, which is the specific variant this citation is attached to; searches for Lys146Gln and position 146 found no such identification in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Glomerular lesions only occurred in APOE Toyonaka (Ser197Cys, Arg158Cys) when the other allele was ApoE2.

“It was reported that glomerular lesions only occurred in APOE Toyonaka (Ser197Cys, Arg158Cys) when the other allele was ApoE2.”

• cites [99] 99) Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E and Saito T: A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep, 2019; 8: 106-111 sourcePartly supported

  The Discussion (page unavailable) reports three cases with glomerular lesions and the combination of APOE Toyonaka and homozygous APOE2/2. The mutation analysis (page unavailable) identifies Ser197Cys and Arg158Cys in the reported patient. These observations do not establish that lesions occur only when the other allele is APOE2. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [101] 101) Fukunaga M, Nagahama K, Aoki M, Shimizu A, Hara S, Matsunaga A, Muso E and Saito T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2. Case Rep Nephrol Dial, 2018; 8: 45-55 sourcePartly supported

  The Case Presentation (Analysis of ApoE Mutation) identifies a patient with heterozygous ApoE Toyonaka (Ser197Cys) and homozygous ApoE2/2 (Arg158Cys), and the Discussion reports glomerular lesions in that patient. This single case does not establish that lesions occur only when the other allele is ApoE2; the authors say the combination may cause the disease. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [102] 102) Hirashima H, Komiya T, Toriu N, Hara S, Matsunaga A, Saito T and Muso E: A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka. Clin Nephrol Case Stud, 2018; 6: 45-51 sourcePartly supported

  The Case presentation (page unavailable) identifies both ApoE2/2 and heterozygous ApoE Toyonaka (Ser197Cys) in a patient with glomerular lesions, and notes a previous case with the same combination. The Discussion (page unavailable) says the combination may contribute to MN-like lesions and calls for further cases; it does not establish that lesions occur only when the other allele is ApoE2. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [103] 103) Koshino A, Takaeda C, Matsuno T, Kitajima S, Iwata Y, Sakai N, Nagahama K, Niida Y, Saito T, Yokoyama H and Wada T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits. Case Rep Nephrol Dial, 2022; 12: 96-104 sourcePartly supported

  The Case Presentation reports glomerular apoE accumulation in a patient with heterozygous apoE Toyonaka (Ser197Cys) and apoE2/E2, while the Introduction describes similar lesions in earlier cases with that genotype. The paper does not establish that lesions occur only when the other allele is apoE2; its Discussion notes that only four cases had been reported. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Whole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH.

“Subsequently, whole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH29, 57, 118).”

• cites [29] 29) Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchke P, Jais JP, French Research Network on ADH, Abifadel M, Kathiresan S, Leren TP, Rabes JP, Boileau C and Varret M: Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat, 2013; 34: 83-87 sourcePartly supported

  The Abstract reports whole-exome sequencing and functional analyses in a large French ADH family and concludes that APOE p.Leu167del is associated with ADH. It does not report the claimed analysis of large Italian families; its additional screened groups were French and Norwegian. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [57] 57) Wintjens R, Bozon D, Belabbas K, F MB, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M and Dufernez F: Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J Lipid Res, 2016; 57: 482-491 sourcePartly supported

  The APOE variants and structural analysis section (p. 487) identifies p.Leu167del in a French patient with probable ADH, and the discussion (p. 489) says it is thought to contribute to the ADH phenotype. But this paper studied a French cohort using targeted Sanger sequencing and in silico analysis, not whole-exome sequencing and functional analysis of large French and Italian families; it says the variant’s binding defect was not demonstrated. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites [118] 118) Okorodudu DE, Crowley MJ, Sebastian S, Rowell JV and Guyton JR: Inherited lipemic splenomegaly and the spectrum of apolipoprotein E p.Leu167del mutation phenotypic variation. J Clin Lipidol, 2013; 7: 566-572 sourceNot checked — no full text of the source

The histological features of renal biopsies of ApoE2 homozygote glomerulopathy include a prominent foamy macrophage infiltrate that can be explained by the mechanism of atherosclerosis glomerulosclerosis.

“The histological features of renal biopsies of ApoE2 homozygote glomerulopathy include a prominent foamy macrophage infiltrate that can be explained by the mechanism of atherosclerosis glomerulosclerosis99).”

• cites [99] 99) Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E and Saito T: A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep, 2019; 8: 106-111 sourcePartly supported

  The Discussion (page unavailable) says apoE2 homozygote glomerulopathy is generally characterized by foam-cell infiltration in the glomerulus. It does not identify those cells as macrophages or explain the infiltration through an atherosclerosis–glomerulosclerosis mechanism; the Pathological findings section says this case’s lesions differed from foam cells. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

ApoE2 (Arg158Cys) homozygote glomerulopathy has been reported in 10 cases worldwide.

“ApoE2 (Arg158Cys) homozygote glomerulopathy has been reported in 10 cases worldwide97, 98).”

• cites [97] 97) Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S and Muso E: Apolipoprotein E-related glomerular disorders. Kidney Int, 2020; 97: 279-288 sourceNot checked — no full text of the source
• cites [98] 98) Kawanishi K, Sawada A, Ochi A, Moriyama T, Mitobe M, Mochizuki T, Honda K, Oda H, Nishikawa T and Nitta K: Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature. Case Rep Nephrol Urol, 2013; 3: 128-135 sourceSupported

A new glomerular disease was identified in four non-consanguineous carriers possessing the novel variant APOE Toyonaka (Ser197Cys).

“A new glomerular disease was identified in four non-consanguineous carriers possessing the novel variant APOE Toyonaka (Ser197Cys) (Fig.5, Table 3)99, 101-103).”

• cites [99] 99) Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E and Saito T: A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep, 2019; 8: 106-111 sourcePartly supported

  The Introduction describes ApoE Toyonaka (Ser197Cys) as a novel variant associated with distinctive glomerular lesions, and the Discussion says this patient had no consanguinity. But the Discussion calls this the third reported case and does not establish four non-consanguineous carriers; the count of four is not supported by this source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [101] 101) Fukunaga M, Nagahama K, Aoki M, Shimizu A, Hara S, Matsunaga A, Muso E and Saito T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2. Case Rep Nephrol Dial, 2018; 8: 45-55 sourcePartly supported

  The Case Presentation reports one patient with APOE Toyonaka (Ser197Cys), and the Discussion suggests her findings represent a new form of ApoE-related glomerular disease. This paper supports one case among those cited, but it does not establish four carriers or that they were non-consanguineous. No page numbers are provided in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [102] 102) Hirashima H, Komiya T, Toriu N, Hara S, Matsunaga A, Saito T and Muso E: A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka. Clin Nephrol Case Stud, 2018; 6: 45-51 sourcePartly supported

  The Introduction describes a possible new form of APOE-related glomerular disease, and the Case presentation identifies APOE Toyonaka (Ser197Cys) in the patient. This paper reports one patient, not four non-consanguineous carriers, and does not establish that the proposed disease was identified in such a group. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [103] 103) Koshino A, Takaeda C, Matsuno T, Kitajima S, Iwata Y, Sakai N, Nagahama K, Niida Y, Saito T, Yokoyama H and Wada T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits. Case Rep Nephrol Dial, 2022; 12: 96-104 sourcePartly supported

  The Discussion/Conclusion identifies this as the fourth reported case of MN-like apoE deposition disease with apoE Toyonaka, and the Case Report/Case Presentation confirms the Ser197Cys variant in this patient. Our copy does not establish that the four carriers were non-consanguineous; it reports only that this patient had no significant family history. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In animal models, APOE Sendai (Arg145Pro) and APOE Kyoto (Arg25Cys) variants have been expressed in APOE-deficient mice, with LPG-like renal pathology having been observed in each.

“In animal models, APOE Sendai (Arg145Pro) and APOE Kyoto (Arg25Cys) variants have been expressed in APOE-deficient mice, with LPG-like renal pathology having been observed in each95, 96).”

• cites [95] 95) Ishigaki Y, Oikawa S, Suzuki T, Usui S, Magoori K, Kim DH, Suzuki H, Sasaki J, Sasano H, Okazaki M, Toyota T, Saito T and Yamamoto TT: Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice. J Biol Chem, 2000; 275: 31269-31273 sourceNot checked — no full text of the source
• cites [96] 96) Wu H, Yang J, Liu YQ, Lei S, Yang M, Yang Z, Yang Y and Hu Z: Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice. J Transl Med, 2021; 19: 97 sourceSupported

APOE Toyonaka (Ser197Cys) was considered to be in linkage disequilibrium with apoE2 (Arg158Cys).

“This variant was considered to be in linkage disequilibrium with apoE2 (Arg158Cys).”

• cites [99] 99) Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E and Saito T: A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep, 2019; 8: 106-111 sourcePartly supported

  The ‘Analysis of ApoE mutations and the clinical course’ section identifies both heterozygous Toyonaka (Ser197Cys) and homozygous apoE2 (Arg158Cys) in the patient; the Discussion also notes this combination in three cases. The paper describes their co-occurrence but does not state or establish that the variants are in linkage disequilibrium. No page number is available in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [101] 101) Fukunaga M, Nagahama K, Aoki M, Shimizu A, Hara S, Matsunaga A, Muso E and Saito T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2. Case Rep Nephrol Dial, 2018; 8: 45-55 sourcePartly supported

  The Case Presentation, under “Analysis of ApoE Mutation” (page not provided), identifies homozygous apoE2 (Arg158Cys) and heterozygous APOE Toyonaka (Ser197Cys) in the same patient. The paper does not state that the variants were in linkage disequilibrium or assess their association beyond this case. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [102] 102) Hirashima H, Komiya T, Toriu N, Hara S, Matsunaga A, Saito T and Muso E: A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka. Clin Nephrol Case Stud, 2018; 6: 45-51 sourcePartly supported

  The Case presentation, under “Analysis of ApoE mutation” (page unavailable), identifies both homozygous apoE2 (Arg158Cys) and heterozygous ApoE Toyonaka (Ser197Cys) in the patient. It does not state or establish that the variants are in linkage disequilibrium; their co-occurrence in this case does not establish that relationship. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [103] 103) Koshino A, Takaeda C, Matsuno T, Kitajima S, Iwata Y, Sakai N, Nagahama K, Niida Y, Saito T, Yokoyama H and Wada T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits. Case Rep Nephrol Dial, 2022; 12: 96-104 sourcePartly supported

  The Case Report/Case Presentation section reports both apoE Toyonaka (Ser197Cys) and apoE2/E2 in the patient, and the Introduction notes other cases with both. Neither section states that Toyonaka is in linkage disequilibrium with apoE2; co-occurrence in cases does not establish that genetic association. Page numbers are unavailable in our copy. (LLM, conf=0.81)

  Experimental — accuracy not yet measured

APOE Kyoto (Arg25Cys) has been reported as the most common variant in LPG worldwide, including southwestern China, Japan, France, and the United States.

“Moreover, APOE Kyoto (Arg25Cys)87) has been reported as the most common variant in LPG worldwide, including southwestern China, Japan, France, and the United States70, 94).”

• cites [70] 70) Matsunaga A and Saito T: Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia. Clin Exp Nephrol, 2014; 18: 220-224 sourceNot checked — no full text of the source
• cites [94] 94) Li MS, Li Y, Liu Y, Zhou XJ and Zhang H: An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne), 2022; 9: 905007 sourceSupported

In some cases of apoE2 homozygote glomerulopathy, non-lamellar lipoprotein thrombi were observed, which is distinct from lipoprotein glomerulopathy.

“In some cases of apoE2 homozygote glomerulopathy, non-lamellar lipoprotein thrombi were observed, which is distinct from lipoprotein glomerulopathy100).”

• cites [100] 100) Sakatsume M, Kadomura M, Sakata I, Imai N, Kondo D, Osawa Y, Shimada H, Ueno M, Miida T, Nishi S, Arakawa M and Gejyo F: Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity. Kidney Int, 2001; 59: 1911-1918 sourceSupported

APOE Tokyo/Maebashi (141-143del) has been reported in cases from Japan and eastern China.

“Meanwhile, APOE Tokyo/Maebashi (141–143del) has been reported in cases from Japan and eastern China94).”

• cites [94] 94) Li MS, Li Y, Liu Y, Zhou XJ and Zhang H: An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne), 2022; 9: 905007 sourcePartly supported

  The Epidemiology section and Figure 4 report APOE Tokyo-Maebashi in cases from central Japan and Beijing, while the Epidemiology text also describes it in southeastern China. The copy does not identify the variant specifically as a 141–143 deletion; a References entry describes APOE Tokyo only as a three-amino-acid deletion. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

The clinical data for the 10 listed APOE variants (p.Arg50Cys, p.Thr60Ala, p.Pro102Gln, p.Ala117Thr, p.Arg132Ser, p.Glu139Val, p.Glu150Gly, p.Arg152Gln, p.Glu189Lys, and p.Gln205Arg) were unknown.

“have only been analyzed in silico for APOE SNPs and their clinical data were unknown (Table 5)126).”

• cites [126] 126) Masoodi TA, Al Shammari SA, Al-Muammar MN and Alhamdan AA: Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer’s Disease. Neurol Res Int, 2012; 2012: 480609 sourcePartly supported

  The Methods and Results describe computational analyses of APOE SNPs, supporting the statement that the paper analyzed variants in silico. But the passages in our copy do not identify the ten listed amino-acid variants or state that their clinical data were unknown; the Results’ reference to an unknown risk score for ten SNPs is not a statement about clinical data. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Within a Norwegian hyperlipidemic cohort, APOE p.Arg235Trp (Arg217Trp) was found in a 56-year-old man with total cholesterol, triglyceride, LDL, and HDL levels of 363, 239, 247, and 69.6 mg/dL, respectively, along with the apoE3/E4 isoforms.

“Within a Norwegian hyperlipidemic cohort, APOE p.Arg235Trp (Arg217Trp) was found in a 56-year-old man with total cholesterol, triglyceride, LDL, and HDL levels of 363, 239, 247, and 69.6 mg/dL, respectively, along with the apoE3/E4 isoforms29).”

• cites [29] 29) Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchke P, Jais JP, French Research Network on ADH, Abifadel M, Kathiresan S, Leren TP, Rabes JP, Boileau C and Varret M: Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat, 2013; 34: 83-87 sourceSupported

The 10 listed APOE variants (p.Arg50Cys, p.Thr60Ala, p.Pro102Gln, p.Ala117Thr, p.Arg132Ser, p.Glu139Val, p.Glu150Gly, p.Arg152Gln, p.Glu189Lys, and p.Gln205Arg) have only been analyzed in silico for APOE SNPs.

“have only been analyzed in silico for APOE SNPs and their clinical data were unknown (Table 5)126).”

• cites [126] 126) Masoodi TA, Al Shammari SA, Al-Muammar MN and Alhamdan AA: Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer’s Disease. Neurol Res Int, 2012; 2012: 480609 sourcePartly supported

  The Methods and Results (sections 3.1–3.5) describe computational analysis of APOE SNPs, supporting the in-silico characterization. The passages do not identify the ten variants by the listed amino-acid changes or establish that they had only been analyzed in silico; they also do not state that clinical data for those variants were unknown. (LLM, conf=0.79)

  Experimental — accuracy not yet measured

The 11 listed APOE variants (p.Thr11Ser, p.Phe12Tyr, p.Ala23Val, p.Arg33Cys, p.Ser72Phe, p.Glu114Lys, p.Lys161Asn, p.Ala210Ser, p.Ser215Phe, p.Gly218Ser, and p.Val305Met) had not been reported.

“but the following 11 variants had not (Table 5): APOE p.Thr11Ser, APOE p.Phe12Tyr, APOE p.Ala23Val (Ala5Val), APOE p.Arg33Cys (Arg15Cys), APOE p.Ser72Phe (Ser54Phe), APOE p.Glu114Lys (Glu96Lys), APOE p.Lys161Asn (Lys143Asn), APOE p.Ala210Ser (Ala192Ser), APOE p.Ser215Phe (Ser197Phe), APOE p.Gly218Ser (Gly200Ser), and APOE p.Val305Met (Val287Met) 127).”

• cites [127] 127) Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG and Frikke-Schmidt R: APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement, 2020; 16: 1624-1637 sourceCould not verify

  The Methods and Results list or analyze Thr11Ser, Ala23Val, and Glu114Lys, but do not say whether they had previously been reported. The retrieved passages do not address the reporting history of the other eight listed variants either, so this copy does not establish the claim about all 11. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Nine of the 20 rare nonsynonymous APOE variants reported in the Danish screening had already been reported.

“Nine of these variants had already been reported”

• cites [127] 127) Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG and Frikke-Schmidt R: APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement, 2020; 16: 1624-1637 sourcePartly supported

  The Results and Methods report nine rare amino acid–changing APOE variants selected for further genotyping. They do not say that nine of 20 rare nonsynonymous variants had already been reported; the searches for that count and prior reporting found no such passage. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

A Danish genetic screening of the APOE gene for an association with dementia reported 20 rare nonsynonymous APOE variants in 105,597 individuals.

“Genetic screening of the APOE gene for an association with dementia conducted in Denmark reported 20 rare nonsynonymous APOE variants in 105,597 individuals127).”

• cites [127] 127) Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG and Frikke-Schmidt R: APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement, 2020; 16: 1624-1637 sourcePartly supported

  The Methods > Participants section reports 105,597 Danish participants, and the Background describes screening APOE for its relationship to dementia. But the Results report 27 rare variants found by resequencing 10,369 people, with nine amino acid–changing variants subsequently genotyped in the larger cohort—not 20 rare nonsynonymous variants reported in 105,597 people. The indexed passages provide no page numbers. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Ten novel APOE variants-APOE p.Thr11Ala, APOE p.Pro102Leu (Pro84Leu), APOE p.Arg137Cys (Arg119Cys), APOE p.Arg137His (Arg119His), APOE p.Leu155Phe (Leu137Phe), APOE p.Val179Ala (Val161Ala), APOE p.Val213Glu (Val195Glu), APOE p.Gly218Cys (Gly200Cys), APOE p.Glu249Lys (Glu231Lys), and APOE p.Glu252Lys (Glu234Lys)-were reported in a recent French cohort of ADH and CHL patients.

“Finally, 10 novel APOE variants, namely, APOE p.Thr11Ala, APOE p.Pro102Leu (Pro84Leu), APOE p.Arg137Cys (Arg119Cys), APOE p.Arg137His (Arg119His), APOE p.Leu155Phe (Leu137Phe), APOE p.Val179Ala (Val161Ala), APOE p.Val213Glu (Val195Glu), APOE p.Gly218Cys (Gly200Cys), APOE p.Glu249Lys (Glu231Lys), and APOE p.Glu252Lys (Glu234Lys), were reported in a recent French cohort of ADH and CHL patients (”

• cites [40] 40) Abou Khalil Y, Marmontel O, Ferrieres J, Paillard F, Yelnik C, Carreau V, Charriere S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrie A, Rabes JP and Varret M: APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci, 2022; 23: sourceSupported

The interaction of apoE with HSPGs may be the first step in the clearance of lipoproteins containing apoE from plasma.

“The interaction of apoE with HSPGs may be the first step in the clearance of lipoproteins containing apoE from plasma (Fig.1).”

HSPG binding activity is significantly reduced by variants in the basic amino acids Arg142, Arg145, and Lys146, suggesting that these residues contribute to heparin binding.

“In fact, HSPG binding activity is significantly reduced by variants in the basic amino acids Arg142, Arg145, and Lys146, suggesting that these residues contribute to heparin binding.”

One of the main functions of apoE is to mediate lipoprotein clearance through the uptake of remnants and HDL by hepatocytes.

“One of the main functions of apoE is to mediate lipoprotein clearance through the uptake of remnants (chylomicron and VLDL) and HDL by hepatocytes (Fig.1).”

In plasma, apoE associates primarily with chylomicrons, chylomicron remnants, VLDL, IDL, and HDL.

“In plasma, apoE associates primarily with chylomicrons, chylomicron remnants, VLDL, IDL, and high-density lipoprotein (HDL).”

ApoE is associated with lipoprotein glomerulopathy, a renal glomerular lesion.

“In fact, apoE is associated not only with dyslipidemia but also with lipoprotein glomerulopathy, a renal glomerular lesion, and late-onset Alzheimer’s disease (AD).”

The common isoforms ε2, ε3, and ε4 can be distinguished at the protein level by isoelectric electrophoresis into apoE2, apoE3, and apoE4.

“The common isoforms ε2, ε3, and ε4 can be distinguished at the protein level by isoelectric electrophoresis into apoE2, apoE3, and apoE4 (Fig.3)14).”

• cites [14] 14) Matsunaga A, Sasaki J, Moriyama K, Arakawa F, Takada Y, Nishi K, Hidaka K and Arakawa K: Population frequency of apolipoprotein E5 (Glu3-->Lys) and E7 (Glu244-->Lys, Glu245-->Lys) variants in western Japan. Clin Genet, 1995; 48: 93-99 sourceNot checked — no full text of the source

ApoE2 retains the ability to bind to HSPG and other related receptors.

“However, apoE2 retains the ability to bind to HSPG and other related receptors.”

ApoE mediates remnant lipoprotein catabolism through its interaction with receptors and the HSPG-LRP pathway.

“Through its interaction with these receptors and the HSPG-LRP pathway, apoE mediates remnant lipoprotein catabolism (Fig.1).”

The presence of cysteine at position 158 in ε2 disrupts the normal salt bridging required for the interaction of arginine at position 150 in the receptor binding region with the LDL receptor.

“The presence of cysteine at position 158 in ε2 disrupts the normal salt bridging required for the interaction of arginine at position 150 in the receptor binding region with the LDL receptor17).”

• cites [17] 17) Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW and Agard DA: Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure, 1994; 2: 713-718 sourceNot checked — no full text of the source

ApoE can bind to the LDL receptor and related receptors.

“It has the following features: high hydrophobicity, the ability to bind to the low-density-lipoprotein (LDL) receptor and related receptors, production in various tissues throughout the body, acting as a central apoprotein of cerebrospinal fluid lipoproteins, having three major isoforms (apoE2, apoE3, and apoE4) that vary in their function and susceptibility to genetic mutations1).”

• cites [1] 1) Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR and Blum C: Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res, 1982; 23: 911-914 sourceNot checked — no full text of the source

A 60-year-old Caucasian male compound heterozygous for APOE1 (Gly127Asp, Arg158Cys) and a nucleotide deletion of guanosine at codon 31 (Gly31fsTer29) had a severe form of familial type III HLP.

“A 60-year-old Caucasian male compound heterozygous for APOE1 (Gly127Asp, Arg158Cys) and a nucleotide deletion of guanosine at codon 31 (Gly31fsTer29) was reported to have a severe form of familial type III HLP (Table 1)37, 38).”

• cites [37] 37) Feussner G, Funke H, Weng W, Assmann G, Lackner KJ and Ziegler R: Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/’null’ genotype. Eur J Clin Invest, 1992; 22: 599-608 sourceNot checked — no full text of the source
• cites [38] 38) Feussner G and Ziegler R: Response to therapy of a type III hyperlipoproteinemic subject with the rare apolipoprotein E1 (Gly127----Asp, Arg158----Cys) variant. Clin Investig, 1992; 70: 614-617 sourceNot checked — no full text of the source

More than 90% of affected individuals with familial type III HLP are APOE2 homozygotes, with the remainder having rare APOE variants, including those causing apoE deficiency or compound heterozygotes of APOE variants and APOE2.

“In fact, more than 90% of affected individuals are APOE2 homozygotes, with the remainder having rare APOE variants, including those causing apoE deficiency or compound heterozygotes of APOE variants and APOE2 23, 25-28).”

• cites [23] 23) Mahley RW, Huang Y and Rall SC, Jr.: Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res, 1999; 40: 1933-1949 sourceNot checked — no full text of the source
• cites [25] 25) Blum CB: Type III Hyperlipoproteinemia: Still Worth Considering? Prog Cardiovasc Dis, 2016; 59: 119-124 sourceNot checked — no full text of the source
• cites [26] 26) Civeira F, Pocovi M, Cenarro A, Casao E, Vilella E, Joven J, Gonzalez J, Garcia-Otin AL and Ordovas JM: Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis, 1996; 127: 273-282 sourceNot checked — no full text of the source
• cites [27] 27) Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H and Marz W: Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat, 1998; 11: 417-423 sourceNot checked — no full text of the source
• cites [28] 28) Sniderman AD: Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipoproteinemia. Clin Chem, 2019; 65: 225-227 sourceNot checked — no full text of the source

A case heterozygous for APOE (Ala166fs) was discovered upon screening diabetic patients in the United Kingdom.

“In addition, a case heterozygous for APOE (Ala166fs) was discovered upon screening diabetic patients in the United Kingdom43).”

• cites [43] 43) Stephens JW, Sozen MM, Whittall RA, Caslake MJ, Bedford D, Acharya J, Hurel SJ and Humphries SE: Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem, 2005; 51: 119-124 sourceNot checked — no full text of the source

Familial type III HLP is caused by the accumulation of chylomicron remnants derived from intestinal lipoproteins and VLDL remnants derived from hepatic lipoproteins.

“Familial type III HLP is caused by the accumulation of chylomicron remnants derived from intestinal lipoproteins and VLDL remnants derived from hepatic lipoproteins; these abnormal cholesterol, triglyceride, and apoE-enriched lipoproteins, collectively termed β-VLDL, are the diagnostic features of this disease.”

Measurement of serum cholesterol and triglyceride levels alone often leads to the diagnosis of familial hypercholesterolemia (FH), combined hyperlipidemia (CHL), or hypertriglyceridemia rather than type III HLP.

“As the diagnosis of type III HLP requires analysis of lipoproteins and apoE, measurement of serum cholesterol and triglyceride levels alone often leads to the diagnosis of familial hypercholesterolemia (FH), combined hyperlipidemia (CHL), or hypertriglyceridemia.”

APOE (Trp20Ter) was detected by phenotypic and genotypic analyses of apoE in German type III HLP cases.

“Elsewhere, APOE (Trp20Ter) was detected by phenotypic and genotypic analyses of apoE in German type III HLP cases27).”

• cites [27] 27) Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H and Marz W: Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat, 1998; 11: 417-423 sourceNot checked — no full text of the source

Heterozygosity for APOE (136fsTer96) was found in an Indigenous Australian woman.

“Heterozygosity for APOE (136fsTer96) was also found in an Indigenous Australian woman42).”

• cites [42] 42) Tate JR, Hoffmann MM, Lovelock PK, Kesting JB and Shaw JT: Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian. Ann Clin Biochem, 2001; 38: 46-53 sourceNot checked — no full text of the source

Because many researchers have been unaware of the p. numbering, some papers misidentify the number of amino acid residues in apoE, causing previously reported variants to be incorrectly reported as new ones.

“Because many researchers have been unaware of this, some papers misidentify the number of amino acid residues in apoE, causing previously reported variants to be incorrectly reported as new ones.”

Additional genetic, hormonal, or environmental factors such as obesity, hypothyroidism, estrogen status, and diabetes are necessary for the development of familial type III HLP.

“Thus, additional genetic, hormonal, or environmental factors such as obesity, hypothyroidism, estrogen status, and diabetes are necessary for the development of familial type III HLP.”

Homozygotes for the APOE 10-bp deletion (Ala209GlyfsTer20), in which 19 amino acids from among the 209 amino acids at the C-terminus were nonfunctional, exhibited severe familial type III HLP.

“Homozygotes for the APOE 10-bp deletion (Ala209GlyfsTer20), in which 19 amino acids from among the 209 amino acids at the C-terminus were nonfunctional, also exhibited severe familial type III HLP35).”

• cites [35] 35) Feussner G, Dobmeyer J, Grone HJ, Lohmer S and Wohlfeil S: A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet, 1996; 58: 281-291 sourceNot checked — no full text of the source

Other FH-causing genes include PCSK9, LDLRAP1, APOB, and APOE.

“Other FH-causing genes include proprotein convertase subtilisin kexin 9 (PCSK9), low-density-lipoprotein receptor adapter protein 1 (LDLRAP1), APOB, and APOE.”

Plasma lipid and lipoprotein cholesterol values of two heterozygous offspring were found to be within the normal range.

“Plasma lipid and lipoprotein cholesterol values of two heterozygous offspring were found to be within the normal range.”

In heterozygotes with APOE deficiency, when the mutant apoE is absent or dysfunctional, the nature of the apoE of the remaining allele affects the manifestation of familial type III HLP, with some cases showing type III HLP and others showing no lipid abnormalities.

“In heterozygotes with APOE deficiency, when the mutant apoE was absent or dysfunctional, the nature of the apoE of the remaining allele affected the manifestation of familial type III HLP, with some cases showing type III HLP and others showing no lipid abnormalities.”

Relatively few cases of familial type III HLP are correctly diagnosed as type III because of their good response to lipid-lowering drugs and the difficulty of achieving an accurate diagnosis.

“Relatively few cases of familial type III HLP are correctly diagnosed as type III because of their good response to lipid-lowering drugs and the difficulty of achieving an accurate diagnosis28).”

• cites [28] 28) Sniderman AD: Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipoproteinemia. Clin Chem, 2019; 65: 225-227 sourceNot checked — no full text of the source

LPG-induced kidney damage gradually progresses to end-stage renal failure.

“LPG-induced kidney damage gradually progresses to end-stage renal failure.”

In cases of rare APOE variants causing familial type III HLP with dominant inheritance, a single defective APOE allele is usually sufficient to cause hyperlipidemia.

“In these cases, a single defective APOE allele is usually sufficient to cause hyperlipidemia.”

A secondary factor promoting the accumulation of residual dominant type III HLPs has been reported to exist in helix 4 of the N-terminal domain.

“A secondary factor promoting the accumulation of these residual dominant type III HLPs has been reported to exist in helix 4 of the N-terminal domain (Fig.2, Fig.5).”

The first APOE variant associated with LPG was reported in Japan and is known as APOE Sendai (Arg145Pro).

“The first APOE variant associated with LPG was reported in Japan and is known as APOE Sendai (Arg145Pro)72).”

• cites [72] 72) Oikawa S, Matsunaga A, Saito T, Sato H, Seki T, Hoshi K, Hayasaka K, Kotake H, Midorikawa H, Sekikawa A, Hara S, Abe K, Toyota T, Jingami H, Nakamura H and Sasaki J: Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 sourceNot checked — no full text of the source

The efficacy of fibrates, including fenofibrate, has been reported in several cases of LPG in Japan and China.

“Prevention of hypertriglyceridemia may be important in LPG therapy, and the efficacy of fibrates, including fenofibrate, has been reported in several cases in Japan and China.”

LPG was initially identified as a glomerular disease associated with type III HLP.

“LPG was initially identified as a glomerular disease associated with type III HLP68).”

• cites [68] 68) Saito T, Sato H, Kudo K, Oikawa S, Shibata T, Hara Y, Yoshinaga K and Sakaguchi H: Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis, 1989; 13: 148-153 sourceNot checked — no full text of the source

LPG is characterized by dilated glomerular capillaries with lipoprotein clots showing lamellar formation, as seen on renal biopsy.

“LPG is characterized by dilated glomerular capillaries with lipoprotein clots showing lamellar formation, as seen on renal biopsy69).”

• cites [69] 69) Saito T, Matsunaga A and Oikawa S: Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis, 2006; 47: 199-211 sourceNot checked — no full text of the source

The renal involvement in apoE2 homozygote glomerulopathy is thought to follow the mechanism of atherosclerosis, with mesangial cells and macrophages infiltrating the mesangial space taking up lipoproteins and contributing to the development of glomerulosclerosis.

“The renal involvement in apoE2 homozygote glomerulopathy is thought to follow the mechanism of atherosclerosis, with mesangial cells and macrophages infiltrating the mesangial space taking up lipoproteins and contributing to the development of glomerulosclerosis.”

Variants that cause both familial type III HLP and LPG are concentrated in the LDL receptor binding region (amino acids 136-150).

“Variants that cause both familial type III HLP and LPG are concentrated in the LDL receptor binding region (amino acids 136–150).”

APOE Tsukuba (Arg114Cys) was identified as a mutation near Cys112 in helix 3.

“APOE Tsukuba (Arg114Cys) was identified as a mutation near Cys112 in helix 3 86).”

• cites [86] 86) Hagiwara M, Yamagata K, Matsunaga T, Arakawa Y, Usui J, Shimizu Y, Aita K, Nagata M, Koyama A, Zhang B, Mastunaga A, Saku K and Saito T: A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy. Nephrol Dial Transplant, 2008; 23: 381-384 sourceNot checked — no full text of the source

These type III HLPs are highly penetrant dominant traits.

“These type III HLPs are highly penetrant dominant traits.”

The genetics and pathology of LPG differ from those of apoE2 homozygote glomerulopathy, which causes type III HLP.

“However, its genetics and pathology differ from those of apoE2 homozygote glomerulopathy, which causes type III HLP.”

Nine carriers (all heterozygotes) of APOE3' (Arg136His) were reported to have levels of VLDL cholesterol and triglycerides twice as high as those of nine noncarriers.

“Nine carriers (all heterozygotes) of APOE3’ (Arg136His) were reported to have levels of very low-density-lipoprotein (VLDL) cholesterol and triglycerides twice as high as those of nine noncarriers59).”

• cites [59] 59) Minnich A, Weisgraber KH, Newhouse Y, Dong LM, Fortin LJ, Tremblay M and Davignon J: Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3’ (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res, 1995; 36: 57-66 sourceNot checked — no full text of the source

Most APOE variants associated with LPG were heterozygous apoE missense variants close to the LDL receptor binding site.

“Most were heterozygous apoE missense variants close to the LDL receptor binding site.”

APOE1 Nagoya (Arg142Ser, Arg158Cys) was reported from a case of familial hypercholesterolemia and type III HLP, occurring in an apoE2 homozygote.

“Meanwhile, APOE1 Nagoya (Arg142Ser, Arg158Cys) was reported from a case of familial hypercholesterolemia and type III HLP, occurring in an apoE2 homozygote60).”

• cites [60] 60) Sakuma N, Hibino T, Saeki T, Nagata T, Sato T, Okuda N, Matsunaga A and Sasaki J: Compound heterozygotes for a novel mutation, apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with severe type III hyperlipoproteinemia and familial hypercholesterolemia. J Atheroscler Thromb, 2014; 21: 983-988 sourceNot checked — no full text of the source

APOE2 Toranomon (Gln187Glu) located in the hinge region was found in association with the recessive expression of type III HLP with coronary atherosclerosis.

“Finally, APOE2 Toranomon (Gln187Glu) located in the hinge region was found in association with the recessive expression of type III HLP with coronary atherosclerosis66, 67).”

• cites [66] 66) Okubo M, Aoyama Y, Harada K, Fukawa M, Tsukada T, Mokuno H, Yamada N and Murase T: A novel apolipoprotein E2 variant, E2Toranomon (Q187E), identified in a type III hyperlipoproteinemia patient with coronary atherosclerosis. Atherosclerosis, 1998; 140: 187-190Not matched

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

• cites [67] 67) Hayakawa M, Okubo M, Katori H, Nagahama K, Murase T, Kobayashi T, Tanaka S, Nakanishi K, Odawara M, Matsushita H and Yamada A: A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy. Am J Kidney Dis, 2002; 39: E15 sourceNot checked — no full text of the source

To date, 14 different variants in the APOE gene have been reported as causes of LPG.

“To date, 14 different variants in the APOE gene have been reported as causes of LPG (Fig.5, Table 3).”

APOE3' (Arg136His) might be associated with recessive expression of type III HLP.

“APOE3’ (Arg136His) might be associated with recessive expression of type III HLP.”

• cites [59] 59) Minnich A, Weisgraber KH, Newhouse Y, Dong LM, Fortin LJ, Tremblay M and Davignon J: Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3’ (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res, 1995; 36: 57-66 sourceNot checked — no full text of the source

A survey of LPG-affected families revealed that each variant exhibits low penetrance.

“A survey of LPG-affected families also revealed that each variant exhibits low penetrance.”

Severe type III HLP has been reported in APOE4 Philadelphia (Glu13Lys, Arg145Cys) homozygotes.

“Furthermore, severe type III HLP has been reported in APOE4 Philadelphia (Glu13Lys, Arg145Cys) homozygotes63)”

• cites [63] 63) Lohse P, Mann WA, Stein EA and Brewer HB, Jr.: Apolipoprotein E-4Philadelphia (Glu13----Lys,Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem, 1991; 266: 10479-10484 sourceNot checked — no full text of the source

Proteinuria in LPG may start out mild but frequently progresses to nephrotic syndrome.

“While proteinuria may start out mild, it frequently progresses to nephrotic syndrome69).”

• cites [69] 69) Saito T, Matsunaga A and Oikawa S: Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis, 2006; 47: 199-211 sourceNot checked — no full text of the source

Two APOE1 Barden (Arg180Cys) heterozygotes in a family study showed hypertriglyceridemia.

“Furthermore, two APOE1 Barden (Arg180Cys) heterozygotes in a family study showed hypertriglyceridemia112)”

• cites [112] 112) Ruzicka V, Marz W, Russ A, Fisher E, Mondorf W and Gross W: Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis. Electrophoresis, 1993; 14: 1032-1037 sourceNot checked — no full text of the source

APOE p.Gly191Cys (Gly173Cys), APOE1 Barden (Arg180Cys), and APOE p.Pro220Leu (Pro202Leu) were shown to be located in the hinge region.

“APOE p.Gly191Cys (Gly173Cys), APOE1 Barden (Arg180Cys), and APOE p.Pro220Leu (Pro202Leu) were shown to be located in the hinge region44, 119).”

• cites [44] 44) Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 sourceNot checked — no full text of the source
• cites [119] 119) Hoffmann MM, Scharnagl H, Koster W, Winkler K, Wieland H and Marz W: Apolipoprotein E1 Baden (Arg(180)-->Cys). A new apolipoprotein E variant associated with hypertriglyceridemia. Clin Chim Acta, 2001; 303: 41-48 sourceNot checked — no full text of the source

APOE5 Frankfurt (Gln81Lys, Cys112Arg) heterozygosity was identified in a 43-year-old man with moderate CHL.

“Moreover, APOE5 Frankfurt (Gln81Lys, Cys112Arg) heterozygosity was identified in a 43-year-old man with moderate CHL112).”

• cites [112] 112) Ruzicka V, Marz W, Russ A, Fisher E, Mondorf W and Gross W: Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis. Electrophoresis, 1993; 14: 1032-1037 sourceNot checked — no full text of the source

A case of an APOE p.Met82Ile (Met64Ile) heterozygote showed hypertriglyceridemia.

“In addition, a case of an APOE p.Met82Ile (Met64Ile) heterozygote showed hypertriglyceridemia44).”

• cites [44] 44) Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 sourceNot checked — no full text of the source

The APOE4 isoform has consistently emerged as a factor conferring susceptibility to late-onset AD.

“The APOE4 isoform has consistently emerged as a factor conferring susceptibility to late-onset AD.”

APOE p.Leu167del (Leu149del) was originally reported to be associated with sea blue histiocytosis and familial combined hyperlipidemia.

“As another example of an APOE variant, APOE p.Leu167del (Leu149del) was originally reported to be associated with sea blue histiocytosis and familial combined hyperlipidemia115-117).”

• cites [115] 115) Nguyen TT, Kruckeberg KE, O’Brien JF, Ji ZS, Karnes PS, Crotty TB, Hay ID, Mahley RW and O’Brien T: Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]. J Clin Endocrinol Metab, 2000; 85: 4354-4358 sourceNot checked — no full text of the source
• cites [116] 116) Faivre L, Saugier-Veber P, Pais de Barros JP, Verges B, Couret B, Lorcerie B, Thauvin C, Charbonnier F, Huet F, Gambert P, Frebourg T and Duvillard L: Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation. Eur J Hum Genet, 2005; 13: 1186-1191 sourceNot checked — no full text of the source
• cites [117] 117) Solanas-Barca M, de Castro-Oros I, Mateo-Gallego R, Cofan M, Plana N, Puzo J, Burillo E, Martin-Fuentes P, Ros E, Masana L, Pocovi M, Civeira F and Cenarro A: Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. Atherosclerosis, 2012; 222: 449-455 sourceNot checked — no full text of the source

A case of APOE p.Pro220Leu (Pro202Leu) with CHL was reported.

“while a case of APOE p.Pro220Leu (Pro202Leu) with CHL was also reported44).”

• cites [44] 44) Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 sourceNot checked — no full text of the source

In the presence of diabetes, it is often difficult to distinguish between ApoE2 homozygote glomerulopathy and diabetic nephropathy without a diagnosis of type III HLP.

“In the presence of diabetes, it is often difficult to distinguish between ApoE2 homozygote glomerulopathy and diabetic nephropathy without a diagnosis of type III HLP.”

APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) was found in the same year in a screening focused on hyperlipidemia and in a screening for AD.

“APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) was found in the same year in a screening focused on hyperlipidemia and in a screening for AD108, 109).”

• cites [108] 108) Orth M, Weng W, Funke H, Steinmetz A, Assmann G, Nauck M, Dierkes J, Ambrosch A, Weisgraber KH, Mahley RW, Wieland H and Luley C: 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, 1999; 19: 1306-1315 sourceNot checked — no full text of the source
• cites [109] 109) Kamboh MI, Aston CE, Perez-Tur J, Kokmen E, Ferrell RE, Hardy J and DeKosky ST: A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer’s disease. Neurosci Lett, 1999; 263: 129-132 sourceNot checked — no full text of the source

Carriers of APOE5 (Glu3Lys), including a homozygote, have been shown to exhibit high lipoprotein levels without type III HLP.

“Carriers of APOE5 (Glu3Lys), including a homozygote, have been shown to exhibit high lipoprotein levels without type III HLP106, 107).”

• cites [106] 106) Tajima S, Yamamura T and Yamamoto A: Analysis of apolipoprotein E5 gene from a patient with hyperlipoproteinemia. J Biochem, 1988; 104: 48-52 sourceNot checked — no full text of the source
• cites [107] 107) Kobayashi J, Shirai K, Murano T, Misawa Y, Tashiro J, Yoshida T and Shinomiya M: A case of hyperlipidemia with homozygous apolipoprotein E5 (Glu3-->Lys). Biochim Biophys Acta, 2002; 1583: 117-121 sourceNot checked — no full text of the source

APOE5 (Pro84Arg,Cys112Arg) heterozygosity was found in a 54-year-old woman of European descent with elevated LDL cholesterol levels.

“Furthermore, APOE5 (Pro84Arg,Cys112Arg) heterozygosity was found in a 54-year-old woman of European descent with elevated LDL cholesterol levels113).”

• cites [113] 113) Wardell MR, Rall SC, Jr., Schaefer EJ, Kane JP and Weisgraber KH: Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity. J Lipid Res, 1991; 32: 521-528 sourceNot checked — no full text of the source

A case exhibiting APOE p.Gly191Cys (Gly173Cys) heterozygosity showed isolated hypercholesterolemia.

“Moreover, a case exhibiting APOE p.Gly191Cys (Gly173Cys) heterozygosity showed isolated hypercholesterolemia44).”

• cites [44] 44) Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 sourceNot checked — no full text of the source

APOE Sendai (Arg145Pro) was observed mainly in central and northern Japan, especially in Yamagata and Miyagi, but not in China.

“APOE Sendai (Arg145Pro) was observed mainly in central and northern Japan, especially in Yamagata and Miyagi, but not in China71, 93).”

• cites [71] 71) Saito T and Matsunaga A: Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis. Kidney Int, 2014; 85: 243-245 sourceNot checked — no full text of the source
• cites [93] 93) Toyota K, Hashimoto T, Ogino D, Matsunaga A, Ito M, Masakane I, Degawa N, Sato H, Shirai S, Umetsu K, Tamiya G, Saito T and Hayasaka K: A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet, 2013; 58: 254-258 sourceNot checked — no full text of the source

APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) heterozygotes tended to have higher triglyceride levels.

“APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) heterozygotes tended to have higher triglyceride levels.”

• cites [108] 108) Orth M, Weng W, Funke H, Steinmetz A, Assmann G, Nauck M, Dierkes J, Ambrosch A, Weisgraber KH, Mahley RW, Wieland H and Luley C: 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, 1999; 19: 1306-1315 sourceNot checked — no full text of the source

APOE5 (Val135_Arg142dup ValArgLeuAlaSerHisLeuArg) heterozygosity was detected in a patient with elevated triglyceride levels.

“Finally, APOE5 (Val135_Arg142dup ValArgLeuAlaSerHisLeuArg) heterozygosity was detected in a patient with elevated triglyceride levels114).”

• cites [114] 114) Yamanouchi Y, Takano T, Hamaguchi H and Tokunaga K: A novel apolipoprotein E5 variant with a 24-bp insertion causing hyperlipidemia. J Hum Genet, 2001; 46: 633-639 sourceNot checked — no full text of the source

APOE p.Arg108Trip (Arg90Trp) and APOE p.Tyr136His (Tyr118His) heterozygotes were detected in a normolipidemic group.

“APOE p.Arg108Trip (Arg90Trp) and APOE p.Tyr136His (Tyr118His) heterozygotes were detected in a normolipidemic group (Table 5)44).”

• cites [44] 44) Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 sourceNot checked — no full text of the source

APOE2 Fukuoka (Arg224Gln) heterozygosity was identified in a 54-year-old Japanese woman with xanthomas.

“Elsewhere, APOE2 Fukuoka (Arg224Gln) heterozygosity was identified in a 54-year-old Japanese woman with xanthomas120).”

• cites [120] 120) Moriyama K, Sasaki J, Takada Y, Arakawa F, Matsunaga A, Ito Y and Arakawa K: Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 --> Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta, 1996; 1301: 185-190 sourceNot checked — no full text of the source

When untreated (at 48 years old), the APOE2 Fukuoka heterozygote had dyslipidemia with total cholesterol of 1149 mg/dL and triglycerides of 1162 mg/dL.

“When untreated (at 48 years old), she had dyslipidemia with total cholesterol of 1149 mg/dL and triglycerides of 1162 mg/dL.”

• cites [120] 120) Moriyama K, Sasaki J, Takada Y, Arakawa F, Matsunaga A, Ito Y and Arakawa K: Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 --> Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta, 1996; 1301: 185-190 sourceNot checked — no full text of the source

APOE2 Dunedin (Arg228Cys), APOE2 (Val236Glu), APOE7 Suita (Glu244,245Lys) (all heterozygotes), and APOE3 (Arg251 Gly, Cys112Arg) in the C-terminal domain were identified as variants that cause hypertriglyceridemia or CHL.

“APOE2 Dunedin (Arg228Cys)121), APOE2 (Val236Glu)122), APOE7 Suita (Glu244,245Lys)123, 14) (all heterozygotes), and APOE3 (Arg251 Gly, Cys112Arg) 122) in the C-terminal domain were identified as variants that cause hypertriglyceridemia or CHL.”

• cites [121] 121) Wardell MR, Rall SC, Jr., Brennan SO, Nye ER, George PM, Janus ED and Weisgraber KH: Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity. J Lipid Res, 1990; 31: 535-543 sourceNot checked — no full text of the source
• cites [122] 122) van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van’t Hooft FM, Assmann G, Hofker MH and et al.: Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet, 1993; 52: 937-946Not matched

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

• cites [123] 123) Yanagi K, Yamashita S, Hiraoka H, Ishigami M, Kihara S, Hirano K, Sakai N, Nozaki S, Funahashi T, Kameda-Takemura K, Kubo M, Tokunaga K and Matsuzawa Y: Increased serum remnant lipoproteins in patients with apolipoprotein E7 (apo E Suita). Atherosclerosis, 1997; 131: 49-58 sourceNot checked — no full text of the source
• cites [14] 14) Matsunaga A, Sasaki J, Moriyama K, Arakawa F, Takada Y, Nishi K, Hidaka K and Arakawa K: Population frequency of apolipoprotein E5 (Glu3-->Lys) and E7 (Glu244-->Lys, Glu245-->Lys) variants in western Japan. Clin Genet, 1995; 48: 93-99 sourceNot checked — no full text of the source

APOE1 (Leu252Glu, Arg158Cys) was found in the course of an apoE screening among hypercholesterolemic patients in Münster in 1985.

“APOE1 (Leu252Glu, Arg158Cys) was found in the course of an apoE screening among hypercholesterolemic patients in Münster in 1985 122).”

• cites [122] 122) van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van’t Hooft FM, Assmann G, Hofker MH and et al.: Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet, 1993; 52: 937-946Not matched

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

Recombinant APOE2 Fukuoka (Arg224Gln) showed almost the same LDL receptor-binding activity and heparin-binding capacity as recombinant APOE3.

“Possibly because of the variant being located in the C-terminal domain, recombinant APOE2 Fukuoka (Arg224Gln) showed almost the same LDL receptor-binding activity and heparin-binding capacity as recombinant APOE3 120).”

• cites [120] 120) Moriyama K, Sasaki J, Takada Y, Arakawa F, Matsunaga A, Ito Y and Arakawa K: Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 --> Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta, 1996; 1301: 185-190 sourceNot checked — no full text of the source

APOE has genetic variants that readily cause pathological conditions.

“ApoE is not only a very important apoprotein, but also has genetic variants that readily cause pathological conditions.”

APOE5 (Glu212Lys) was identified in a Turkish family.

“Elsewhere, APOE5 (Glu212Lys) was identified in a Turkish family124).”

• cites [124] 124) Feussner G, Scharnagl H, Scherbaum C, Acar J, Dobmeyer J, Lohrmann J, Wieland H and Marz W: Apolipoprotein E5 (Glu212-->Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res, 1996; 37: 1632-1645 sourceNot checked — no full text of the source

Screening of diabetic patients in the United Kingdom found one African patient who was heterozygous for APOE (Arg150His) with the E2/E2 phenotype, but no serum lipid abnormalities.

“Moreover, screening of diabetic patients in the United Kingdom found one African patient who was heterozygous for APOE (Arg150His) with the E2/E2 phenotype, but no serum lipid abnormalities43).”

• cites [43] 43) Stephens JW, Sozen MM, Whittall RA, Caslake MJ, Bedford D, Acharya J, Hurel SJ and Humphries SE: Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem, 2005; 51: 119-124 sourceNot checked — no full text of the source

Compared with non-carriers, carriers of APOE5 (Glu212Lys) had slightly higher triglyceride levels (110.7 versus 98.3 mg/L).

“Compared with the non-carriers, carriers of the variant had slightly higher triglyceride levels (110.7 versus 98.3 mg/L).”

• cites [124] 124) Feussner G, Scharnagl H, Scherbaum C, Acar J, Dobmeyer J, Lohrmann J, Wieland H and Marz W: Apolipoprotein E5 (Glu212-->Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res, 1996; 37: 1632-1645 sourceNot checked — no full text of the source