RBCC

Full text data of APOE

APOE [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Apolipoprotein E; Apo-E; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00021842
IPI00021842 Apolipoprotein E precursor Apolipoprotein E precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 extracellular binds RBC n/a found at its expected molecular weight found at molecular weight

UniProt P02649
ID APOE_HUMAN Reviewed; 317 AA.
AC P02649; B2RC15; C0JYY5; Q9P2S4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 185.
DE RecName: Full=Apolipoprotein E;
DE Short=Apo-E;
DE Flags: Precursor;
GN Name=APOE;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (VARIANT E3).
RX PubMed=6325438;
RA Zannis V.I., McPherson J., Goldberger G., Karathanasis S.K.,
RA Breslow J.L.;
RT "Synthesis, intracellular processing, and signal peptide of human
RT apolipoprotein E.";
RL J. Biol. Chem. 259:5495-5499(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (VARIANT E3).
RX PubMed=6327682;
RA McLean J.W., Elshourbagy N.A., Chang D.J., Mahley R.W., Taylor J.M.;
RT "Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing
RT of a new variant.";
RL J. Biol. Chem. 259:6498-6504(1984).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (VARIANT E4).
RX PubMed=2987927; DOI=10.1073/pnas.82.10.3445;
RA Paik Y.-K., Chang D.J., Reardon C.A., Davies G.E., Mahley R.W.,
RA Taylor J.M.;
RT "Nucleotide sequence and structure of the human apolipoprotein E
RT gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:3445-3449(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (VARIANT E2).
RX PubMed=3243553; DOI=10.1016/0888-7543(88)90130-9;
RA Emi M., Wu L.L., Robertson M.A., Myers R.L., Hegele R.A.,
RA Williams R.R., White R., Lalouel J.-M.;
RT "Genotyping and sequence analysis of apolipoprotein E isoforms.";
RL Genomics 3:373-379(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10520737;
RA Freitas E.M., Zhang W.J., Lalonde J.P., Tay G.K., Gaudieri S.,
RA Ashworth L.K., Van Bockxmeer F.M., Dawkins R.L.;
RT "Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene:
RT PEREC1.";
RL DNA Seq. 9:89-100(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PRO-46; ARG-130;
RP CYS-163 AND CYS-176.
RX PubMed=11042151; DOI=10.1101/gr.146900;
RA Nickerson D.A., Taylor S.L., Fullerton S.M., Weiss K.M., Clark A.G.,
RA Stengard J.H., Salomaa V., Boerwinkle E., Sing C.F.;
RT "Sequence diversity and large-scale typing of SNPs in the human
RT apolipoprotein E gene.";
RL Genome Res. 10:1532-1545(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-78, AND VARIANT HIS-64.
RC TISSUE=Blood;
RA Imura T., Kimura H., Kawasaki M.;
RT "A new apolipoprotein E variant (Gln46-->His).";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 99-317 (VARIANT E3).
RX PubMed=6897404;
RA Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W.,
RA Lofquist-Kahl F., Karathanasis S.K., Zannis V.I.;
RT "Identification and DNA sequence of a human apolipoprotein E cDNA
RT clone.";
RL J. Biol. Chem. 257:14639-14641(1982).
RN [12]
RP ERRATUM.
RA Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W.,
RA Lofquist-Kahl F., Karathanasis S.K., Zannis V.I.;
RL J. Biol. Chem. 258:11422-11422(1983).
RN [13]
RP PROTEIN SEQUENCE OF 19-317 (VARIANT E2).
RX PubMed=7068630;
RA Rall S.C. Jr., Weisgraber K.H., Mahley R.W.;
RT "Human apolipoprotein E. The complete amino acid sequence.";
RL J. Biol. Chem. 257:4171-4178(1982).
RN [14]
RP REVIEW.
RX PubMed=3283935; DOI=10.1126/science.3283935;
RA Mahley R.W.;
RT "Apolipoprotein E: cholesterol transport protein with expanding role
RT in cell biology.";
RL Science 240:622-630(1988).
RN [15]
RP HEPARIN-BINDING SITES.
RX PubMed=3947350; DOI=10.1016/S0006-291X(86)80489-2;
RA Cardin A.D., Hirose N., Blankenship D.T., Jackson R.L.,
RA Harmony J.A.K., Sparrow D.A., Sparrow J.T.;
RT "Binding of a high reactive heparin to human apolipoprotein E:
RT identification of two heparin-binding domains.";
RL Biochem. Biophys. Res. Commun. 134:783-789(1986).
RN [16]
RP ASSOCIATION OF APOE*4 WITH ALZHEIMER DISEASE.
RX PubMed=8346443; DOI=10.1126/science.8346443;
RA Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E.,
RA Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A.;
RT "Gene dose of apolipoprotein E type 4 allele and the risk of
RT Alzheimer's disease in late onset families.";
RL Science 261:921-923(1993).
RN [17]
RP GLYCATION AT LYS-93, AND MASS SPECTROMETRY.
RX PubMed=10452964; DOI=10.1016/S0925-4439(99)00047-2;
RA Shuvaev V.V., Fujii J., Kawasaki Y., Itoh H., Hamaoka R., Barbier A.,
RA Ziegler O., Siest G., Taniguchi N.;
RT "Glycation of apolipoprotein E impairs its binding to heparin:
RT identification of the major glycation site.";
RL Biochim. Biophys. Acta 1454:296-308(1999).
RN [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-212; THR-307 AND SER-308,
RP STRUCTURE OF CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP GLYCOSYLATION AT THR-26; THR-36 AND SER-314, AND MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan
RT structures of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 41-184.
RX PubMed=2063194; DOI=10.1126/science.2063194;
RA Wilson C., Wardell M.R., Weisgraber K.H., Mahley R.W., Agard D.A.;
RT "Three-dimensional structure of the LDL receptor-binding domain of
RT human apolipoprotein E.";
RL Science 252:1817-1822(1991).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 41-181.
RX PubMed=8756331; DOI=10.1038/nsb0896-718;
RA Dong L.-M., Parkin S., Trakhanov S.D., Rupp B., Simmons T.,
RA Arnold K.S., Newhouse Y.M., Innerarity T.L., Weisgraber K.H.;
RT "Novel mechanism for defective receptor binding of apolipoprotein E2
RT in type III hyperlipoproteinemia.";
RL Nat. Struct. Biol. 3:718-722(1996).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 22-165.
RX PubMed=10850798;
RA Segelke B.W., Forstner M., Knapp M., Trakhanov S.D., Parkin S.,
RA Newhouse Y.M., Bellamy H.D., Weisgraber K.H., Rupp B.;
RT "Conformational flexibility in the apolipoprotein E amino-terminal
RT domain structure determined from three new crystal forms: implications
RT for lipid binding.";
RL Protein Sci. 9:886-897(2000).
RN [24]
RP REVIEW ON VARIANTS.
RX PubMed=7833947; DOI=10.1002/humu.1380040303;
RA de Knijff P., van den Maagdenberg A.M.J.M., Frants R.R., Havekes L.M.;
RT "Genetic heterogeneity of apolipoprotein E and its influence on plasma
RT lipid and lipoprotein levels.";
RL Hum. Mutat. 4:178-194(1994).
RN [25]
RP VARIANT E5 LYS-21.
RX PubMed=2760009;
RA Maeda H., Nakamura H., Kobori S., Okada M., Niki H., Ogura T.,
RA Hiraga S.;
RT "Molecular cloning of a human apolipoprotein E variant: E5 (Glu-
RT 3-->Lys).";
RL J. Biochem. 105:491-493(1989).
RN [26]
RP VARIANT HLPP3 E3 LEIDEN GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS.
RX PubMed=2556398;
RA Wardell M.R., Weisgraber K.H., Havekes L.M., Rall S.C. Jr.;
RT "Apolipoprotein E3-Leiden contains a seven-amino acid insertion that
RT is a tandem repeat of residues 121-127.";
RL J. Biol. Chem. 264:21205-21210(1989).
RN [27]
RP VARIANTS HLPP3 E4 PHILADELPHIA LYS-31 AND CYS-163.
RX PubMed=1674745;
RA Lohse P., Mann W.A., Stein E.A., Brewer H.B. Jr.;
RT "Apolipoprotein E-4 Philadelphia (Glu-13-->Lys,Arg-145-->Cys).
RT Homozygosity for two rare point mutations in the apolipoprotein E gene
RT combined with severe type III hyperlipoproteinemia.";
RL J. Biol. Chem. 266:10479-10484(1991).
RN [28]
RP VARIANTS GLU-254; GLY-269; GLU-270; HIS-292 AND ARG-314.
RX PubMed=8488843;
RA van den Maagdenberg A.M.J.M., Weng W., de Bruijn I.H., de Knijff P.,
RA Funke H., Smelt A.H.M., Leuven J.A.G., van 't Hooft F.M., Assmann G.,
RA Hofker M.H., Havekes L.M., Frants R.R.;
RT "Characterization of five new mutants in the carboxyl-terminal domain
RT of human apolipoprotein E: no cosegregation with severe
RT hyperlipidemia.";
RL Am. J. Hum. Genet. 52:937-946(1993).
RN [29]
RP VARIANTS HLPP3 ARG-130; ASP-145; SER-154; CYS-160 AND CYS-176.
RX PubMed=8287539;
RA Richard P., Thomas G., de Zulueta M.P., de Gennes J.-L., Thomas M.,
RA Cassaigne A., Bereziat G., Iron A.;
RT "Common and rare genotypes of human apolipoprotein E determined by
RT specific restriction profiles of polymerase chain reaction-amplified
RT DNA.";
RL Clin. Chem. 40:24-29(1994).
RN [30]
RP VARIANT LPG PRO-163.
RX PubMed=9176854;
RA Oikawa S., Matsunaga A., Saito T., Sato H., Seki T., Hoshi K.,
RA Hayasaka K., Kotake H., Midorikawa H., Sekikawa A., Hara S., Abe K.,
RA Toyota T., Jingami H., Nakamura H., Sasaki J.;
RT "Apolipoprotein E Sendai (arginine 145-->proline): a new variant
RT associated with lipoprotein glomerulopathy.";
RL J. Am. Soc. Nephrol. 8:820-823(1997).
RN [31]
RP VARIANTS E4/3 ARG-130 AND GLY-269.
RX PubMed=9360638; DOI=10.1016/S1383-5726(97)00009-5;
RA Kang A.K., Jenkins D.J.A., Wolever T.M.S., Huff M.W., Maguire G.F.,
RA Connelly P.W., Hegele R.A.;
RT "Apolipoprotein E R112; R251G: a carboxy-terminal variant found in
RT patients with hyperlipidemia and coronary heart disease.";
RL Mutat. Res. 382:57-65(1997).
RN [32]
RP VARIANT LPG CYS-43.
RX PubMed=10432380; DOI=10.1046/j.1523-1755.1999.00572.x;
RA Matsunaga A., Sasaki J., Komatsu T., Kanatsu K., Tsuji E.,
RA Moriyama K., Koga T., Arakawa K., Oikawa S., Saito T., Kita T.,
RA Doi T.;
RT "A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein
RT glomerulopathy.";
RL Kidney Int. 56:421-427(1999).
RN [33]
RP VARIANT SBHD LEU-167 DEL.
RX PubMed=11095479; DOI=10.1210/jc.85.11.4354;
RA Nguyen T.T., Kruckeberg K.E., O'Brien J.F., Ji Z.-S., Karnes P.S.,
RA Crotty T.B., Hay I.D., Mahley R.W., O'Brien T.;
RT "Familial splenomegaly: macrophage hypercatabolism of lipoproteins
RT associated with apolipoprotein E mutation [apolipoprotein E (delta149
RT Leu)].";
RL J. Clin. Endocrinol. Metab. 85:4354-4358(2000).
RN [34]
RP VARIANT E3 BASEL VAL-124.
RX PubMed=12864777; DOI=10.1046/j.1365-2362.2003.01180.x;
RA Miserez A.R., Scharnagl H., Muller P.Y., Mirsaidi R., Stahelin H.B.,
RA Monsch A., Marz W., Hoffmann M.M.;
RT "Apolipoprotein E3Basel: new insights into a highly conserved protein
RT region.";
RL Eur. J. Clin. Invest. 33:677-685(2003).
RN [35]
RP VARIANTS ARG-130 AND CYS-176.
RX PubMed=12966036; DOI=10.1093/hmg/ddg314;
RA Morabia A., Cayanis E., Costanza M.C., Ross B.M., Flaherty M.S.,
RA Alvin G.B., Das K., Gilliam T.C.;
RT "Association of extreme blood lipid profile phenotypic variation with
RT 11 reverse cholesterol transport genes and 10 non-genetic
RT cardiovascular disease risk factors.";
RL Hum. Mol. Genet. 12:2733-2743(2003).
RN [36]
RP VARIANT SBHD LEU-167 DEL.
RX PubMed=16094309; DOI=10.1038/sj.ejhg.5201480;
RA Faivre L., Saugier-Veber P., Pais de Barros J.-P., Verges B.,
RA Couret B., Lorcerie B., Thauvin C., Charbonnier F., Huet F.,
RA Gambert P., Frebourg T., Duvillard L.;
RT "Variable expressivity of the clinical and biochemical phenotype
RT associated with the apolipoprotein E p.Leu149del mutation.";
RL Eur. J. Hum. Genet. 13:1186-1191(2005).
RN [37]
RP VARIANT LPG CYS-43.
RX PubMed=18077821; DOI=10.1056/NEJMc072088;
RA Rovin B.H., Roncone D., McKinley A., Nadasdy T., Korbet S.M.,
RA Schwartz M.M.;
RT "APOE Kyoto mutation in European Americans with lipoprotein
RT glomerulopathy.";
RL N. Engl. J. Med. 357:2522-2524(2007).
RN [38]
RP VARIANT HIS-64, AND MASS SPECTROMETRY.
RX PubMed=22028381; DOI=10.1093/jmcb/mjr024;
RA Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H.,
RA Lin X., Zeng R., Wu J.R.;
RT "Quantitative detection of single amino acid polymorphisms by targeted
RT proteomics.";
RL J. Mol. Cell Biol. 3:309-315(2011).
RN [39]
RP VARIANT HLPP3 SER-154, AND VARIANT LEU-167 DEL.
RX PubMed=22481068; DOI=10.1016/j.atherosclerosis.2012.03.011;
RA Solanas-Barca M., de Castro-Oros I., Mateo-Gallego R., Cofan M.,
RA Plana N., Puzo J., Burillo E., Martin-Fuentes P., Ros E., Masana L.,
RA Pocovi M., Civeira F., Cenarro A.;
RT "Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia
RT and a clinical diagnosis of familial combined hyperlipidemia.";
RL Atherosclerosis 222:449-455(2012).
RN [40]
RP VARIANT FH LEU-167 DEL.
RX PubMed=22949395; DOI=10.1002/humu.22215;
RA Marduel M., Ouguerram K., Serre V., Bonnefont-Rousselot D.,
RA Marques-Pinheiro A., Erik Berge K., Devillers M., Luc G., Lecerf J.M.,
RA Tosolini L., Erlich D., Peloso G.M., Stitziel N., Nitchke P.,
RA Jais J.P., Abifadel M., Kathiresan S., Leren T.P., Rabes J.P.,
RA Boileau C., Varret M.;
RT "Description of a large family with autosomal dominant
RT hypercholesterolemia associated with the APOE p.Leu167del mutation.";
RL Hum. Mutat. 34:83-87(2013).
CC -!- FUNCTION: Mediates the binding, internalization, and catabolism of
CC lipoprotein particles. It can serve as a ligand for the LDL (apo
CC B/E) receptor and for the specific apo-E receptor (chylomicron
CC remnant) of hepatic tissues.
CC -!- INTERACTION:
CC Q16543:CDC37; NbExp=3; IntAct=EBI-1222467, EBI-295634;
CC Q9BQ95:ECSIT; NbExp=4; IntAct=EBI-1222467, EBI-712452;
CC P00738:HP; NbExp=7; IntAct=EBI-1222467, EBI-1220767;
CC Q53EL6:PDCD4; NbExp=3; IntAct=EBI-1222467, EBI-935824;
CC P50502:ST13; NbExp=3; IntAct=EBI-1222467, EBI-357285;
CC O75069:TMCC2; NbExp=5; IntAct=EBI-1222467, EBI-726731;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Occurs in all lipoprotein fractions in plasma.
CC It constitutes 10-20% of very low density lipoproteins (VLDL) and
CC 1-2% of high density lipoproteins (HDL). APOE is produced in most
CC organs. Significant quantities are produced in liver, brain,
CC spleen, lung, adrenal, ovary, kidney and muscle.
CC -!- PTM: Synthesized with the sialic acid attached by O-glycosidic
CC linkage and is subsequently desialylated in plasma. O-glycosylated
CC with core 1 or possibly core 8 glycans. Thr-307 and Thr-314 are
CC minor glycosylation siteS compared to Ser-308.
CC -!- PTM: Glycated in plasma VLDL of normal subjects, and of
CC hyperglycemic diabetic patients at a higher level (2-3 fold).
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- POLYMORPHISM: Three common APOE alleles have been identified:
CC APOE*2, APOE*3, and APOE*4. The corresponding three major
CC isoforms, E2, E3, and E4, are recognized according to their
CC relative position after isoelectric focusing. Different mutations
CC causing the same migration pattern after isoelectric focusing
CC define different isoform subtypes. The most common isoform is E3
CC and is present in 40-90% of the population. Common APOE variants
CC influence lipoprotein metabolism in healthy individuals.
CC -!- DISEASE: Hyperlipoproteinemia 3 (HLPP3) [MIM:107741]: A disorder
CC characterized by the accumulation of intermediate-density
CC lipoprotein particles (IDL or broad-beta-lipoprotein) rich in
CC cholesterol. Clinical features include xanthomas, yellowish lipid
CC deposits in the palmar crease, or less specific on tendons and on
CC elbows. The disorder rarely manifests before the third decade in
CC men. In women, it is usually expressed only after the menopause.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry. The vast majority of the patients are
CC homozygous for APOE*2 alleles. More severe cases of HLPP3 have
CC also been observed in individuals heterozygous for rare APOE
CC variants. The influence of APOE on lipid levels is often suggested
CC to have major implications for the risk of coronary artery disease
CC (CAD). Individuals carrying the common APOE*4 variant are at
CC higher risk of CAD.
CC -!- DISEASE: Alzheimer disease 2 (AD2) [MIM:104310]: A late-onset
CC neurodegenerative disorder characterized by progressive dementia,
CC loss of cognitive abilities, and deposition of fibrillar amyloid
CC proteins as intraneuronal neurofibrillary tangles, extracellular
CC amyloid plaques and vascular amyloid deposits. The major
CC constituent of these plaques is the neurotoxic amyloid-beta-APP
CC 40-42 peptide (s), derived proteolytically from the transmembrane
CC precursor protein APP by sequential secretase processing. The
CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC products such as C31 derived from APP, are also implicated in
CC neuronal death. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry. The
CC APOE*4 allele is genetically associated with the common late onset
CC familial and sporadic forms of Alzheimer disease. Risk for AD
CC increased from 20% to 90% and mean age at onset decreased from 84
CC to 68 years with increasing number of APOE*4 alleles in 42
CC families with late onset AD. Thus APOE*4 gene dose is a major risk
CC factor for late onset AD and, in these families, homozygosity for
CC APOE*4 was virtually sufficient to cause AD by age 80. The
CC mechanism by which APOE*4 participates in pathogenesis is not
CC known.
CC -!- DISEASE: Sea-blue histiocyte disease (SBHD) [MIM:269600]:
CC Characterized by splenomegaly, mild thrombocytopenia and, in the
CC bone marrow, numerous histiocytes containing cytoplasmic granules
CC which stain bright blue with the usual hematologic stains. The
CC syndrome is the consequence of an inherited metabolic defect
CC analogous to Gaucher disease and other sphingolipidoses. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Lipoprotein glomerulopathy (LPG) [MIM:611771]: Uncommon
CC kidney disease characterized by proteinuria, progressive kidney
CC failure, and distinctive lipoprotein thrombi in glomerular
CC capillaries. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Familial hypercholesterolemia (FH) [MIM:143890]: Common
CC autosomal semi-dominant disease that affects about 1 in 500
CC individuals. The receptor defect impairs the catabolism of LDL,
CC and the resultant elevation in plasma LDL-cholesterol promotes
CC deposition of cholesterol in the skin (xanthelasma), tendons
CC (xanthomas), and coronary arteries (atherosclerosis). Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein A1/A4/E family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APOE";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=APOE";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Apolipoprotein E entry;
CC URL="http://en.wikipedia.org/wiki/Apolipoprotein_E";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Tangled - Issue 83 of
CC June 2007;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt083.shtml";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
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DR EMBL; M12529; AAB59518.1; -; mRNA.
DR EMBL; K00396; AAB59546.1; -; mRNA.
DR EMBL; M10065; AAB59397.1; -; Genomic_DNA.
DR EMBL; AF050154; AAD02505.1; -; Genomic_DNA.
DR EMBL; AF261279; AAG27089.1; -; Genomic_DNA.
DR EMBL; AK314898; BAG37412.1; -; mRNA.
DR EMBL; FJ525876; ACN81314.1; -; Genomic_DNA.
DR EMBL; BC003557; AAH03557.1; -; mRNA.
DR EMBL; AB035149; BAA96080.1; -; Genomic_DNA.
DR PIR; A92478; LPHUE.
DR RefSeq; NP_000032.1; NM_000041.2.
DR RefSeq; XP_005258925.1; XM_005258868.1.
DR UniGene; Hs.654439; -.
DR PDB; 1B68; X-ray; 2.00 A; A=19-209.
DR PDB; 1BZ4; X-ray; 1.85 A; A=40-183.
DR PDB; 1EA8; X-ray; 1.95 A; A=19-209.
DR PDB; 1GS9; X-ray; 1.70 A; A=19-183.
DR PDB; 1H7I; X-ray; 1.90 A; A=19-209.
DR PDB; 1LE2; X-ray; 3.00 A; A=41-184.
DR PDB; 1LE4; X-ray; 2.50 A; A=41-184.
DR PDB; 1LPE; X-ray; 2.25 A; A=41-184.
DR PDB; 1NFN; X-ray; 1.80 A; A=19-209.
DR PDB; 1NFO; X-ray; 2.00 A; A=19-209.
DR PDB; 1OEF; NMR; -; A=281-304.
DR PDB; 1OEG; NMR; -; A=285-307.
DR PDB; 1OR2; X-ray; 2.50 A; A=19-183.
DR PDB; 1OR3; X-ray; 1.73 A; A=19-183.
DR PDB; 2KC3; NMR; -; A=19-201.
DR PDB; 2KNY; NMR; -; A=147-167.
DR PDB; 2L7B; NMR; -; A=19-317.
DR PDBsum; 1B68; -.
DR PDBsum; 1BZ4; -.
DR PDBsum; 1EA8; -.
DR PDBsum; 1GS9; -.
DR PDBsum; 1H7I; -.
DR PDBsum; 1LE2; -.
DR PDBsum; 1LE4; -.
DR PDBsum; 1LPE; -.
DR PDBsum; 1NFN; -.
DR PDBsum; 1NFO; -.
DR PDBsum; 1OEF; -.
DR PDBsum; 1OEG; -.
DR PDBsum; 1OR2; -.
DR PDBsum; 1OR3; -.
DR PDBsum; 2KC3; -.
DR PDBsum; 2KNY; -.
DR PDBsum; 2L7B; -.
DR DisProt; DP00355; -.
DR ProteinModelPortal; P02649; -.
DR SMR; P02649; 19-317.
DR DIP; DIP-1120N; -.
DR IntAct; P02649; 19.
DR MINT; MINT-4999641; -.
DR STRING; 9606.ENSP00000252486; -.
DR DrugBank; DB00062; Human Serum Albumin.
DR DrugBank; DB00064; Serum albumin iodonated.
DR PhosphoSite; P02649; -.
DR DMDM; 114039; -.
DR DOSAC-COBS-2DPAGE; P02649; -.
DR SWISS-2DPAGE; P02649; -.
DR PaxDb; P02649; -.
DR PeptideAtlas; P02649; -.
DR PRIDE; P02649; -.
DR DNASU; 348; -.
DR Ensembl; ENST00000252486; ENSP00000252486; ENSG00000130203.
DR GeneID; 348; -.
DR KEGG; hsa:348; -.
DR UCSC; uc002pab.3; human.
DR CTD; 348; -.
DR GeneCards; GC19P045408; -.
DR HGNC; HGNC:613; APOE.
DR HPA; CAB008363; -.
DR MIM; 104310; phenotype.
DR MIM; 107741; gene+phenotype.
DR MIM; 143890; phenotype.
DR MIM; 269600; phenotype.
DR MIM; 611771; phenotype.
DR neXtProt; NX_P02649; -.
DR Orphanet; 238616; Alzheimer disease.
DR Orphanet; 1648; Dementia with Lewy body.
DR Orphanet; 406; Familial hypercholesterolemia.
DR Orphanet; 412; Hyperlipidemia type 3.
DR Orphanet; 329481; Lipoprotein glomerulopathy.
DR Orphanet; 158029; Sea-blue histiocytosis.
DR PharmGKB; PA55; -.
DR eggNOG; NOG44867; -.
DR HOGENOM; HOG000034006; -.
DR HOVERGEN; HBG010582; -.
DR InParanoid; P02649; -.
DR KO; K04524; -.
DR OMA; PLQERAQ; -.
DR OrthoDB; EOG793B87; -.
DR PhylomeDB; P02649; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR ChiTaRS; APOE; human.
DR EvolutionaryTrace; P02649; -.
DR GeneWiki; Apolipoprotein_E; -.
DR GenomeRNAi; 348; -.
DR NextBio; 1435; -.
DR PMAP-CutDB; P02649; -.
DR PRO; PR:P02649; -.
DR ArrayExpress; P02649; -.
DR Bgee; P02649; -.
DR CleanEx; HS_APOE; -.
DR Genevestigator; P02649; -.
DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL.
DR GO; GO:0030425; C:dendrite; NAS:BHF-UCL.
DR GO; GO:0005769; C:early endosome; TAS:Reactome.
DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome.
DR GO; GO:0031232; C:extrinsic to external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0005770; C:late endosome; IEA:Ensembl.
DR GO; GO:0034362; C:low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; NAS:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0016209; F:antioxidant activity; IDA:BHF-UCL.
DR GO; GO:0001540; F:beta-amyloid binding; IDA:UniProtKB.
DR GO; GO:0017127; F:cholesterol transporter activity; IEA:Ensembl.
DR GO; GO:0008201; F:heparin binding; IDA:BHF-UCL.
DR GO; GO:0046848; F:hydroxyapatite binding; IEA:Ensembl.
DR GO; GO:0005319; F:lipid transporter activity; IDA:BHF-UCL.
DR GO; GO:0071813; F:lipoprotein particle binding; IEA:Ensembl.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IDA:BHF-UCL.
DR GO; GO:0046911; F:metal chelating activity; IDA:BHF-UCL.
DR GO; GO:0060228; F:phosphatidylcholine-sterol O-acyltransferase activator activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IDA:BHF-UCL.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0071397; P:cellular response to cholesterol; IEA:Ensembl.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEA:Ensembl.
DR GO; GO:0019934; P:cGMP-mediated signaling; IDA:BHF-UCL.
DR GO; GO:0006707; P:cholesterol catabolic process; IEA:Ensembl.
DR GO; GO:0033344; P:cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IDA:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL.
DR GO; GO:0034382; P:chylomicron remnant clearance; IMP:BHF-UCL.
DR GO; GO:0007010; P:cytoskeleton organization; TAS:UniProtKB.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0034380; P:high-density lipoprotein particle assembly; IDA:BHF-UCL.
DR GO; GO:0034384; P:high-density lipoprotein particle clearance; IDA:BHF-UCL.
DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IGI:BHF-UCL.
DR GO; GO:0046907; P:intracellular transport; TAS:UniProtKB.
DR GO; GO:0042158; P:lipoprotein biosynthetic process; IEA:Ensembl.
DR GO; GO:0042159; P:lipoprotein catabolic process; IEA:Ensembl.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; IEA:Ensembl.
DR GO; GO:0051651; P:maintenance of location in cell; IEA:Ensembl.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0045541; P:negative regulation of cholesterol biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IC:BHF-UCL.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0010544; P:negative regulation of platelet activation; IDA:BHF-UCL.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IDA:BHF-UCL.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IEA:Ensembl.
DR GO; GO:0014012; P:peripheral nervous system axon regeneration; IEA:Ensembl.
DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0045773; P:positive regulation of axon extension; IEA:Ensembl.
DR GO; GO:0030828; P:positive regulation of cGMP biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0010873; P:positive regulation of cholesterol esterification; IDA:BHF-UCL.
DR GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IDA:BHF-UCL.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL.
DR GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; IDA:BHF-UCL.
DR GO; GO:0006898; P:receptor-mediated endocytosis; IDA:BHF-UCL.
DR GO; GO:0030516; P:regulation of axon extension; TAS:UniProtKB.
DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; TAS:UniProtKB.
DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0032868; P:response to insulin stimulus; IEA:Ensembl.
DR GO; GO:0000302; P:response to reactive oxygen species; NAS:UniProtKB.
DR GO; GO:0032526; P:response to retinoic acid; IEA:Ensembl.
DR GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome.
DR GO; GO:0043691; P:reverse cholesterol transport; IDA:BHF-UCL.
DR GO; GO:0007271; P:synaptic transmission, cholinergic; TAS:UniProtKB.
DR GO; GO:0006641; P:triglyceride metabolic process; IDA:BHF-UCL.
DR GO; GO:0042311; P:vasodilation; IEA:Ensembl.
DR GO; GO:0034447; P:very-low-density lipoprotein particle clearance; IDA:BHF-UCL.
DR GO; GO:0034372; P:very-low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR InterPro; IPR000074; ApoA1_A4_E.
DR Pfam; PF01442; Apolipoprotein; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alzheimer disease; Amyloidosis; Cholesterol metabolism;
KW Chylomicron; Complete proteome; Direct protein sequencing;
KW Disease mutation; Glycation; Glycoprotein; HDL; Heparin-binding;
KW Hyperlipidemia; Lipid metabolism; Lipid transport; Neurodegeneration;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat; Secreted;
KW Signal; Steroid metabolism; Sterol metabolism; Transport; VLDL.
FT SIGNAL 1 18
FT CHAIN 19 317 Apolipoprotein E.
FT /FTId=PRO_0000001987.
FT REPEAT 80 101 1.
FT REPEAT 102 123 2.
FT REPEAT 124 145 3.
FT REPEAT 146 167 4.
FT REPEAT 168 189 5.
FT REPEAT 190 211 6.
FT REPEAT 212 233 7.
FT REPEAT 234 255 8.
FT REGION 80 255 8 X 22 AA approximate tandem repeats.
FT REGION 158 168 LDL receptor binding (Potential).
FT REGION 162 165 Heparin-binding.
FT REGION 229 236 Heparin-binding.
FT CARBOHYD 26 26 O-linked (GalNAc...).
FT CARBOHYD 36 36 O-linked (GalNAc...).
FT CARBOHYD 93 93 N-linked (Glc) (glycation).
FT CARBOHYD 212 212 O-linked (GalNAc...).
FT CARBOHYD 307 307 O-linked (GalNAc...).
FT CARBOHYD 308 308 O-linked (GalNAc...).
FT CARBOHYD 314 314 O-linked (GalNAc...).
FT VARIANT 21 21 E -> K (in form E5; associated with
FT hyperlipoproteinemia and
FT atherosclerosis).
FT /FTId=VAR_000645.
FT VARIANT 31 31 E -> K (in HLPP3; form E4 Philadelphia
FT and form E5-type; only form E4
FT Philadelphia is disease-linked;
FT dbSNP:rs201672011).
FT /FTId=VAR_000646.
FT VARIANT 43 43 R -> C (in LPG; form E2 Kyoto).
FT /FTId=VAR_042734.
FT VARIANT 46 46 L -> P (in form E4 Freiburg;
FT dbSNP:rs769452).
FT /FTId=VAR_000647.
FT VARIANT 60 60 T -> A (in form E3 Freiburg;
FT dbSNP:rs28931576).
FT /FTId=VAR_000648.
FT VARIANT 64 64 Q -> H (polymorphism confirmed at protein
FT level).
FT /FTId=VAR_014114.
FT VARIANT 99 99 Q -> K (in form E5 Frankfurt).
FT /FTId=VAR_000649.
FT VARIANT 102 102 P -> R (in form E5-type; no
FT hyperlipidemia; dbSNP:rs28931578).
FT /FTId=VAR_000650.
FT VARIANT 117 117 A -> T (in form E3*; dbSNP:rs28931577).
FT /FTId=VAR_000651.
FT VARIANT 124 124 A -> V (in form E3 Basel).
FT /FTId=VAR_016789.
FT VARIANT 130 130 C -> R (in HLPP3; form E3**, form E4,
FT form E4/3 and some forms E5-type; only
FT form E3** is disease-linked;
FT dbSNP:rs429358).
FT /FTId=VAR_000652.
FT VARIANT 145 145 G -> D (in form E1 Weisgraber).
FT /FTId=VAR_000653.
FT VARIANT 145 145 G -> GEVQAMLG (in HLPP3; form E3 Leiden).
FT /FTId=VAR_000654.
FT VARIANT 152 152 R -> Q (in form E2-type; no
FT hyperlipidemia; dbSNP:rs28931578).
FT /FTId=VAR_000655.
FT VARIANT 154 154 R -> C (in HLPP3; form E2-type).
FT /FTId=VAR_000657.
FT VARIANT 154 154 R -> S (in HLPP3; form E2 Christchurch).
FT /FTId=VAR_000656.
FT VARIANT 160 160 R -> C (in HLPP3; form E3**).
FT /FTId=VAR_000658.
FT VARIANT 163 163 R -> C (in HLPP3; form E4 Philadelphia
FT and form E2-type; only form E4
FT Philadelphia is disease-linked;
FT dbSNP:rs769455).
FT /FTId=VAR_000659.
FT VARIANT 163 163 R -> H (in E3 Kochi).
FT /FTId=VAR_000660.
FT VARIANT 163 163 R -> P (in LPG; form E2 Sendai).
FT /FTId=VAR_042735.
FT VARIANT 164 164 K -> E (in HLPP3; form E1 Harrisburg).
FT /FTId=VAR_000662.
FT VARIANT 164 164 K -> Q (in HLPP3; form E2**).
FT /FTId=VAR_000661.
FT VARIANT 167 167 Missing (in SBHD and FH; also found in
FT patients with a diagnosis of familial
FT combined hyperlipidemia).
FT /FTId=VAR_035015.
FT VARIANT 170 170 A -> P (in form E3*).
FT /FTId=VAR_000663.
FT VARIANT 176 176 R -> C (in HLPP3; forms E1 Weisgraber,
FT form E2 and form E3**; dbSNP:rs7412).
FT /FTId=VAR_000664.
FT VARIANT 242 242 R -> Q (in form E2 Fukuoka).
FT /FTId=VAR_000665.
FT VARIANT 246 246 R -> C (in form E2 Dunedin).
FT /FTId=VAR_000666.
FT VARIANT 254 254 V -> E (in form E2 W.G.).
FT /FTId=VAR_000667.
FT VARIANT 262 263 EE -> KK (in HLPP3; form E7 Suita).
FT /FTId=VAR_000668.
FT VARIANT 269 269 R -> G (in form E3 H.B. and isoform E4/
FT 3).
FT /FTId=VAR_000669.
FT VARIANT 270 270 L -> E (in form E1 H.E.; requires 2
FT nucleotide substitutions).
FT /FTId=VAR_000670.
FT VARIANT 292 292 R -> H (in form E4 P.D.).
FT /FTId=VAR_000671.
FT VARIANT 314 314 S -> R (in form E4 H.G.;
FT dbSNP:rs28931579).
FT /FTId=VAR_000672.
FT STRAND 22 24
FT HELIX 31 39
FT TURN 40 42
FT HELIX 43 60
FT HELIX 63 70
FT HELIX 73 96
FT TURN 97 99
FT HELIX 106 141
FT TURN 143 145
FT HELIX 149 179
FT TURN 180 182
FT TURN 187 190
FT HELIX 193 198
FT STRAND 200 202
FT HELIX 209 217
FT HELIX 228 241
FT HELIX 257 283
FT HELIX 286 303
FT STRAND 307 309
SQ SEQUENCE 317 AA; 36154 MW; 91AFC04210A30689 CRC64;
MKVLWAALLV TFLAGCQAKV EQAVETEPEP ELRQQTEWQS GQRWELALGR FWDYLRWVQT
LSEQVQEELL SSQVTQELRA LMDETMKELK AYKSELEEQL TPVAEETRAR LSKELQAAQA
RLGADMEDVC GRLVQYRGEV QAMLGQSTEE LRVRLASHLR KLRKRLLRDA DDLQKRLAVY
QAGAREGAER GLSAIRERLG PLVEQGRVRA ATVGSLAGQP LQERAQAWGE RLRARMEEMG
SRTRDRLDEV KEQVAEVRAK LEEQAQQIRL QAEAFQARLK SWFEPLVEDM QRQWAGLVEK
VQAAVGTSAA PVPSDNH
//

MIM 104310
*RECORD*
*FIELD* NO
104310
*FIELD* TI
#104310 ALZHEIMER DISEASE 2
;;AD2;;
ALZHEIMER DISEASE 2, LATE-ONSET;;
ALZHEIMER DISEASE ASSOCIATED WITH APOE4
read more*FIELD* TX
A number sign (#) is used with this entry because of the association of
the apolipoprotein E (107741) E4 allele with Alzheimer disease (AD).

For a general phenotypic description and a discussion of genetic
heterogeneity of Alzheimer disease, see 104300.

CLINICAL FEATURES

Using positron emission tomography (PET), Reiman et al. (1996) found
that 11 cognitively normal subjects aged 50 to 65 years who were
homozygous for the APOE4 allele had reduced glucose metabolism in the
same regions of the brain as patients with probable Alzheimer disease.
The affected areas included temporal, parietal, posterior cingulate, and
prefrontal regions. These findings provided preclinical evidence that
the presence of the APOE4 allele is a risk factor for Alzheimer disease.
Reiman et al. (1996) suggested that PET may offer a relatively rapid way
of testing treatments to prevent Alzheimer disease in the future.

Reiman et al. (2001) found that 10 cognitively normal apoE4
heterozygotes aged 50 to 63 years also had abnormally low measurements
of the cerebral metabolic rate for glucose in the same regions as AD
patients. Over a period of 2 years, the E4 heterozygotes had declines in
several regions, including temporal, posterior cingulate, prefrontal
cortex, basal forebrain, parahippocampal gyrus, and thalamus. These
declines were significantly greater than those of 15 non-E4 carriers.

Using PET scans, Reiman et al. (2004) found that 12 young adult
volunteers, ranging in age from 20 to 39 years, who were heterozygous
for the apoE4 allele had abnormally low rates of glucose metabolism
bilaterally in the posterior cingulate, parietal, temporal, and
prefrontal cortex. Reiman et al. (2004) concluded that carriers of the
E4 allele have brain abnormalities in young adulthood, several decades
before the possible onset of dementia.

Rippon et al. (2006) examined potential modifying risk factors for
familial AD in a Latino population comprising 778 AD patients from 350
families. The population was primarily from the Dominican Republic and
Puerto Rico and had been previously studied by Romas et al. (2002). The
APOE E4 allele was associated with a nearly 2-fold increased risk of AD,
a history of stroke (601367) was associated with a 4-fold increase, and
a statistical interaction between APOE E4 and stroke was observed. Women
with the E4 allele who were on estrogen replacement therapy did not have
an increased risk of AD, but in women with a history of stroke, estrogen
therapy was a deleterious effect modifier. Among risk factors, diabetes
mellitus, myocardial infarction, head injury, hypertension, and smoking
were not associated with AD.

Among 100 patients with AD, van der Flier et al. (2006) found an
association between presence of the E4 allele and the typical amnestic
phenotype, characterized by initial presentation of forgetfulness and
difficulties with memory. Those with the memory phenotype were 3 times
more likely to carry an E4 allele compared to AD patients who displayed
a nonmemory phenotype, with initial complaints including problems with
calculation, agnosia, and apraxia. The memory phenotype was almost
exclusively observed in homozygous E4 carriers.

Borroni et al. (2007) also reported an association between the memory
phenotype of AD and presence of the E4 allele. Among 319 late-onset AD
patients, 77.6% of E4 allele carriers presented with the memory
phenotype compared to 64.6% of noncarriers.

Wolk et al. (2010) compared the phenotypes of 67 AD patients carrying at
least 1 APOE E4 allele to 24 AD patients without an E4 allele. Both
groups of patients had a cerebrospinal fluid profile consistent with AD.
E4 carriers had significantly greater impairment on measures of memory
retention, whereas noncarriers were more impaired on tests of working
memory, executive control, and lexical access. E4 carriers also had
greater atrophy of the medial temporal lobe and smaller hippocampal
volumes on neuroimaging, whereas noncarriers had greater frontoparietal
atrophy. The findings suggested that APOE genotype may influence
selective regional brain pathology, which in turns reflects phenotypic
variation in the specific cognitive symptoms of AD.

MAPPING

Pericak-Vance et al. (1988) excluded linkage to the AD1 locus on
chromosome 21 (104300) in 13 families with FAD. Pericak-Vance et al.
(1989, 1990) presented evidence for linkage to 2 markers on chromosome
19. When analysis was limited to the affecteds only, a lod score of 2.5
at theta = 0 was obtained for linkage with BCL3 (109560). Pericak-Vance
et al. (1991) found evidence of linkage to chromosome 19 in their
late-onset FAD families, and to chromosome 21 in their early-onset FAD
families. When only affected persons were used in the analysis, a high
lod score was obtained also with ATP1A3 (182350), which maps to
19q12-q13.2.

In a study of 48 kindreds with multiple cases of Alzheimer disease in 2
or more generations and with family age-at-onset means ranging from 41
to 83 years, Schellenberg et al. (1991) found negative lod scores for
those families with onset after age 60, those families with onset before
age 60, and for Volga German families with mean age of onset of 56. The
early-onset non-Volga German families with onset before age 60 had low
positive lod scores. Schellenberg et al. (1991) concluded that the AD
gene on chromosome 21 is not responsible for late-onset FAD nor for the
early-onset FAD represented by the Volga German kindreds.

Of 23 families with FAD, Schellenberg et al. (1992) excluded linkage to
19q in early-onset families, but small positive lod scores were obtained
for late-onset families. Specific linkage to the APOC2 locus (608083)
was excluded in all families.

Sillen et al. (2006) conducted a genomewide linkage study on 188
individuals with AD from 71 Swedish families, using 365 markers (average
intermarker distance 8.97 cM). They performed nonparametric linkage
analyses in the total family material as well as stratified the families
with respect to the presence or absence of APOE4. The results suggested
that the disorder in these families was tightly linked to the APOE
region (19q13). The next highest lod score was to chromosome 5q35, and
no linkage was found to chromosomes 9, 10, and 12.

Harold et al. (2009) undertook a 2-stage genomewide association study of
Alzheimer disease involving 16,000 individuals, which they stated was
the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848
controls), they replicated the established association with the APOE
locus (most significant SNP, dbSNP rs2075650, P = 1.8 x 10(-157)).

MOLECULAR GENETICS

Corder et al. (1993) found that the risk for late-onset AD increased
from 20 to 90% and mean age of onset decreased from 84 to 68 years with
increasing number of APOE*E4 alleles (107741.0016) in 42 families with
late-onset AD. Onset was early in 4 other families tested; 2 had
chromosome 21 APP (104760) mutations and 2 showed linkage to chromosome
14, thus representing AD1 (104300) and AD3 (607822), respectively. The
frequency of APOE*E4 was not elevated in these families or in 12 other
early-onset families. Homozygosity for APOE*E4 was virtually sufficient
alone to cause AD by age 80.

Bray et al. (2004) applied highly quantitative measures of allele
discrimination to cortical RNA from individuals heterozygous for the
APOE E2, E3, and E4 alleles. A small, but significant, increase in the
expression of E4 allele was observed relative to that of the E3 and E2
alleles (P less than 0.0001). Similar differences were observed in brain
tissue from confirmed late-onset Alzheimer disease subjects, and between
cortical regions BA10 (frontopolar) and BA20 (inferior temporal).
Stratification of E4/E3 allelic expression ratios according to
heterozygosity for the -219G-T promoter polymorphism (107741.0030)
revealed significantly lower relative expression of haplotypes
containing the -219T allele (P = 0.02). Bray et al. (2004) concluded
that, in human brain, most of the cis-acting variance in APOE expression
may be accounted for by the E4 haplotype, but there are additional small
cis-acting influences associated with the promoter genotype.

POPULATION GENETICS

Romas et al. (2002) found that both early-onset and late-onset familial
AD occurs in Caribbean Hispanics. In contrast to sporadic AD, late-onset
familial AD among Caribbean Hispanics was strongly associated with
APOE4.

*FIELD* SA
Edwards (1987); Weeks and Lange (1988)
*FIELD* RF
1. Borroni, B.; Di Luca, M.; Padovani, A.: The effect of APOE genotype
on clinical phenotype in Alzheimer disease. Neurology 68: 624 only,
2007.

2. Bray, N. J.; Jehu, L.; Moskvina, V.; Buxbaum, J. D.; Dracheva,
S.; Haroutunian, V.; Williams, J.; Buckland, P. R.; Owen, M. J.; O'Donovan,
M. C.: Allelic expression of APOE in human brain: effects of epsilon
status and promoter haplotypes. Hum. Molec. Genet. 13: 2885-2892,
2004.

3. Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel,
D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.;
Pericak-Vance, M. A.: Gene dose of apolipoprotein E type 4 allele
and the risk of Alzheimer's disease in late onset families. Science 261:
921-923, 1993.

4. Edwards, J. H.: Exclusion mapping. J. Med. Genet. 24: 539-543,
1987.

5. Harold, D.; Abraham, R.; Hollingworth, P.; Sims, R.; Gerrish, A.;
Hamshere, M. L.; Pahwa, J. S.; Moskvina, V.; Dowzell, K.; Williams,
A.; Jones, N.; Thomas, C.; and 74 others: Genome-wide association
study identifies variants at CLU and PICALM associated with Alzheimer's
disease. Nature Genet. 41: 1088-1093, 2009. Note: Erratum: Nature
Genet. 41: 1156 only, 2009.

6. Pericak-Vance, M. A.; Bebout, J. L.; Gaskell, P. C., Jr.; Yamaoka,
L. H.; Hung, W.-Y.; Alberts, M. J.; Walker, A. P.; Bartlett, R. J.;
Haynes, C. A.; Welsh, K. A.; Earl, N. L.; Heyman, A.; Clark, C. M.;
Roses, A. D.: Linkage studies in familial Alzheimer disease: evidence
for chromosome 19 linkage. Am. J. Hum. Genet. 48: 1034-1050, 1991.

7. Pericak-Vance, M. A.; Bebout, J. L.; Haynes, C. A.; Gaskell, P.
C., Jr.; Yamaoka, L. A.; Hung, W.-Y.; Alberts, M. J.; Walker, A. P.;
Bartlett, R. J.; Welsh, K. A.; Earl, N. L.; Heyman, A.; Clark, C.
M.; Roses, A. D.: Linkage studies in familial Alzheimer's disease:
evidence for chromosome 19 linkage. (Abstract) Am. J. Hum. Genet. 47
(suppl.): A194 only, 1990.

8. Pericak-Vance, M. A.; Yamaoka, L. H.; Bebout, J.; Gaskell, P. C.;
Clark, C.; Haynes, C. S.; Earl, N.; Welch, K.; Hung, W.-Y.; Alberts,
M. J.; Heyman, A.; Roses, A. D.: Linkage studies in familial Alzheimer's
disease. (Abstract) Cytogenet. Cell Genet. 51: 1058-1059, 1989.

9. Pericak-Vance, M. A.; Yamaoka, L. H.; Haynes, C. S.; Speer, M.
C.; Haines, J. L.; Gaskell, P. C.; Hung, W.-Y.; Clark, C. M.; Heyman,
A. L.; Trofatter, J. A.; Eisenmenger, J. P.; Gilbert, J. R.; Lee,
J. E.; Alberts, M. J.; Dawson, D. V.; Bartlett, R. J.; Earl, N. L.;
Siddique, T.; Vance, J. M.; Conneally, P. M.; Roses, A. D.: Genetic
linkage studies in Alzheimer's disease families. Exp. Neurol. 102:
271-279, 1988.

10. Reiman, E. M.; Caselli, R. J.; Chen, K.; Alexander, G. E.; Bandy,
D.; Frost, J.: Declining brain activity in cognitively normal apolipoprotein
E epsilon-4 heterozygotes: a foundation for using positron emission
tomography to efficiently test treatments to prevent Alzheimer's disease. Proc.
Nat. Acad. Sci. 98: 3334-3339, 2001.

11. Reiman, E. M.; Caselli, R. J.; Yun, L. S.; Chen, K.; Bandy, D.;
Minoshima, S.; Thibodeau, S. N.; Osborne, D.: Preclinical evidence
of Alzheimer's disease in persons homozygous for the epsilon-4 allele
for apolipoprotein E. New Eng. J. Med. 334: 752-758, 1996.

12. Reiman, E. M.; Chen, K.; Alexander, G. E.; Caselli, R. J.; Bandy,
D.; Osborne, D.; Saunders, A. M.; Hardy, J.: Functional brain abnormalities
in young adults at genetic risk for late-onset Alzheimer's dementia. Proc.
Nat. Acad. Sci. 101: 284-289, 2004.

13. Rippon, G. A.; Tang, M.-X.; Lee, J. H.; Lantigua, R.; Medrano,
M.; Mayeux, R.: Familial Alzheimer disease in Latinos: interaction
between APOE, stroke, and estrogen replacement. Neurology 66: 35-40,
2006.

14. Romas, S. N.; Santana, V.; Williamson, J.; Ciappa, A.; Lee, J.
H.; Rondon, H. Z.; Estevez, P.; Lantigua, R.; Medrano, M.; Torres,
M.; Stern, Y.; Tycko, B.; Mayeux, R.: Familial Alzheimer disease
among Caribbean Hispanics: a reexamination of its association with
APOE. Arch. Neurol. 59: 87-91, 2002.

15. Schellenberg, G. D.; Boehnke, M.; Wijsman, E. M.; Moore, D. K.;
Martin, G. M.; Bird, T. D.: Genetic association and linkage analysis
of the apolipoprotein CII locus and familial Alzheimer's disease. Ann.
Neurol. 31: 223-227, 1992.

16. Schellenberg, G. D.; Pericak-Vance, M. A.; Wijsman, E. M.; Moore,
D. K.; Gaskell, P. C., Jr.; Yamaoka, L. A.; Bebout, J. L.; Anderson,
L.; Welsh, K. A.; Clark, C. M.; Martin, G. M.; Roses, A. D.; Bird,
T. D.: Linkage analysis of familial Alzheimer disease, using chromosome
21 markers. Am. J. Hum. Genet. 48: 563-583, 1991.

17. Sillen, A.; Forsell, C.; Lilius, L.; Axelman, K.; Bjork, B. F.;
Onkamo, P.; Kere, J.; Winblad, B.; Graff, C.: Genome scan on Swedish
Alzheimer's disease families. Molec. Psychiat. 11: 182-186, 2006.

18. van der Flier, W. M.; Schoonenboom, S. N. M.; Pijnenburg, Y. A.
L.; Fox, N. C.; Scheltens, P.: The effect of APOE genotype on clinical
phenotype in Alzheimer disease. Neurology 67: 526-527, 2006.

19. Weeks, D. E.; Lange, K.: The affected-pedigree-member method
of linkage analysis. Am. J. Hum. Genet. 42: 315-326, 1988.

20. Wolk, D. A.; Dickerson, B. C.; Alzheimer's Disease Neuroimaging
Initiative: Apolipoprotein E (APOE) genotype has dissociable effects
on memory and attentional-executive network function in Alzheimer's
disease. Proc. Nat. Acad. Sci. 107: 10256-10261, 2010.

*FIELD* CS

Neuro:
Presenile and senile dementia;
Parkinsonism;
Long tract signs

Misc:
Late onset

Lab:
Neurofibrillary tangles composed of disordered microtubules in neurons

Inheritance:
Autosomal dominant allele (19q) with additional multifactorial component
in late-onset cases

*FIELD* CN
Cassandra L. Kniffin - updated: 3/18/2013
Cassandra L. Kniffin - updated: 8/18/2010
Ada Hamosh - updated: 1/12/2010
Cassandra L. Kniffin - updated: 2/7/2008
Cassandra L. Kniffin - updated: 9/20/2007
George E. Tiller - updated: 5/22/2007
John Logan Black, III - updated: 7/18/2006
Victor A. McKusick - updated: 4/5/2005
Cassandra L. Kniffin - updated: 5/27/2003

*FIELD* CD
Victor A. McKusick: 11/4/1988

*FIELD* ED
carol: 04/02/2013
ckniffin: 3/18/2013
wwang: 8/18/2010
ckniffin: 8/18/2010
alopez: 1/13/2010
terry: 1/12/2010
wwang: 2/25/2008
ckniffin: 2/7/2008
wwang: 9/25/2007
ckniffin: 9/20/2007
wwang: 5/30/2007
terry: 5/22/2007
alopez: 1/29/2007
ckniffin: 7/18/2006
carol: 2/10/2006
ckniffin: 12/28/2005
ckniffin: 12/19/2005
wwang: 4/14/2005
wwang: 4/5/2005
ckniffin: 9/24/2003
ckniffin: 5/28/2003
ckniffin: 5/27/2003
ckniffin: 5/21/2003
dkim: 6/30/1998
carol: 4/6/1994
mimadm: 3/11/1994
carol: 10/4/1993
carol: 9/28/1993
carol: 11/4/1992
supermim: 3/16/1992

MIM 107741
*RECORD*
*FIELD* NO
107741
*FIELD* TI
+107741 APOLIPOPROTEIN E; APOE
APOLIPOPROTEIN E, DEFICIENCY OR DEFECT OF, INCLUDED;;
read moreHYPERLIPOPROTEINEMIA, TYPE III, INCLUDED;;
DYSBETALIPOPROTEINEMIA DUE TO DEFECT IN APOLIPOPROTEIN E-d, INCLUDED;;
FAMILIAL HYPERBETA- AND PREBETALIPOPROTEINEMIA, INCLUDED;;
FAMILIAL HYPERCHOLESTEROLEMIA WITH HYPERLIPEMIA, INCLUDED;;
HYPERLIPEMIA WITH FAMILIAL HYPERCHOLESTEROLEMIC XANTHOMATOSIS, INCLUDED;;
BROAD-BETALIPOPROTEINEMIA, INCLUDED;;
FLOATING-BETALIPOPROTEINEMIA, INCLUDED;;
CORONARY ARTERY DISEASE, SEVERE, SUSCEPTIBILITY TO, INCLUDED;;
LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
5, INCLUDED; LDLCQ5, INCLUDED
*FIELD* TX

DESCRIPTION

- Early Delineation

Utermann et al. (1979) described 2 phenotypes, apoE(IV+) and apoE(IV-),
differentiated by analytical isoelectric focusing. They concluded that
this polymorphism of apolipoprotein E in human serum is determined by 2
autosomal codominant alleles, apoE(n) and apoE(d). Homozygosity for the
latter results in primary dysbetalipoproteinemia but only some persons
develop gross hyperlipidemia (hyperlipoproteinemia type III). Vertical
transmission is pseudodominance due to high frequency of the apoE(d)
gene (Utermann et al., 1979). Dysbetalipoproteinemia is already
expressed in childhood. They concluded that primary
dysbetalipoproteinemia is a frequent monogenic variant of lipoprotein
metabolism, but not a disease. Coincidence of the genes for this
dyslipoproteinemia with any of the genes for monogenic or polygenic
forms of familial hyperlipemia results in hyperlipoproteinemia type III.
Further complexities of the genetics of the apolipoprotein E system were
discussed by Utermann et al. (1980). Apolipoprotein E (apoE) of very low
density lipoprotein (VLDL) from different persons shows 1 of 2 complex
patterns, termed alpha and beta (Zannis et al., 1981). Three subclasses
of each pattern were found and designated alpha-II, alpha-III and
alpha-IV and beta-II, beta-III and beta-IV. From family studies, Zannis
et al. (1981) concluded that a single locus with 3 common alleles is
responsible for these patterns. The alleles were designated epsilon-II,
-III, and-IV. The authors further concluded that beta class phenotypes
represent homozygosity for one of the epsilon alleles, e.g., beta-II
results from homozygosity for the epsilon-II allele. In contrast, the
alpha phenotypes are thought to represent compound heterozygosity, i.e.,
heterozygosity for 2 different epsilon alleles: alpha II from epsilon II
and III; alpha III from epsilon III and IV. The frequency of the epsilon
II, III, and IV alleles was estimated at 0.11, 0.72, and 0.17,
respectively. ApoE subclass beta-IV was found to be associated with type
III hyperlipoproteinemia. Rall et al. (1982) published the full amino
acid sequence. Mature apoE is a 299-amino acid polypeptide.

- Molecular Basis of Polymorphism

The 3 major isoforms of human apolipoprotein E (apoE2, -E3, and -E4), as
identified by isoelectric focusing, are coded for by 3 alleles (epsilon
2, 3, and 4). The E2 (107741.0001), E3 (107741.0015), and E4
(107741.0016) isoforms differ in amino acid sequence at 2 sites, residue
112 (called site A) and residue 158 (called site B). At sites A/B,
apoE2, -E3, and -E4 contain cysteine/cysteine, cysteine/arginine, and
arginine/arginine, respectively (Weisgraber et al., 1981; Rall et al.,
1982). The 3 forms have 0, 1+, and 2+ charges to account for
electrophoretic differences (Margolis, 1982). (The nomenclature of the
apolipoprotein E isoforms, defined by isoelectric focusing, has gone
through an evolution.) E3 is the most frequent ('wildtype') isoform. As
reviewed by Smit et al. (1990), E4 differs from E3 by a cys-to-arg
change at position 112 and is designated E4(cys112-to-arg). Four
different mutations giving a band at the E2 position with isoelectric
focusing have been described: E2(arg158-to-cys), E2(lys146-to-gln),
E2(arg145-to-cys) and E2-Christchurch(arg136-to-ser). E2(arg158-to-cys)
is the most common of the 4.

In a comprehensive review of apoE variants, de Knijff et al. (1994)
found that 30 variants had been characterized, including the most common
variant, apoE3. To that time, 14 apoE variants had been found to be
associated with familial dysbetalipoproteinemia, characterized by
elevated plasma cholesterol and triglyceride levels and an increased
risk for atherosclerosis.

Data on gene frequencies of apoE allelic variants were tabulated by
Roychoudhury and Nei (1988). Gerdes et al. (1992) and Gerdes et al.
(1996) reported the frequency of apoE polymorphisms in the Danish
population and in Greenland Inuit, respectively, in relation to the
findings in 45 other study populations around the world.

- Role of APOE in Abnormalities of Blood Lipids and in Cardiovascular
Disease

In normal individuals, chylomicron remnants and very low density
lipoprotein (VLDL) remnants are rapidly removed from the circulation by
receptor-mediated endocytosis in the liver. In familial
dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III),
increased plasma cholesterol and triglycerides are the consequence of
impaired clearance of chylomicron and VLDL remnants because of a defect
in apolipoprotein E. Accumulation of the remnants can result in
xanthomatosis and premature coronary and/or peripheral vascular disease.
Hyperlipoproteinemia III can be either due to primary heritable defects
in apolipoprotein metabolism or secondary to other conditions such as
hypothyroidism, systemic lupus erythematosus, or diabetic acidosis. Most
patients with familial dysbetalipoproteinemia (HLP III) are homozygous
for the E2 isoform (Breslow et al., 1982). Only rarely does the disorder
occur with the heterozygous phenotypes E3E2 or E4E2. The E2 isoform
shows defective binding of remnants to hepatic lipoprotein receptors
(Schneider et al., 1981; Rall et al., 1982) and delayed clearance from
plasma (Gregg et al., 1981). Additional genetic and/or environmental
factors must be required for development of the disorder, however,
because only 1-4% of E2E2 homozygotes develop familial
dysbetalipoproteinemia. Since the defect in this disorder involves the
exogenous cholesterol transport system, the degree of
hypercholesterolemia is sensitive to the level of cholesterol in the
diet (Brown et al., 1981). Even on a normal diet, the patient may show
increased plasma cholesterol and the presence of an abnormal lipoprotein
called beta-VLDL. VLDL in general is markedly increased while LDL is
reduced. Carbohydrate induces or exacerbates the hyperlipidemia,
resulting in marked variability in plasma levels and ready therapy
through dietary means. Often tuberous and planar and sometimes tendon
xanthomas occur as well as precocious atherosclerosis and abnormal
glucose tolerance. Tuberous and tuberoeruptive xanthomas are
particularly characteristic. Hazzard (1978) demonstrated the eliciting
effects of electric shock in a man revived from accidental electrocution
and later showing striking xanthomas of the palms. Development of the
phenotype is age dependent, being rarely evident before the third
decade. The nosography of the type III hyperlipoproteinemia phenotype up
to 1977 was reviewed by Levy and Morganroth (1977). Subsequent
description of specific biochemical alterations in apolipoprotein
structure and metabolism has proven this phenotype to be genetically
heterogeneous. In the first application of apoprotein immunoassay to
this group of disorders, Kushwaha et al. (1977) found that
apolipoprotein E (arginine-rich lipoprotein) is high in the VLD
lipoproteins of type III. They also found that exogenous estrogen, which
stimulates triglyceride production in normal women and those with
endogenous hypertriglyceridemia, exerted a paradoxical
hypotriglyceridemic effect in this disorder (Kushwaha et al., 1977). The
abnormal pattern of apoE by isoelectric focusing (IEF), specifically,
the absence of apoE3, is the most characteristic biochemical feature of
HLP III. Gregg et al. (1981) showed that apoE isolated from subjects
with type III HLP had a decreased fractional catabolic rate in vivo in
both type III HLP patients and normal persons.

Hazzard et al. (1981) reported on the large O'Donnell kindred, studied
because of a proband with type III HLP. They studied specifically the
VLDL isoapolipoprotein E distributions. The findings confirmed earlier
work indicating that the ratio of E3 to E2 is determined by two apoE3
alleles, designated d and n, which produce 3 phenotypes, apoE3-d,
apoE3-nd, and apoE3-n, corresponding to the low, intermediate, and high
ratios.

Ghiselli et al. (1981) studied a black kindred with type III HLP due to
deficiency of apolipoprotein E. No plasma apolipoprotein E could be
detected. Other families with type III HLP have had increased amounts of
an abnormal apoE. In addition, the patients of Ghiselli et al. (1981)
had only mild hypertriglyceridemia, increased LDL cholesterol, and a
much higher ratio of VLDL cholesterol to plasma triglyceride than
reported in other type III HLP families. The proband was a 60-year-old
woman with a 10-year history of tuberoeruptive xanthomas of the elbows
and knees, a 3-year history of angina pectoris, and 80% narrowing of the
first diagonal coronary artery by arteriography. Her father had
xanthomas and died at age 62 of myocardial infarction. Her mother was
alive and well at age 86. Three of 7 sibs also had xanthomas; her 2
offspring had no xanthomas. The evidence suggests that apoE is important
for the catabolism of chylomicron fragments. The affected persons in the
family studied by Ghiselli et al. (1981) had plasma levels of apoE less
than 0.05 mg/dl by radioimmunoassay, and no structural variants of apoE
were detected by immunoblot of plasma or VLDL separated by 2-dimensional
gel electrophoresis. Anchors et al. (1986) reported that the apoE gene
was present in the apoE-deficient patient and that there were no major
insertions or deletions in the gene by Southern blot analysis. Blood
monocyte-macrophages isolated from a patient contained levels of apoE
mRNA 1 to 3% of that present in monocyte-macrophages isolated from
normal subjects. The mRNA from the patient appeared to be of normal
size. Anchors et al. (1986) suggested that the decreased apoE mRNA might
be due to a defect in transcription or processing of the primary
transcript or to instability of the apoE mRNA. The decreased plasma
level of apoE resulted in delayed clearance of remnants of
triglyceride-rich lipoproteins, hyperlipidemia, and the phenotype of
type III HLP. In the kindred with apolipoprotein E deficiency studied by
Ghiselli et al. (1981), the defect was shown by Cladaras et al. (1987)
to involve an acceptor splice site mutation in intron 3 of the APOE gene
(107741.0005).

ApoE, a main apoprotein of the chylomicron, binds to a specific receptor
on liver cells and peripheral cells. The E2 variant binds less readily.
A defect in the receptor for apoE on liver and peripheral cells might
also lead to dysbetalipoproteinemia, but such has not been observed.
Weisgraber et al. (1982) showed that human E apoprotein of the E2 form,
which contains cysteine (rather than arginine) at both of the 2 variable
sites, binds poorly with cell surface receptors, whereas E3 and E4 bind
well. They postulated that a positively charged residue at variable site
B is important for normal binding. To test the hypothesis, they treated
E2 apoE with cysteamine to convert cysteine to a positively charged
lysine analog. This resulted in a marked increase in the binding
activity of the E2 apoE. Although nearly every type III
hyperlipoproteinemic person has the E2/E2 phenotype, 95 to 99% of
persons with this phenotype do not have type III HLP nor do they have
elevated plasma cholesterol levels. Rall et al. (1983) showed that apoE2
of hypo-, normo-, and hypercholesterolemic subjects showed the same
severe functional abnormalities. Thus, factors in addition to the
defective receptor binding activity of the apoE2 are necessary for
manifestation of type III HLP. A variety of factors exacerbate or
modulate type III. In women, it most often occurs after the menopause
and in such patients is particularly sensitive to estrogen therapy.
Hypothyroidism exacerbates type III and thyroid hormone is known to
enhance receptor-mediated lipoprotein metabolism. Obesity, diabetes, and
age are associated with increased hepatic synthesis of VLDL and/or
cholesterol; occurrence of type III in E2/E2 persons with these factors
may be explained thereby. Furthermore, the defect in familial combined
HLP (144250), which is, it seems, combined with E2/E2 in the production
of type III (Utermann et al., 1979; Hazzard et al., 1981), may be
hepatic overproduction of cholesterol and VLDL. As pointed out by Brown
and Goldstein (1983), familial hypercholesterolemia (FH) is a genetic
defect of the LDL receptor (LDLR; 606945), whereas familial
dysbetalipoproteinemia is a genetic defect in a ligand. The puzzle that
all apoE2/2 homozygotes do not have extremely high plasma levels of IDL
and chylomicron remnants (apoE-containing lipoproteins) may be solved by
the observation that the lipoprotein levels in these patients are
exquisitely sensitive to factors that reduce hepatic LDL receptors,
e.g., age, decreased levels of thyroid hormone and estrogen, and the
genetic defect of FH. Presumably, high levels of hepatic LDL receptors
can compensate for the genetic binding defect of E2 homozygotes.

Gregg et al. (1983) suggested that apoE4 is associated with severe type
V hyperlipoproteinemia (144650) in a manner comparable to the
association of apoE2 with type III. Vogel et al. (1985) showed that
large amounts of apoE can be produced by E. coli transformed with a
plasmid containing a human apoE cDNA. The use in studies of
structure-function relationships through production of site-specific
mutants was noted. Wardell et al. (1989) demonstrated that the defect is
a 7-amino acid insertion that represents a tandem repeat of amino acid
residues 121-127 resulting in the normal protein having 306 amino acids
rather than the normal 299. Schaefer et al. (1986) described a unique
American black kindred with premature cardiovascular disease,
tuberoeruptive xanthomas, and type III HLP associated with familial
apolipoprotein E deficiency. Four homozygotes had marked increases in
cholesterol-rich, very low density lipoproteins and intermediate density
lipoproteins (IDL). Homozygotes had only trace amounts of plasma apoE,
and accumulations of apoB-48 (107730) and apoA-4 (107690) in VLDL, IDL,
and low density lipoproteins. Obligate heterozygotes generally had
normal plasma lipids and mean plasma apoE concentrations that were 42%
of normal. The findings indicated that apoE is essential for the normal
catabolism of triglyceride-rich lipoprotein constituents. It had been
shown that cultured peripheral blood monocytes synthesized low amounts
of 2 aberrant forms of apoE mRNA but produced no immunoprecipitable
forms of apoE. The expression studies were done comparing the normal and
abnormal APOE genes transfected into mouse cells in combination with the
mouse metallothionein I promoter. Bersot et al. (1983) studied atypical
dysbetalipoproteinemia characterized by severe hypercholesterolemia and
hypertriglyceridemia, xanthomatosis, premature vascular disease, the
apoE3/3 phenotype (rather than the classic E2/2 phenotype), and a
preponderance of beta-VLDL. They showed that the beta-VLDL from these
subjects stimulated cholesteryl ester accumulation in mouse peritoneal
macrophages. They suggested that the accelerated vascular disease
results from this uptake by macrophages which are converted into the
foam cells of atherosclerotic lesions. Smit et al. (1987) described 3
out of 41 Dutch dysbetalipoproteinemic patients who were apparent E3/E2
heterozygotes rather than the usual E2/E2 homozygotes. All 3 genetically
unrelated patients showed an uncommon E2 allele that contained only 1
cysteine residue. The uncommon allele cosegregated with familial
dysbetalipoproteinemia which in these families seemed to behave as a
dominant. Smit et al. (1990) showed that these 3 unrelated patients had
E2(lys146-to-gln). Eto et al. (1989) presented data from Japan
indicating that both the E2 allele and the E4 allele are associated with
an increased risk of ischemic heart disease as compared with the E3
allele. Boerwinkle and Utermann (1988) studied the simultaneous effect
of apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B,
and cholesterol metabolism. Since both apoB and apoE bind to the LDL
receptor and since the different isoforms show different binding
affinity, these effects are not unexpected.

Subjects with typical dysbetalipoproteinemia are homozygous for an amino
acid substitution in apoE at residue 158 (107741.0001). Chappell (1989)
studied the binding properties of lipoproteins in 9 subjects with
dysbetalipoproteinemia who were either homozygous or heterozygous for
substitutions at atypical sites: at residue 142 in 6, at 145 in 2, and
at 146 in 1.

In 5 of 19 Australian men, aged 30 to 50, who were referred for coronary
angioplasty (26%), van Bockxmeer and Mamotte (1992) observed
homozygosity for E4. This represented a 16-fold increase compared with
controls. Payne et al. (1992), O'Malley and Illingworth (1992), and de
Knijff et al. (1992) expressed doubts concerning a relationship between
E4 and atherosclerosis.

In a case-control study of 338 centenarians compared with adults aged 20
to 70 years of age, Schachter et al. (1994) found that the E4 allele of
apoE, which promotes premature atherosclerosis, was significantly less
frequent in centenarians than in controls (p = less than 0.001), while
the frequency of the E2 allele, associated previously with types III and
IV hyperlipidemia, was significantly increased (p = less than 0.01).

Feussner et al. (1996) reported a 20-year-old man with a combination of
type III hyperlipoproteinemia and heterozygous familial
hypercholesterolemia (FH; 143890). Multiple xanthomas were evident on
the elbows, interphalangeal joints and interdigital webs of the hands.
Lipid-lowering therapy caused significant decrease of cholesterol and
triglycerides as well as regression of the xanthomas. Flat xanthomas of
the interdigital webs were also described in 3 out of 4 previously
reported patients with combination of these disorders of lipoprotein
metabolism. Feussner et al. (1996) stated that these xanthomas may
indicate compound heterozygosity (actually double heterozygosity) for
type III hyperlipoproteinemia and FH.

To study the effect of birth weight on apoE genetic determinants of
circulating lipid levels, Garces et al. (2002) evaluated apoE genotypes
and plasma lipid and apolipoprotein concentrations in 933 children (491
males and 442 females), aged 6 to 8 years (mean 6.7 years), with known
birth weights. A greater effect of the apoE polymorphism on total
cholesterol (TC), LDL cholesterol (LDL-C), and apoB levels was found in
the lower tertile than in the upper tertiles of birth weight in both
genders. A decrease in TC, LDL-C and apoB associated with the E2 allele
became more marked the lower the birth weight and could be explained by
the significant positive interaction between birth weight and the E2
allele shown by linear regression analysis. Garces et al. (2002)
suggested that the interaction of apoE genotype and birth weight may be
an important determinant for atherosclerosis.

In 802 patients undergoing transthoracic echocardiography, Novaro et al.
(2003) evaluated the association between apoE alleles and calcific
valvular lesions of the heart. The authors found that the genotype
distribution of patients with aortic stenosis (AS) differed
significantly from those without AS (p = 0.03), with increasing
prevalences of the apoE4 allele (27% in those without vs 40% in those
with AS, p = 0.01). In multivariate analyses adjusting for age, gender,
LDL cholesterol levels, and coronary artery disease, increasing age and
the apoE4 allele were significant predictors of AS (OR = 1.94, 95% CI =
1.01-3.71, p = 0.046). There was no difference in genotype distribution
or prevalence of apoE4 between those with or without mitral annular
calcification, however, and the apoE4 allele was not predictive of
mitral annular calcification.

Witsch-Baumgartner et al. (2004) determined common APOE and DHCR7
(602858) genotypes in 137 unrelated patients with Smith-Lemli-Opitz
syndrome (270400) and 108 of their parents (59 mothers and 49 fathers).
There was a significant correlation between patients' clinical severity
scores and maternal APOE genotypes (p = 0.028) but not between severity
scores and patients' or paternal APOE genotypes. Presence of the
maternal APOE2 allele was associated with a more severe phenotype, and
the association persisted after stratification for DHCR7 genotype.
Witsch-Baumgartner et al. (2004) suggested that the efficiency of
cholesterol transport from the mother to the embryo is affected by
maternal APOE genotype, and that APOE plays a role in modulation of
embryonic development and malformations.

Frikke-Schmidt et al. (2007) presented evidence that combinations of
SNPs in APOE and LPL (609708) identify subgroups of individuals at
substantially increased risk of ischemic heart disease beyond that
associated with smoking, diabetes, and hypertension.

Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from
the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9
SNPs, including dbSNP rs4420638 of APOE, had previously been associated
with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the
associations with each SNP and created a genotype score on the basis of
the number of unfavorable alleles. With increasing genotype scores, the
level of LDL cholesterol increased, whereas the level of HDL cholesterol
decreased. At 10-year follow-up, the genotype score was found to be an
independent risk factor for incident cardiovascular disease (myocardial
infarction, ischemic stroke, or death from coronary heart disease); the
score did not improve risk discrimination but modestly improved clinical
risk reclassification for individual subjects beyond standard clinical
factors.

Among 1,383 Scottish adult patients with diabetes taking statin
medication to reduce serum LDL cholesterol levels, Donnelly et al.
(2008) found an association of APOE genotype with both baseline and
treatment responses. E2 homozygotes achieved significantly lower LDL
levels compared to E4 homozygotes (mean 0.6 versus 1.7 mmol/L; p = 2.96
x 10(-12)). All E2 homozygotes reached the target serum LDL level,
compared to 32% of E4 homozygotes who did not (p = 5.3 x 10(-5)). The
findings indicated that APOE genotype may be an important marker for
clinical responses to statin drugs.

- Role in Immunologic Response

Van den Elzen et al. (2005) defined the pathways mediating markedly
efficient exogenous lipid antigen delivery by apolipoproteins to achieve
T-cell activation. Apolipoprotein E binds lipid antigens and delivers
them by receptor-mediated uptake into endosomal compartments containing
CD1 (e.g., 188370) in antigen-presenting cells. Apolipoprotein E
mediates the presentation of serum-borne lipid antigens and can be
secreted by antigen-presenting cells as a mechanism to survey the local
environment to capture antigens or to transfer microbial lipids from
infected cells to bystander antigen-presenting cells. Thus, van den
Elzen et al. (2005) concluded that the immune system has co-opted a
component of lipid metabolism to develop immunologic responses to lipid
antigens.

- Role in Alzheimer Disease

Saunders et al. (1993) reported an increased frequency of the E4 allele
in a small prospective series of possible-probable AD patients
presenting to the memory disorders clinic at Duke University, in
comparison with spouse controls. Corder et al. (1993) found that the
APOE*E4 allele is associated with the late-onset familial and sporadic
forms of Alzheimer disease. In 42 families with the late-onset form of
Alzheimer disease (AD2; 104310), the gene had been mapped to the same
region of chromosome 19 as the APOE gene. Corder et al. (1993) found
that the risk for AD increased from 20 to 90% and mean age of onset
decreased from 84 to 68 years with increasing number of APOE*E4 alleles.
Homozygosity for APOE*E4 was virtually sufficient to cause AD by age 80.

Lannfelt et al. (1995) compared allelic frequency of apolipoprotein E4
in 13 dizygotic twin pairs discordant for Alzheimer disease and found
the expected increased frequency of the epsilon-4 allele in Alzheimer
compared to healthy cotwins. In a well-known American kindred with
late-onset Alzheimer disease, descended from a couple who immigrated to
the United States from France in the 18th century, Borgaonkar et al.
(1993) found evidence confirming a dosage effect of the E4 allele of 6
affected individuals; 4 E4/E4 homozygotes had onset in their 60s,
whereas 2 E4/E3 heterozygotes had onset at ages 77 and 78, respectively.
Apolipoprotein E is found in senile plaques, congophilic angiopathy, and
neurofibrillary tangles of Alzheimer disease. Strittmatter et al. (1993)
compared the binding of synthetic amyloid beta peptide to purified APOE4
and APOE3, the most common isoforms. Both isoforms in oxidized form
bound the amyloid beta peptide; however, binding to APOE4 was observed
in minutes, whereas binding to APOE3 required hours. Strittmatter et al.
(1993) concluded that binding of amyloid beta peptide by oxidized apoE
may determine their sequestration and that isoform-specific differences
in apoE binding or oxidation may be involved in the pathogenesis of the
lesions of Alzheimer disease.

In a study of 91 patients with sporadic Alzheimer disease and 74
controls, Poirier et al. (1993) found a significant association between
E4 and sporadic AD. The association was more pronounced in women. Scott
(1993) pointed to the need for caution in the application of knowledge
gained through screening of E4 in relation to this very common disorder.

Talbot et al. (1994) presented data suggesting that the E2 allele may
confer protection against Alzheimer disease and that its effect is not
simply the absence of an E4 allele. Corder et al. (1994) presented data
demonstrating a protective effect of the E2 allele, in addition to the
dosage effect of the E4 allele in sporadic AD. Although a substantial
proportion (65%) of AD is attributable to the presence of E4 alleles,
risk of AD is lowest in subjects with the E2/E3 genotype, with an
additional 23% of AD attributable to the absence of an E2 allele. The
opposite actions of the E2 and E4 alleles were interpreted by Corder et
al. (1994) to provide further support for the direct involvement of APOE
in the pathogenesis of AD.

Sanan et al. (1994) demonstrated that the E4 isoform binds to the beta
amyloid (A-beta) peptide more rapidly than the E3 isoform. Soluble
SDS-stable complexes of E3 or E4, formed by coincubation with the A-beta
peptide, precipitated after several days of incubation at 37 degrees C,
with E4 complexes precipitating more rapidly than E3 complexes.

Hyman et al. (1996) demonstrated homozygosity for the E4 genotype in an
86-year-old man with no history of neurologic disease and whose autopsy
did not reveal any neurofibrillary tangles and only rare mature senile
plaques. This suggested to the authors that inheritance of apoE4 does
not necessarily result in the development of dementia or Alzheimer
disease.

Myers et al. (1996) examined the association of apolipoprotein E4 with
Alzheimer disease and other dementias in 1,030 elderly individuals in
the Framingham Study cohort. They found an increased risk for Alzheimer
disease as well as other dementias in patients who were homozygous or
heterozygous for E4. However they pointed out that most apoE4 carriers
do not develop dementia and about one-half of Alzheimer disease is not
associated with apoE4.

Kawamata et al. (1994) examined the E4 frequency in 40 patients with
late-onset sporadic Alzheimer disease, 13 patients with early-onset
sporadic Alzheimer disease, 19 patients with vascular dementia, and 49
nondemented control subjects. In the late-onset sporadic Alzheimer
group, the allele frequency was 0.25, considerably higher than the
frequency in controls, 0.09. In contrast, there was no increased
frequency in early-onset sporadic Alzheimer disease or in patients with
vascular dementia. Olichney et al. (1996) found that the apolipoprotein
E4 allele is strongly associated with increased neuritic plaques but not
neocortical or fibrillary tangles in both Alzheimer disease and the Lewy
body variant.

Kawamata et al. (1994) speculated that the lower magnitude of the raised
frequency of E4 in the Japanese group compared to that of North American
families may be due to a lower E4 frequency in the normal Japanese
population and lower morbidity from Alzheimer disease in Japan.
Nalbantoglu et al. (1994) performed apolipoprotein analysis on 113
postmortem cases of sporadic Alzheimer disease and 77 control brains in
Montreal. In this population, the odds ratio associating E4 with
Alzheimer disease was 15.5 and the population attributable risk was
0.53. Yoshizawa et al. (1994) examined the apolipoprotein genotypes in
83 Japanese patients with Alzheimer disease. They found a significant
increase in apoE4 frequency in late-onset sporadic Alzheimer disease and
a mild increase of apoE4 frequency in late- and early-onset familial
Alzheimer disease. In contrast, they found no association between apoE4
and early-onset sporadic Alzheimer disease.

Lucotte et al. (1994) examined the apoE4 frequency in 132 French
patients with onset of Alzheimer disease after 60 years of age. They
found that homozygosity for the E4 allele was associated with a younger
age of disease occurrence than was heterozygosity or absence of the E4
allele. Osuntokun et al. (1995) found no association between E4 and
Alzheimer disease in elderly Nigerians, in contrast to the strong
association reported in their previous study of African Americans in
Indianapolis. Levy-Lahad et al. (1995) found that the epsilon 4 allele
did not affect the age of onset in either Alzheimer disease type 4
present in Volga Germans (600753) or Alzheimer disease type 3 (607822).
This suggested to them that some forms of early onset familial Alzheimer
disease are not influenced by the apolipoprotein E system.

By genotype analysis of 109 carriers of the E280A PSEN1 mutation
(104311.0009), including 52 individuals with AD, Pastor et al. (2003)
found that those with at least 1 APOE4 allele were more likely to
develop AD at an earlier age than those without an APOE4 allele,
indicating an epistatic effect.

Wijsman et al. (2005) noted the wide range in age at onset of Alzheimer
disease in Volga German families with the N141I mutation in PSEN2
(600759.0001). To examine evidence for a genetic basis for the variation
in age at onset, the authors performed a Bayesian oligogenic segregation
and linkage analysis on 9 Volga German families known to have a least 1
affected PSEN2 mutation carrier. The analysis was designed to estimate
the effects of APOE and PSEN2 and the number and effects of additional
loci and the environment (family effects) affecting age at onset of AD.
The analysis showed that APOE plays a small but significant role in
modifying the age at onset in these Volga German families. There was
evidence of a dose-dependent relationship between the number of E4
alleles and age at onset. Wijsman et al. (2005) calculated an
approximately 83% posterior probability of at least one modifier locus
in addition to APOE; the fraction of the variance in age at onset
attributable to PSEN2, APOE, other loci, and family effects was
approximately 70%, 2%, 6.5%, and 8.5%, respectively.

Bennett et al. (1995) examined the APOE genotype in family
history-positive and family history-negative cases of Alzheimer disease
and found a distortion of the APOE allele frequencies similar to those
with previous studies. However, they also examined the allele
distribution of at-risk sibs and found an excess of the E4 allele which
did not differ from that of affected sibs. In these families, they found
no evidence for linkage between the APOE4 locus and Alzheimer disease.
They concluded that the APOE locus is neither necessary nor sufficient
to cause Alzheimer disease and speculated that it may modify the
preclinical progression, and therefore the age of onset, in people
otherwise predisposed to develop Alzheimer disease.

Head injury is an epidemiologic risk factor for Alzheimer disease and
deposition of A-beta occurs in approximately one-third of individuals
dying after severe head injury. Nicoll et al. (1995) found that the
frequency of APOE4 in individuals with A-beta deposition following head
injury (0.52) was higher than in most studies of Alzheimer disease,
while in those head-injured individuals without A-beta deposition, the
APOE4 frequency (0.16) was similar to controls without Alzheimer disease
(P = less than 0.00001). Thus, environmental and genetic risk factors
for Alzheimer disease may act additively.

In a review of apolipoprotein E and Alzheimer disease, Strittmatter and
Roses (1995) pointed out that isoform-specific differences have been
identified in the binding of apoE to the microtubule-associated protein
tau (MAPT; 157140), which forms the paired helical filament and
neurofibrillary tangles, and to amyloid beta peptide (APP; 104760), a
major component of the neuritic plaque. Identification of apoE in the
cytoplasm of human neurons and isoform-specific binding of apoE to the
microtubule-associated protein tau and MAP-2 (157130) make it possible
that apoE may affect microtubule function in the Alzheimer brain.
Blennow et al. (1994) demonstrated a significant reduction of CSF
apolipoprotein E in Alzheimer disease compared to that of controls. They
suggested that the increased reutilization of apolipoprotein E lipid
complexes in the brain in Alzheimer disease may explain the low CSF
concentration.

The observation that the APOE4 allele is neither necessary nor
sufficient for the expression of AD emphasizes the significance of other
environmental or genetic factors that, either in conjunction with APOE4
or alone, increase the risk of AD. Kamboh et al. (1995) noted that among
the candidate genes that might affect the risk for Alzheimer disease is
alpha-1-antichymotrypsin (AACT; 107280) because, like APOE protein, AACT
binds to beta-amyloid peptide with high affinity in the filamentous
deposits found in the AD brain. Additionally, it serves as a strong
stimulatory factor in the polymerization of beta-amyloid peptide into
amyloid filaments. Kamboh et al. (1995) demonstrated that a common
polymorphism in the signal peptide of AACT (107280.0005) confers a
significant risk for AD and that the APOE4 gene dosage effect associated
with AD risk is significantly modified by the AACT polymorphism. They
identified the combination of the AACT 'AA' genotype with the APOE4/4
genotype as a potential susceptibility marker for AD, as its frequency
was 1/17 in the AD group compared to 1/313 in the general population
controls. It is noteworthy that one form of Alzheimer disease
(designated Alzheimer type 3, 607822), like AACT, maps to 14q; however,
AACT and AD3 are located at somewhat different sites on 14q.

Tang et al. (1996) compared relative risks by APOE genotypes in a
collection of cases and controls from 3 ethnic groups in a New York
community. The relative risk for Alzheimer disease associated with APOE4
homozygosity was increased in all ethnic groups: African American RR =
3.0; Caucasian RR = 7.3; and Hispanic RR = 2.5 (compared with the RR
with APOE3 homozygosity). The risk was also increased for APOE4
heterozygous Caucasians and Hispanics, but not for African Americans.
The age distribution of the proportion of Caucasian and Hispanics
without AD was consistently lower for APOE4 homozygous and APOE4
heterozygous individuals than for those with other APOE genotypes. In
African Americans this relationship was observed only in APOE4
homozygotes. Differences in risk among APOE4 heterozygous African
Americans suggested to the authors that other genetic or environmental
factors may modify the effect of APOE4 in some populations.

In a study of 85 Scottish persons with early onset Alzheimer disease, St
Clair et al. (1995) found highly significant enrichment for both
homozygous and heterozygous APOE epsilon-4 allele carriers in both
familial and sporadic cases with a pattern closely resembling that in
late-onset AD.

As reviewed earlier, the APOE4 allele is associated with sporadic and
late-onset familial Alzheimer disease. Gene dose has an effect on risk
of developing AD, age of onset, accumulation of senile plaques in the
brain, and reduction of choline acetyltransferase (118490) in the
hippocampus of AD patients. Poirier et al. (1995) examined the effect of
APOE4 allele copy number on pre- and postsynaptic markers of cholinergic
activity. APOE4 allele copy number showed an inverse relationship with
residual brain CHAT activity and nicotinic receptor binding sites in
both the hippocampal formation and the temporal cortex of AD subjects.
AD subjects lacking the APOE4 allele showed CHAT activities close to or
within the age-matched normal control range. Poirier et al. (1995) then
assessed the effect of the APOE4 allele on cholinomimetic drug
responsiveness in 40 AD patients who completed a double-blind, 30-week
clinical trial of the cholinesterase inhibitor tacrine. Results showed
that more than 80% of APOE4-negative AD patients showed marked
improvement after 30 weeks, whereas 60% of APOE4 carriers had poor
responses.

Polvikoski et al. (1995) reported on an autopsy study involving
neuropathologic analysis and DNA analysis of frozen blood specimens
performed in 92 of 271 persons who were at least 85 years of age, who
had been living in Vantaa, Finland, on April 1, 1991, and who had died
between that time and the end of 1993. All subjects had been tested for
dementia. Apolipoprotein E genotyping was done with a solid-phase
minisequencing technique. The percentage of cortex occupied by
methenamine silver-stained plaques was used as an estimate of the extent
of beta-amyloid protein deposition. They found that the APOE4 allele was
significantly associated with Alzheimer disease. Even in elderly
subjects without dementia, the apolipoprotein E4 genotype was related to
the degree of deposition of beta-amyloid protein in the cerebral cortex.

In late-onset familial AD, women have a significantly higher risk of
developing the disease than do men. Studying 58 late-onset familial AD
kindreds, Payami et al. (1996) detected a significant gender difference
for the APOE4 heterozygous genotype. In women, APOE4 heterozygotes had
higher risk than those without APOE4; there was no significant
difference between APOE4 heterozygotes and APOE4 homozygotes. In men,
APOE4 heterozygotes had lower risk than APOE4 homozygotes; there was no
significant difference between APOE4 heterozygotes and those without
APOE4. A direct comparison of APOE4 heterozygous men and women revealed
a significant 2-fold increased risk in women. These results were
corroborated in studies of 15 autopsy-confirmed AD kindreds from the
National Cell Repository at Indiana University Alzheimer Disease Center.

Mahley (1988) provided a review documenting the expanding role of apoE
as a cholesterol transport protein in cell biology. The pronounced
production and accumulation of apoE in response to peripheral nerve
injury and during the regenerative process indicates, for example, that
apoE plays a prominent role in the redistribution of cholesterol to the
neurites for membrane biosynthesis during axon elongation and to the
Schwann cells for myelin formation. Poirier (1994) reviewed the
coordinated expression of apoE and its receptor, the apoE/apoB LDL
receptor (606945), in the regulation of transport of cholesterol and
phospholipids during the early and intermediate phases of reinnervation,
both in the peripheral and in the central nervous system. He proposed
that the linkage of the E4 allele to Alzheimer disease (104300) may
represent dysfunction of the lipid transport system associated with
compensatory sprouting and synaptic remodeling central to the Alzheimer
disease process.

Tomimoto et al. (1995) found only 3 cases with focal accumulation of
apolipoprotein E in dystrophic axons and accompanying macrophages in 9
cases of cerebral vascular disease and 4 control subjects. The results
suggested to the authors that apolipoprotein E may have a role in
recycling cholesterol in other membrane components in the brain, but
that this phenomenon is restricted to the periphery of infarctions and
may be less prominent than in the peripheral nervous system.

Egensperger et al. (1996) determined the apoE allele frequencies in 35
subjects with neuropathologically confirmed Lewy body parkinsonism with
and without concomitant Alzheimer lesions, 27 patients with AD, and 54
controls. They concluded that the apoE4 allele does not function as a
risk factor which influences the development of AD lesions in PD.

Myers et al. (1996) examined the association of apolipoprotein E4 with
Alzheimer disease and other dementias in 1,030 elderly individuals in
the Framingham Study cohort. They found an increased risk for Alzheimer
disease as well as other dementias in patients who were homozygous or
heterozygous for E4. However, they pointed out that most apoE4 carriers
do not develop dementia, and about one-half of Alzheimer disease is not
associated with apoE4.

In aggregate, the association studies on apoE in Alzheimer disease
suggest epsilon-4 accelerates the neurodegenerative process in Alzheimer
disease. However, in 3 independent studies, Kurz et al. (1996), Growdon
et al. (1996), and Asada et al. (1996) found no differences in the
clinical rate of decline of newly diagnosed Alzheimer disease patients
with or without the epsilon-4 allele.

Bickeboller et al. (1997) confirmed the increased risk for AD associated
with the APOE4 allele in 417 patients compared with 1,030 control
subjects. When compared to the APOE3 allele, the authors demonstrated an
increased risk associated with the APOE4 allele (odds ratio = 2.7) and a
protective effect of the APOE2 allele (odds ratio = 0.5). An effect of
E4 allele dosage on susceptibility was confirmed: the odds ratio of
E4/E4 versus E3/E3 = 11.2; odds ratio of E3/E4 versus E3/E3 = 2.2. In
E3/E4 individuals, sex-specific lifetime risk estimates by age 85 years
(i.e., sex-specific penetrances by age 85 years) were 0.14 for men and
0.17 for women. Houlden et al. (1998) found that the APOE genotype is
only a risk factor for early-onset AD families with no lesion detectable
in the presenilin or APP gene.

Meyer et al. (1998) presented data on an elderly population which
suggested that apoE genotype influences the age-specific risk of
Alzheimer disease but that, regardless of apoE genotype, more than half
of the population will not develop AD by age 100. ApoE genotype did not
appear to influence whether subjects will develop AD, but the study did
confirm that the apoE4 alleles influence when susceptible individuals
will develop AD. The findings could be explained by a gene or genes
independent of apoE that condition vulnerability.

Wiebusch et al. (1999) conducted a case-control study of 135
pathologically confirmed AD cases and 70 non-AD controls (age of death
greater than or equal to 60 years) in whom they genotyped for APOE
epsilon-4 and BCHE-K (177400.0005). The allelic frequency of BCHE-K was
0.13 in controls and 0.23 in cases, giving a carrier odds ratio of 2.1
(95% confidence interval (CI) 1.1-4.1) for BCHE-K in confirmed AD. In an
older subsample of 27 controls and 89 AD cases with ages of death
greater than or equal to 75 years, the carrier odds ratio increased to
4.5 (95% CI 1.4-15) for BCHE-K. The BCHE-K association with AD became
even more prominent in carriers of APOE epsilon-4. Only 3 of 19 controls
compared with 39 of 81 cases carried both, giving an odds ratio of 5.0
(95% CI 1.3-19) for BCHE-K carriers within APOE epsilon-4 carriers. The
authors concluded that the BCHE-K polymorphism is a susceptibility
factor for AD and enhances the AD risk from APOE epsilon-4 in an
age-dependent manner.

Myeloperoxidase (MPO; 606989) is a potent oxidant found in immune cells
that has been detected in activated microglial macrophages and within
amyloid plaques. Using statistical analysis, Reynolds et al. (2000)
examined the relationship between APOE and MPO polymorphisms in the risk
of AD in a genetically homogeneous Finnish population. They found that
the presence of the MPO A allele in conjunction with APOE4 significantly
increased the risk of AD in men, but not in women (odds ratio for men
with both alleles = 11.4 vs APOE4 alone = 3.0). Reynolds et al. (2000)
also found that estrogen receptor-alpha (133430) binds to the MPO A
promoter, which may explain the gender differences.

Goldstein et al. (2001) genotyped 71 African American patients with
presumed AD and found that each copy of the E4 allele was associated
with a 3.6-year earlier onset of disease. The results fit a clear linear
dose-response relationship, with mean age of onset being 77.9 years with
no E4 alleles, 74.3 years with 1 allele, and 70.7 years with 2 alleles.

Mortensen and Hogh (2001) tested 139 subjects without dementia with the
Wechsler Adult Intelligence Scale and several performance tests at the
ages of 50, 60, 70, and 80 years and found that there was a significant
association between APOE4 genotype and decline in performance tests in
women between 70 and 80 years, but not in men. These findings
corroborated previous findings of gender differences in the association
of APOE genotype and risk of AD.

Multiple reports have linked APOE promoter polymorphisms to AD, both in
association with and independent of APOE alleles, yielding overall
conflicting results. Wang et al. (2000) analyzed 3 promoter
polymorphisms in 237 patients and 274 controls and found a strong
association between -491 AA genotype and AD, in both E4 and non-E4
carriers. They also confirmed the well-described association between
APOE4 and AD. Wang et al. (2000) proposed a mechanistic model of disease
in which the level of expression of APOE in addition to the specific
isoform of APOE influences the deposition of beta-amyloid.

Ghebremedhin et al. (2001) examined 729 routine autopsy brains for the
classic neuropathologic findings in AD, namely intracellular
neurofibrillary tangles (NFT) and extracellular senile plaques (SP), to
determine the effect of APOE genotype on the development of lesions.
Presence of the APOE4 allele was significantly associated with both NFT
and SP, but was differentially modified by age and gender: the effect of
the E4 allele on NFT was noted at ages 80 and above, but not between
ages 60 to 79, in both genders, whereas the association between the E4
allele and SP for women was found only between ages 60 to 79 years, but
not above 80 years, with no age difference in men.

Bonay and Avila (2001) presented evidence that apoE, particularly apoE4,
adds to neuroblastoma cells in culture and stimulates sulfate
incorporation on cell and extracellular matrix glycosaminoglycans. They
hypothesized that elevated levels of sulfated glycosaminoglycans could
facilitate the assembly of beta-amyloid and tau proteins in the plaques
and tangles of AD.

Lambert et al. (2001) measured amyloid-beta load immunohistochemically
in regions 8 and 9 of Brodman's area in 74 people with Alzheimer
disease. The amount of deposited amyloid-beta-40 was significantly
increased in Alzheimer disease brain samples carrying at least one APOE4
allele, compared with samples that did not (p = 0.005). There was also
an increase in amyloid-beta-40 load in individuals carrying the -491AA
genotype independent of E4 status. On the basis of these findings,
Lambert et al. (2001) suggested that the association between increased
amyloid-beta load and alleles of the APOE promoter polymorphisms is
independent of APOE genotype.

Zubenko et al. (2001) described a prospective, longitudinal,
double-blind assessment of the age-specific risk of AD encountered by
325 asymptomatic first-degree relatives of AD probands who carried the
D10S1423 234-bp allele (see 606187), the APOE4 allele, or both, after
11.5 years of systematic follow-up. They found that with the
best-fitting model, only individuals who carried both risk alleles
exhibited a risk ratio that differed significantly from 1. After
controlling for these genotypes, female gender was also significantly
associated with increased risk of developing AD.

Peskind et al. (2001) suggested that the effects of APOE genotype on the
hypothalamic-pituitary-adrenal (HPA) axis may be involved in the
pathobiology of AD. They examined APOE genotype and CSF cortisol levels
in 64 subjects with Alzheimer disease and 34 controls and found that
higher cortisol levels were associated with increased frequency of the
E4 allele and decreased frequency of the E2 allele. They noted that
previous animal studies had shown a correlation between glucocorticoid
elevation and hippocampal dendritic atrophy and neuronal loss, and
postulated that increased cortisol levels in patients with AD may lower
the threshold for neuronal degeneration. Sass et al. (2001) requested
that Peskind et al. (2001) provide specific information on the protocol
they used for CSF cortisol measurement. Wilkinson et al. (2001)
explicitly described the modifications they made to the commercial
cortisol assay protocol used to detect the low concentrations of
cortisol in the CSF in their study.

Scarmeas et al. (2002) followed 87 patients with early-stage AD for up
to 10 years to determine whether APOE genotype was related to the
incidence of psychiatric symptomatology. They found that the presence of
1 E4 allele conferred a 2.5-fold risk and the presence of 2 E4 alleles
conferred a 5.6-fold risk for development of delusions. The associations
were significant even after controlling for variables. No association
was found for depressive symptoms or behavioral disturbances.

In a longitudinal study of 55 patients with Alzheimer disease, Mori et
al. (2002) determined that the rate of hippocampal atrophy was
significantly greater in those with an APOE4 allele, and that the rate
became more severe as the number of E4 alleles increased. However, their
data did not support the findings of previous studies that the E4 allele
is associated with an increased rate of cognitive decline.

Dal Forno et al. (2002) genotyped 125 patients with Alzheimer disease
for the APOE allele and followed the participants for 10 years. They
found that the APOE4 allele was associated with shorter survival in men,
but not in women.

Among 1,732 patients with Alzheimer disease, Lambert et al. (2002) found
that the -491AA and -219TT APOE genotypes were associated with increased
risk for Alzheimer disease (odds ratio for -491AA was 1.7 and for -219TT
was 1.6), with age accentuating the effect of the -219TT genotype. The
authors concluded that because these polymorphisms appear to influence
ApoE levels, the results suggest that APOE expression is an important
determinant of AD pathogenesis.

Using logistic and linear regression statistical analysis to examine
clinical, pathologic, and genetic data from 128 older persons (51 with
probable AD and 77 without dementia), Bennett et al. (2003) determined
that the E4 allele was strongly associated with the likelihood of
clinical AD (odds ratio = 3.46) and decreased level of cognitive
function. However, controlling for the effect of AD pathology, including
neuritic plaques and neurofibrillary tangles, attenuated the
associations, rendering them no longer significant. Bennett et al.
(2003) concluded that the E4 allele is associated with the clinical
manifestations of AD through an association with the pathologic
hallmarks of AD rather than via some other mechanism.

In a study of 966 Swedish patients 75 years of age or older, Qiu et al.
(2003) found that 204 were diagnosed with AD during a 6-year period.
Presence of the APOE4 allele, high systolic blood pressure (140 mm Hg or
greater), and low diastolic blood pressure (less than 70 mm Hg) were
each associated with an increased risk of AD. APOE4 allele combined with
low diastolic pressure greatly increased the risk of AD independent of
antihypertensive drug use. Antihypertensive medication significantly
reduced the risk of AD regardless of APOE4 status and counteracted the
combined risk effect of the APOE4 allele and high blood pressure on the
disease.

Among 563 AD patients and 118 controls, Prince et al. (2004) found that
presence of the APOE4 allele was strongly associated with reduced CSF
levels of beta-amyloid-42 in both patients and controls. The findings
suggested an involvement of ApoE in beta-amyloid metabolism.

In a postmortem analysis of 296 AD brains, including 149 with 1 E4
allele, 38 with 2 E4 alleles, and 109 non-E4 carriers, Tiraboschi et al.
(2004) found that patients with 2 E4 alleles had significantly more
neuritic plaques and neurofibrillary tangles in all neocortical regions
compared to those with 1 or no E4 alleles. There were no significant
differences in neocortical cholinergic activity, as measured by tissue
CHAT (118490) activity, between those with and without the E4 allele.
Patients with the E2 allele had significantly decreased numbers of
neuritic plaques in all neocortical regions, consistent with a putative
protective effect of the E2 allele in AD. Tiraboschi et al. (2004)
suggested that a single E4 allele does not influence neuropathologic
severity in AD.

Huang et al. (2004) reported that 203 of 907 Swedish individuals over
the age of 75 years developed AD over a period of 6 years. Analysis of
the APOE allele genotype showed that individuals with at least 2
affected first-degree relatives or sibs had a significantly increased
risk of disease development only in the presence of the E4 allele.

Bray et al. (2004) applied highly quantitative measures of allele
discrimination to cortical RNA from individuals heterozygous for the
APOE E2, E3, and E4 alleles. A small, but significant, increase in the
expression of E4 allele was observed relative to that of the E3 and E2
alleles (P less than 0.0001). Similar differences were observed in brain
tissue from confirmed late-onset Alzheimer disease subjects, and between
cortical regions BA10 (frontopolar) and BA20 (inferior temporal).
Stratification of E4/E3 allelic expression ratios according to
heterozygosity for the -219G-T promoter polymorphism (107741.0030)
revealed significantly lower relative expression of haplotypes
containing the -219T allele (P = 0.02). Bray et al. (2004) concluded
that, in human brain, most of the cis-acting variance in APOE expression
may be accounted for by the E4 haplotype, but there are additional small
cis-acting influences associated with the promoter genotype.

Tsuang et al. (2005) found a higher frequency of the E4 allele among 74
patients with the Lewy body variant of AD (see 127750) compared to 57
patients with AD without Lewy bodies (47.3% vs 35.1%, respectively). The
findings suggested an association between the E4 allele and the
development of Lewy bodies.

In a study of 140 elderly Nigerian patients with dementia, of which 123
were diagnosed with AD, Gureje et al. (2006) found no association
between the APOE4 allele and dementia or AD.

Among 184 healthy individual with normal cognition aged 21 to 88 years,
Peskind et al. (2006) found that the concentration of CSF
beta-amyloid-42, but not beta-amyloid-40, decreased with age. Those with
an APOE4 allele showed a sharp and significant decline in CSF beta-A-42
beginning in the sixth decade compared to those without the APOE4
allele. The findings were consistent with APOE4-modulated acceleration
of pathogenic beta-A-42 deposition starting in late middle age in
persons with normal cognition, and suggested that early treatment for AD
in susceptible individuals may be necessary in midlife or earlier.

Among 100 patients with AD, van der Flier et al. (2006) found an
association between presence of the E4 allele and the typical amnestic
phenotype, characterized by initial presentation of forgetfulness and
difficulties with memory. Those with the memory phenotype were 3 times
more likely to carry an E4 allele compared to AD patients who displayed
a nonmemory phenotype, with initial complaints including problems with
calculation, agnosia, and apraxia. The memory phenotype was almost
exclusively observed in homozygous E4 carriers.

Borroni et al. (2007) also reported an association between the memory
phenotype of AD and presence of the E4 allele. Among 319 late-onset AD
patients, 77.6% of E4 allele carriers presented with the memory
phenotype compared to 64.6% of noncarriers.

Among 51 patients with probable AD and 31 patients with frontotemporal
dementia (FTD; 600274), Agosta et al. (2009) found that presence of the
E4 allele was associated with greater brain atrophy on imaging studies.
AD E4 allele carriers showed greater atrophy in the bilateral parietal
cortex and right hippocampus, whereas FTD E4 allele carriers
demonstrated greater atrophy in the bilateral medial, dorsolateral, and
orbital frontal cortex, anterior insula, and cingulate cortex with right
predominance. The regional effect was consistent with the hypothesis
that APOE may affect morphologic expression uniquely in different
neurodegenerative diseases, and that E4 carriers are at greater risk for
clinical progression.

ApoE acts normally to scaffold the formation of high-density lipoprotein
particles, which promote the proteolytic degradation of soluble forms of
amyloid-beta. The expression of apoE is transcriptionally regulated by
the ligand-activated nuclear receptors PPAR-gamma (601487) and liver X
receptor (LXR; see 602423), which form obligate heterodimers with
retinoid X receptors (RXRs). Transcriptional activity is regulated by
ligation of either member of the pair. PPAR-gamma:RXR and LXR:RXR act in
a feed-forward manner to induce the expression of apoE, its lipid
transporters ABCA1 (600046) and ABCG1 (603076), and the nuclear
receptors themselves. Agonists of these receptors also act on
macrophages and microglia to stimulate their conversion into
'alternative' activation states and promote phagocytosis.

- Role in Cognitive Impairment

Reiman et al. (1996) found that in late middle age, cognitively normal
subjects who were homozygous for the APOE4 allele had reduced glucose
metabolism in the same regions of the brain as in patients with probable
Alzheimer disease. These findings provided preclinical evidence that the
presence of the APOE4 allele is a risk factor for Alzheimer disease.
Positron-emission tomography (PET) was used in these studies; Reiman et
al. (1996) suggested that PET may offer a relatively rapid way of
testing treatments to prevent Alzheimer disease in the future.

Blesa et al. (1996) found an apoE epsilon-4 frequency of 0.315 in
patients with age-related memory decline without dementia, similar to
the 0.293 allele frequency found in an Alzheimer disease group. This
contrasted to the frequency of 0.057 found in their control group.
Payami et al. (1997) reported the results of a prospective case-control
study that enlisted 114 Caucasian subjects who were physically healthy
and cognitively intact at age 75 years and who were followed, for an
average of 4 years, with neurologic, psychometric, and neuroimaging
examinations. Excellent health at entry did not protect against
cognitive decline. Incidence of cognitive decline rose sharply with age.
E4 and a family history of dementia (independent of E4) were associated
with an earlier age at onset of dementia. Subjects who had E4 or a
family history of dementia had a 9-fold-higher age-specific risk for
dementia than did those who had neither. From these observations, Payami
et al. (1997) suggested that the rate of cognitive decline increases
with age and that APOE and other familial/genetic factors influence the
onset age throughout life.

Yaffe et al. (2000) studied 2,716 women 65 years of age or older by
cognitive testing on 2 or more visits. They analyzed change in score on
the Modified Mini-Mental State Examination as a function of estrogen
use, APOE genotype, and baseline common and internal carotid artery wall
thickening. A total of 297 (11%) women were current estrogen users, and
336 (12%) were past estrogen users. Over the 6-year average follow-up,
baseline current users declined 1.5 points, whereas women who had never
used estrogen declined 2.7 points (P = 0.023). Compared with
APOE4-negative women, APOE4-positive women had a greater adjusted hazard
ratio of cognitive impairment. There was an interaction between estrogen
use and APOE4 presence. Among APOE4-negative women, current estrogen use
reduced the risk of adjusted cognitive impairment by almost half
compared with the risk of those who had never used estrogen, whereas it
did not reduce the risk among APOE4-positive women. Compared with never
having used estrogen, current estrogen use was associated with less
internal and common carotid wall thickening in APOE4-negative women but
not in APOE4-positive women. Differences remained after adjusting for
age, education, race, and stroke. Yaffe et al. (2000) concluded that
estrogen use was associated with less cognitive decline among women who
did not have the APOE4 allele but not among women who had at least one
APOE4 allele.

Cohen et al. (2001) examined 25 healthy women with normal cognition
above the age of 50 in a longitudinal 2-year study and found that a
single APOE4 allele was associated with a significant decrease in
hippocampal volume (mean 2.3% decrease per year), as measured by MRI,
compared to the APOE4-negative group (mean 0.77% decrease per year).
These results suggested that brain structural changes may be associated
with the E4 genotype and that the changes may precede the development of
cognitive deficits.

In a 6-year longitudinal study of 611 participants aged 65 years or
older, Wilson et al. (2002) found that presence of the APOE E4 allele
was associated with a more rapid decline in cognitive functions,
particularly episodic memory, which is an early and defining clinical
characteristic of AD. To identify the determinants of normal age-related
cognitive change, Deary et al. (2002) genotyped 466 healthy subjects who
had taken the Moray House Test (MHT) to measure cognitive ability in
1932 at age 11 and the Mini-Mental State Examination (MMSE) at age 80.
Possession of the APOE4 allele was found to be unrelated to differences
in mental ability in youth, but was significantly associated with
decreased mental ability in old age and the change in ability score from
youth.

In a cohort of 180 asymptomatic individuals with a mean age of 60 years,
Caselli et al. (2004) found that carriers of an E4 allele showed greater
declines in memory performance over a median period of 33 months
compared to those without an E4 allele. Among 494 individuals with mild
cognitive impairment, Farlow et al. (2004) found an association between
the E4 allele and worse scores on cognition tests as well as smaller
total hippocampal volume. Among 6,202 Caucasian middle-aged individuals
(47 to 68 years), Blair et al. (2005) found that carriers of the E4
allele had greater cognitive decline over a 6-year period compared to
those without an E4 allele. Results for 1,693 African American patients
were inconclusive.

Among 136 patients with mild cognitive impairment, 35 of whom developed
AD, Devanand et al. (2005) found no association between APOE4 carrier
status and development of AD or further cognitive decline. After
controlling for known demographic and clinical risk factors, E4 carrier
status was associated with conversion to AD only in patients older than
70 years.

Using EEG to study 89 patients with mild cognitive impairment and 103
with AD, Babiloni et al. (2006) found that the amplitude of alpha
sources in occipital, temporal, and limbic areas was lower in patients
with the E4 allele compared to those not carrying the E4 allele.

Caselli et al. (2009) presented evidence that the APOE E4 allele affects
age-related memory performance independently of mild cognitive
impairment and dementia. A longitudinal study of 815 individuals,
including 317 E4 carriers (79 homozygous subjects and 238 heterozygous
subjects) and 498 E4 noncarriers, showed that carriers of the E4 allele
had a decline in memory beginning in their fifties compared to
noncarriers (p = 0.03). Noncarriers showed a decline in memory beginning
in their seventies. The findings indicated that carriers of the E4
allele may have increased age-related memory decline and decreased
visuospatial function.

In a prospective population-based study of 516 individuals aged 85 years
from the Netherlands, van Vliet et al. (2009) found an association
between high serum calcium and decreased cognitive function in APOE
E3/E4 carriers and to a lesser extent in E3/E3 carriers, but not in
E2/E3 carriers. The p value for interaction between APOE genotype and
serum calcium levels corrected for confounders was 0.025; the p value
for interaction between APOE genotype and serum calcium level in
relation to global cognitive function over time was 0.011. The findings
suggested that APOE genotype modulates an association between serum
calcium and cognitive function in old age.

- Role in Multiple Sclerosis

Chapman et al. (2001) reported on 205 patients with multiple sclerosis
(MS; 126200) and found that the APOE4 allele was associated with
significantly faster progression of disability. The effect was
significant after adjustment for sex and age of onset. Although the E4
allele was associated with slightly earlier disease onset, there was no
support for the E4 allele being a risk factor for development of MS.

Noting that the APOE4 allele has been associated with earlier age of
onset in AD, but not disease progression, and with faster disease
progression in MS, but not age of onset, Chapman et al. (2001) suggested
that these apparent effects are influenced by whether the diagnosis is
made late in disease course (as in AD) or relatively early in disease
course (as in MS). The authors hypothesized that the APOE4 genotype
influences neuronal disease in general via alterations in the efficacy
of neuronal maintenance and repair, and that the apparent effects of the
genotype on these 2 parameters are related to the threshold at which the
disease manifests itself clinically.

In MS, a reduction in concentration of N-acetylaspartate (NAA), which
has been shown to be contained almost exclusively in mature neurons,
reflects neuronal loss, axonal loss, and generalized neuronal
dysfunction. Moreover, the degree of reduction of NAA has been
correlated with disease severity and extent of tissue destruction. In 72
patients with relapsing-remitting MS, Enzinger et al. (2003) showed by
proton magnetic resonance spectroscopy (MRS) that patients with the
APOE4 allele had a higher degree of disability and a significantly lower
NAA:creatine ratio than patients without the E4 allele. During follow-up
in 44 patients, the drop in the NAA:creatine ratio of E4 carriers was
significantly larger and was paralleled by a higher number of relapses
and a faster disease progression. Enzinger et al. (2003) concluded that
the findings indicated more extensive axonal damage associated with the
APOE4 allele.

Kantarci et al. (2004) presented evidence suggesting that the APOE2
allele is associated with lesser disease severity in women with MS, as
indicated by a longer time to reach an expanded disability status scale
(EDSS) score of 6. In contrast, Zwemmer et al. (2004) reported no
favorable role for the E2 allele in a study of 250 women with MS. In
fact, they found a trend in the opposite direction: time to an EDSS
score of 6 was shorter (6.8 years) in E2 carriers than in noncarriers
(10.0 years). In addition, E2 carriers had a higher lesion load on MRI
compared to noncarriers. In a response, Weinshenker and Kantarci (2004)
noted that the study by Zwemmer et al. (2004) had a higher number of
more severe primary progressive cases (22% of subjects) than that
reported by Kantarci et al. (2004) (6.4% of subjects), which may explain
the discrepancy.

Enzinger et al. (2004) noted that decreases in brain size and volume in
patients with MS are related to neuroaxonal injury and loss, and are a
useful surrogate marker of tissue damage and disease progression. In a
study of 99 patients with MS, the authors found that patients who
carried an E4 allele had more relapses during the study period and had a
5-fold higher rate of annual brain volume loss compared to patients
without the E4 allele. Over time, E4 carriers also had an increase in
individual lesions on MRI, termed 'black holes.' Among all genotype
groups, the lowest annual loss of brain volume occurred in patients with
an E2 allele. Among 76 patients with relapsing-remitting MS, de Stefano
et al. (2004) found that carriers of the E4 allele showed significantly
lower total brain volumes compared to MS patients without the E4
alleles. There was no difference in lesion volume between the 2 groups.
The authors suggested that the E4 allele is linked to impaired
mechanisms of cell repair and severe tissue destruction in MS.

Among 125 Greek MS patients, Koutsis et al. (2007) found that E4
carriers had a 6-fold increase in the relative risk of verbal learning
deficits compared to noncarriers. The effect was specific and was not
observed in other cognitive domains.

Among 1,006 Australian patients with relapsing-remitting MS or secondary
progressive MS, van der Walt et al. (2009) found no association between
APOE allele status or promoter region heterogeneity at positions -219G-T
(dbSNP rs405509; 107741.0030) or +113C-G (dbSNP rs440446) and clinical
disease severity, cognition, or cerebral atrophy.

Ghaffar et al. (2010) found no differences in 11 cognitive outcome
variables, including attention, processing speed, verbal and visual
memory, and executive functions in a comparison of 50 MS patients with
the E4 allele and 50 MS patients without the E4 allele who were
well-matched regarding education and disease course and duration. The
presence of cognitive impairment overall was 41%.

- Role in Recovery From Traumatic Brain Injury

Among 89 patients with head injury, Teasdale et al. (1997) found that
patients with the E4 allele were more likely than those without the E4
allele to have an unfavorable outcome 6 months after head injury. The
authors discussed the role of the apoE protein in response to acute
brain injury. In a prospective study of 69 patients with severe blunt
trauma to the head, Friedman et al. (1999) found an odds ratio of 5.69
for more than 7 days of unconsciousness and 13.93 for a suboptimal
neurologic outcome at 6 months for individuals with an APOE4 allele
compared to those without that allele.

In 110 patients with traumatic brain injury (TBI), Crawford et al.
(2002) tested memory and other cognitive variables and found that
patients with the APOE4 allele had more difficulty with memory than
matched patients without the E4 allele. In those with the E4 allele,
performance was poor regardless of severity of injury, whereas in those
without the E4 allele, performance worsened with more severe injury.
Crawford et al. (2002) noted that TBI may result in greater damage to
the medial temporal lobe structures involved in memory and suggested a
role for the APOE protein in neuronal repair.

In 87 patients with mild to moderate TBI, Liberman et al. (2002) used
neuropsychologic testing to examine whether the APOE4 genotype affected
short-term recovery. At 6 weeks, E4-positive patients had lower mean
scores on 11 of 13 tests, but the differences from the E4-negative group
were smaller than the differences observed at 3 weeks. Although Liberman
et al. (2002) stated that the findings are consistent with delayed
recovery among E4-positive TBI patients, perhaps due to interactions
with beta-amyloid, they cautioned against the generalizability of the
results.

Among 60 patients with TBI with a mean follow-up of 31 years, Koponen et
al. (2004) found that presence of the E4 allele increased the risk for
dementia, but there was no association between the E4 allele and
development of other psychiatric illnesses, including depression,
anxiety, psychosis, or personality disorders.

- Role in Other Neurologic Disorders

Saunders et al. (1993) found no association of E4 with other
amyloid-forming diseases, i.e., Creutzfeldt-Jakob disease (CJD; 123400),
familial amyloidotic polyneuropathy, and Down syndrome (190685). On the
other hand, Amouyel et al. (1994) concluded that E4 is a major
susceptibility factor for CJD. They found a relative risk of CJD between
subjects with at least one E4 allele and subjects with none to range
between 1.8 and 4.2, depending on the control group used. A variation in
disease duration was also noted, depending on apoE genotype, with an
increase in duration of illness in E2 allele carriers.

Frisoni et al. (1994) assessed the apoE allele frequency in 51 elderly
control subjects, 23 subjects with vascular dementia, and 93 patients
with Alzheimer disease. There was increased frequency of the E4 allele
both in Alzheimer disease and in vascular dementia with respect to both
elderly and young control subjects. There was no difference in the
proportion of E2, E3, and E4 frequency in Alzheimer disease and vascular
dementia patients. Slooter et al. (1996) compared E4 allele frequency
between 185 patients with Alzheimer disease and those with other types
of dementia. The authors found little predictive value in distinguishing
Alzheimer patients from those with other forms of dementia using APOE
genotyping. In contrast, Mahieux et al. (1994) found an increase of E4
in Alzheimer disease, but not in vascular dementia. They speculated that
the difference between their results and those of Frisoni et al. (1994)
may be attributable to the small size of the groups or to the different
mean ages of the populations that they studied.

McCarron et al. (1999) performed a metaanalysis that demonstrated a
significantly higher frequency of E4 carriers in individuals with
ischemic cerebrovascular disease than in control subjects (odds ratio,
1.73).

Tabaton et al. (1995) found that although apolipoprotein E
immunoreactivity was associated with neurofibrillary tangles in an
autopsy study of 12 patients with progressive supranuclear palsy
(601104), the apolipoprotein E allele frequency was similar to that of
age-matched controls. Farrer et al. (1995) demonstrated that the number
of epsilon-4 alleles was inversely related to the age at onset of Pick
disease (172700). Their results suggested that epsilon-4 may be a
susceptibility factor for dementia and not specifically for AD.

Mui et al. (1995) found no association between apolipoprotein E4 and the
incidence or the age of onset of sporadic or autosomal dominant
amyotrophic lateral sclerosis (105400). Garlepp et al. (1995) found an
increased frequency of the epsilon 4 allele in patients with inclusion
body myositis (147421) compared with that in patients with other
inflammatory muscle diseases or that in the general population.

In a study of apoE genotypes in schizophrenic patients coming to
autopsy, Harrington et al. (1995) found that schizophrenia is associated
with an increased E4 allele frequency. The E4 allele frequency in
schizophrenia was indistinguishable from that found in either Alzheimer
disease or Lewy body dementia (127750). From the age range at autopsy
(from 19 to 95 years), they determined that the epsilon-4 frequency was
not associated with increased age.

Betard et al. (1994) analyzed allele frequencies of apoE in 166
autopsied French-Canadian patients with dementia. The E4 frequency was
highest in Lewy body dementia (0.472); presenile Alzheimer disease
(0.405); senile Alzheimer disease (0.364); and Alzheimer disease with
cerebrovascular disease (0.513). In contrast, the E4 allele frequency
was 0.079 in autopsied cases of individuals with vascular dementia but
no changes of Alzheimer disease. Subjects with vascular dementia
demonstrated an increased relative E2 allele frequency of 0.211 compared
to 0.144 in elderly controls. In contradistinction to the findings of
Betard et al. (1994), Lippa et al. (1995) found much lower frequency of
E4, 0.22, when they were careful to exclude Lewy body patients that had
concurrent Alzheimer disease by the Cerat criterion. They did, however,
find that a neuritic degeneration in CA2-3 was slightly greater in those
Lewy body disease patients with the apoE4 allele than those with the
E3/3 genotype. Hyman et al. (1995) found that senile plaques in the
Alzheimer disease of Down syndrome were abnormally large, whereas those
of APOE4-related Alzheimer disease were unusually numerous. The findings
suggested that the pathology in Down syndrome is due to increased
amyloid production and deposition, whereas that in APOE4, disease is
related to an increased probability of senile plaque initiation. Royston
et al. (1994) assessed the apoE genotype in elderly Down syndrome
patients and found that the epsilon-2 variant was associated both with
increased longevity and a significantly decreased frequency of
Alzheimer-type dementia. They noted that none of their elderly Down
patients was homozygous for the epsilon-4 allele.

In a case-control study of apoE genotypes in Alzheimer disease
associated with Down syndrome, van Gool et al. (1995) showed that the
frequencies of apoE type 2, 3, or 4 were not significantly different in
Down syndrome cases with Alzheimer disease compared with aged-matched
Down syndrome controls. The apoE4 frequency in Down syndrome cases with
Alzheimer disease was significantly lower than in any other Alzheimer
disease populations studied thus far, suggesting that apoE4 does not
significantly affect the pathogenesis of Alzheimer disease in Down
syndrome patients.

Kehoe et al. (1999) showed that the APOE epsilon-2/epsilon-3 genotype is
associated with significantly earlier age of onset of Huntington disease
(143100) in males than in females. This sex difference was not apparent
for any other APOE genotypes.

Greenberg et al. (1995) found that the presence of apolipoprotein E4
significantly increased the odds ratio for moderate or severe cerebral
amyloid angiopathy (CAA; see 605714), even after controlling for the
presence of Alzheimer disease. Yamada et al. (1996) reported a lack of
association between the E4 allele and CAA in elderly Japanese patients.
Nicoll et al. (1996, 1997) did not find an association between the E4
allele and CAA-related hemorrhage. However, they did find a high
frequency of the E2 allele in patients with CAA-related hemorrhage,
regardless of the presence of AD. The authors suggested that patients
with the E2 allele may be protected from parenchymal AD but may be
susceptible to the rupture of amyloid-laden vessels.

In a postmortem study, Greenberg et al. (1998) found an association
between apolipoprotein E2 and vasculopathy in cerebral amyloid
angiopathy. Of 75 brains with complete amyloid replacement of vessel
walls, only 23 had accompanying signs of hemorrhage in cracks of the
vessel wall. The frequency of apolipoprotein E2 was significantly higher
in the group with vasculopathy. The authors suggested that
apolipoprotein E2 and E4 might promote hemorrhage through separate
mechanisms: E4 by enhancing amyloid deposition and E2 by promoting
rupture.

O'Donnell et al. (2000) identified a specific apolipoprotein E genotype
as a risk factor for early recurrence of cerebral amyloid angiopathy:
carriers of the E2 (107741.0001) or E4 (107741.0016) allele had an
increased risk for early recurrence compared to individuals with the
E3/E3 (107741.0015) genotype.

Fetal iodine deficiency disorder (FIDD; 228355) is the principal form of
endemic cretinism, and the most common cause of preventable mental
deficiency in the world. Not everyone at risk develops FIDD and familial
aggregation is common, suggesting that genetic factors may be involved.
The APOE gene encodes a lipoprotein that possesses a thyroid
hormone-binding domain, and the APOE genotype might affect the
efficiency with which thyroid hormone influences neuronal cell growth
during the first and second trimesters of fetal development. For this
reason, Wang et al. (2000) compared APOE genotypes in 91 FIDD cases with
those of 154 local control subjects, recruited from 3 iodine deficiency
areas in central China. They also genotyped 42 FIDD family cases and 158
normal individuals from the families of local controls, and 375
population controls from Shanghai. APOE4 genotypes were significantly
enriched in FIDD probands from each of the 3 iodine deficiency areas;
the E4 allele frequency was 16% versus 6% in controls. They suggested
that this phenomenon may affect population selection and contribute to
the low frequency of the APOE4 allele in Chinese compared with Caucasian
populations.

Using nocturnal polysomnography in a study of 791 middle-aged adults,
Kadotani et al. (2001) found that the probability of moderate to severe
sleep-disordered breathing (apnea/hypopnea) was significantly higher in
persons with apoE4, independent of age, sex, body mass index, and
ethnicity. See sleep apnea (107650).

In a study of 1,775 individuals, Gottlieb et al. (2004) found an
age-dependent association between the E4 allele and obstructive sleep
apnea. E4 carriers younger than 65 years had an odds ratio of 3.08 for
sleep apnea, whereas E4 carriers 65 years of age or older had an odds
ratio of 1.25. The association was stronger in those with hypertension
or cardiovascular disease.

Among 18 older adult APOE4 carriers with obstructive sleep apnea, O'Hara
et al. (2005) found an association between greater numbers of
respiratory events and lower memory performance. No association was
found in 18 older adult noncarriers with sleep apnea. The authors
suggested that sleep apnea may partly account for the association of the
E4 allele and cognitive decline in community-dwelling older adults and
postulated that hypoxia may have a role in neuronal vulnerability to
oxidative stress.

In a study of 79 patients with Parkinson disease, 22 of whom were
demented, Marder et al. (1994) found that the E4 allele frequency was
0.13 in patients without dementia and 0.068 in those with dementia as
opposed to a control value of 0.102. The authors concluded that the
biologic basis for dementia in Parkinson disease differs from that of
Alzheimer disease.

Zareparsi et al. (2002) examined the effect of the APOE genotypes on age
at onset of Parkinson disease using a population of 521 unrelated
Caucasian patients with idiopathic Parkinson disease from movement
disorder clinics in Oregon and Washington. They found that age at onset
was significantly earlier in E3E4/E4E4 patients (mean onset 56.1 years)
than in E3E3 patients (mean onset 59.6 years) (p = 0.003). This earlier
onset was not influenced by effects of recruitment site, family history,
or gender on onset of Parkinson disease.

Li et al. (2004) presented evidence suggesting that the E4 allele
increases disease risk for familial PD and is associated with earlier
age at disease onset independent of cognitive impairment; however, the
effect was not as strong as that observed in AD. In a review and
metaanalysis of 22 studies, Huang et al. (2004) concluded that the E2
allele, but not the E4 allele, was positively associated with sporadic
Parkinson disease.

Frikke-Schmidt et al. (2001) genotyped over 9,000 individuals and found
no association between APOE genotype and ischemic cerebrovascular
disease, defined as the sudden onset of focal neurologic symptoms.
However, they did find an association between the genotype E4E3 and
'other dementia,' which included vascular dementia, alcohol-induced
dementia, and unclassifiable dementia. They confirmed the findings of
previous studies that APOE genotypes E4E3 and E4E4 are significant risk
factors for AD. The increases in all dementia risks were independent of
plasma lipid and lipoprotein levels.

Broderick et al. (2001) examined data from a tissue plasminogen
activator (t-PA; 173370) trial and concluded that the efficacy of
intravenous t-PA in patients with acute ischemic stroke, as measured by
favorable outcome at 3 months, may be enhanced in those with an APOE E2
phenotype.

Verpillat et al. (2002) determined the APOE genotype frequencies in 94
unrelated patients with frontotemporal dementia (600274) and 392 age-
and sex-matched controls without cognitive deficits or behavioral
disturbances (after excluding 6 patients with autosomal dominant
inheritance and mutation in the MAPT gene). Homozygosity for the E2E2
genotype was significantly associated with frontotemporal dementia (odds
ratio = 11.3, P = 0.033, exact test) but was based on very few subjects
(3 patients and 1 control). The result was even more significant in the
group with a positive familial history (odds ratio = 23.8, P = 0.019,
exact test). For the metaanalysis of the APOE polymorphism in
frontotemporal dementia, Verpillat et al. (2002) pooled 10 case-control
studies with available genotype or allele information (total of 364
patients and 2,671 controls), but the E2E2 genotype did not reach
statistical significance. Because of heterogeneity, Verpillat et al.
(2002) analyzed on one hand the neuropathologically-confirmed studies,
and on the other hand the clinical-based studies. A significant increase
in the E2 allele frequency was found in the
neuropathologically-confirmed patients, and heterogeneity disappeared
(Mantel-Haenszel statistics). The authors concluded that the APOE E2
allele may be a risk factor for frontotemporal dementia, but that the
data should be interpreted with caution due to the rarity of the E2E2
genotype.

Matsumoto et al. (2003) provided evidence suggesting that patients with
primary dystonia who have the APOE4 genotype have an earlier age at
disease onset than APOE4 noncarriers with dystonia, which they suggested
was caused in part by a defect in neuronal repair in those with the
APOE4 allele.

In a large population-based study of 9,294 French individuals, Dufouil
et al. (2005) found a decreased risk for the development of non-AD
dementia among those who used lipid lowering agents and maintained
normal lipid levels. The odds for non-AD dementia were increased in
subjects with hyperlipidemia. The findings were not modified by APOE
genotype.

Among 32 patients with a clinical diagnosis of frontotemporal dementia,
including 15 patient with primary progressive aphasia, Acciarri et al.
(2006) found increased frequency of the E2 and E4 alleles and
significantly decreased frequency of the E3 allele compared to 87
control individuals. The E2E4 genotype in particular was significantly
associated with primary progressive aphasia.

Among 87 patients with medically intractable temporal lobe epilepsy
necessitating temporal lobectomy, Busch et al. (2007) found that the
presence of the E4 allele was associated with significantly reduced
verbal and nonverbal memory in those with a long duration of epilepsy
(greater than 22 years), particularly in those with an earlier age at
onset. Busch et al. (2007) suggested that medically refractory seizures
are similar to traumatic brain injury and that neuronal recovery after
seizures may be impaired by the presence of the E4 allele. Surgery had
no significant effects on the results.

In a metaanalysis including 8 published studies comprising 696 patients
with subarachnoid hemorrhage, Lanterna et al. (2007) found that patients
with the E4 allele had approximately 2-fold increased risk of negative
outcome and delayed ischemia compared to those without the allele.

Gozal et al. (2007) found that the E4 allele was more common in nonobese
children with obstructive sleep apnea (107650) compared to controls, and
particularly in those who developed neurocognitive deficits.

Silva et al. (2013) studied a total of 44 unrelated FMR1 premutation
(309550.0004) carriers, 22 with fragile X-associated tremor/ataxia
syndrome (FXTAS; 300623) and 22 without, and genotyped them for the ApoE
locus. All ApoE4 homozygous genotype carriers detected and 6 of the 7
ApoE4/3 genotype carriers (85.7%) were patients presenting with FXTAS,
whereas only 40% of the ApoE3/3 genotype carriers belonged to the FXTAS
group. These results showed that the presence of the ApoE4 allele
increases the risk of developing FXTAS (OR = 12.041; p = 0.034). Silva
et al. (2013) concluded that the presence of at least 1 ApoE4 allele
acts as a genetic factor predisposing individuals to develop FXTAS.

- Role in Ocular Disorders

Primary open-angle glaucoma (POAG; 137760) is an optic neuropathy that
has a high worldwide prevalence and that shows strong evidence of
complex inheritance. The myocilin gene (MYOC; 601652) has been shown to
have mutations in patients with POAG. Apolipoprotein E plays an
essential role in lipid metabolism, and the APOE gene has been involved
in the neuronal degeneration that occurs in Alzheimer disease. Copin et
al. (2002) reported that 2 APOE-promoter single nucleotide polymorphisms
(SNPs) previously associated with Alzheimer disease also modified the
POAG phenotype. APOE(-219G) is associated with increased optic nerve
damage, as reflected by increased cup:disc ratio and visual field
alteration. In addition, APOE(-491T), interacting at a highly
significant level with a SNP in the MYOC promoter, MYOC(-1000G), is
associated with increased intraocular pressure (IOP) and with limited
effectiveness of IOP-lowering treatments in patients with POAG.
Together, these findings establish APOE as a potent modifier for POAG,
which could explain the linkage to chromosome 19q previously observed by
use of a genome scan for this condition (Wiggs et al., 2000) and an
increased frequency of glaucoma in patients with Alzheimer disease
(Bayer et al., 2002). The findings also shed new light on potential
mechanisms of optic nerve damage and of IOP regulation in POAG. Bunce et
al. (2003) criticized the statistical approach used by Copin et al.
(2002) and concluded that without supportive clinical data, evidence is
lacking that APOE SNPs either are associated with a more severe
phenotype or interact at a highly significant level with a SNP in the
MYOC promoter.

Zetterberg et al. (2007) studied the association of AD-associated APOE
polymorphisms in 242 patients with POAG and 187 controls. They found no
differences between patients and controls with regard to APOE genotypes.

Because clinical studies had shown an association between glaucoma and
AD (Bayer et al., 2002), which is also a complex trait, Ressiniotis et
al. (2004) examined DNA from 137 unrelated patients with POAG and 75
control subjects. In this cohort, APOE genotype did not constitute a
risk factor for developing POAG, even in patients with normal tension
glaucoma. The authors concluded that APOE polymorphisms did not appear
to be contributory to POAG.

The inheritance of specific ApoE alleles is linked to the incidence of
age-related macular degeneration (ARMD; see 603075). ApoE appears to be
a ubiquitous component of drusen, which are the hallmark of ARMD
irrespective of clinical phenotype. Anderson et al. (2001) found ApoE
located at the same anatomic locus at which drusen are situated and
suggested that the retinal pigment epithelium is the most likely local
biosynthetic source of ApoE at that site. They concluded that
age-related alteration of lipoprotein biosynthesis and/or processing at
the level of the retinal pigment epithelium and/or Bruch membrane might
be a significant contributing factor in drusen formation and ARMD
pathogenesis.

Schultz et al. (2003) found no evidence to support an association
between ARMD in medium to large families and the E4 or E2 alleles of
ApoE. They also found no evidence for an association of ApoE
polymorphisms in a set of unrelated patients with ARMD. They did,
however, find a trend for a decreased risk of ARMD associated with ApoE4
in a set of unrelated patients with a family history of ARMD.

Baird et al. (2006) studied progression of ARMD in a cohort of 238
individuals from a single center. Individuals with an E2 genotype
(526C-T; 107741.0001) of the APOE gene showed a strong association with
disease with a significant 4.8-fold increased relative risk compared to
individuals with an E4 genotype (388T-C; 107741.0016) (odds ratio, 4.8)
and a nearly significant 3-fold increased relative risk compared to
individuals with an E3 (107741.0015) genotype. This finding was present
only in females who progressed with ARMD, which suggested that there may
be a gender-specific role in progression of ARMD in individuals with an
E2 allele.

Bojanowski et al. (2006) investigated the association between apoE2
(158C), apoE3, and apoE4 (112R) variants and ARMD in 133 clinically
screened controls, 94 volunteers with a younger mean age, 120 patients
with advanced ARMD, and 40 archived ocular ARMD slides. They also tested
the effects of recombinant apoE variants on the expression of a
chemokine (CCL2; 158105), a chemokine receptor (CX3CR1; 601470), and a
cytokine (VEGF; 192240) in cultured human retinal pigment epithelial
(RPE) cells and analyzed the serum cholesterol profiles of the
clinically screened subjects. The apoE4 distribution differed
significantly between ARMD patients and controls. The arg112 allele
frequency was 10.9% in the ARMD group when compared with 16.5% in the
younger controls and 18.8% in the clinically screened controls. The
pathologically diagnosed archived ARMD cases had the lowest allele
frequency of 5%. No significant differences in apoE2 distribution were
observed among the groups. A metaanalysis of 8 cohorts, including 4,289
subjects, showed a strong association between ARMD and 112R, but not
158C. In vitro studies found that recombinant apoE suppressed CCL2 and
VEGF expression in RPE cells. However, the E4 isoform showed more
suppression than E3 in both cases. Bojanowski et al. (2006) concluded
that these results further confirm the association between apoE4 and a
decreased risk of ARMD development. They suggested that the underlying
mechanisms may involve differential regulation of both CCL2 and VEGF by
the apoE isoforms.

MOLECULAR GENETICS

Using a yeast 1-hybrid screen with the proximal region of the APOE
promoter as bait, Salero et al. (2001) isolated cDNAs encoding the ZIC1
(600470) and ZIC2 (603073) transcription factors. Electrophoretic
mobility shift and mutational analyses identified binding sites in the
-136 to -125, -65 to -54, and -185 to -174 regions of the APOE promoter.
Luciferase reporter analysis showed that the ZIC proteins stimulate
potent transcriptional activation of APOE through these binding sites.

Using a variety of structural tools, Morrow et al. (2002) determined
that the 22 kD N terminus of APOE4 forms a stable folding intermediate
(called a molten globule structure) more readily than does APOE3 or
APOE2. They concluded that the differential abilities of the APOE
isoforms to form a molten globule may contribute to the isoform-specific
effects of APOE in disease.

Infante-Rivard et al. (2003) studied the transmission of the 3 APOE
alleles from heterozygous parents to newborns with intrauterine growth
restriction (IUGR), defined as birth weight below the 10th centile for
gestational age and sex, based on Canadian standards. They found a
significantly reduced transmission of the E2 allele. The E2 allele had
been associated with a lower risk of cardiovascular disease and babies
born with growth restriction had been reported to be at higher risk for
such disease later in life; the data seemed to reconcile these 2
observations.

To investigate the association of APOE and TGFB1 (190180) with obesity,
Long et al. (2003) analyzed several SNPs of each gene in 1,873 subjects
from 405 white families to test for linkage or association with 4
obesity phenotypes including BMI, fat mass, percentage fat mass (PFM),
and lean mass, with the latter 3 being measured by dual energy x-ray
absorptiometry. A significant linkage disequilibrium (p less than 0.01)
was observed between pairs of SNPs within each gene except for SNP5 and
SNP6 in TGFB1 (p greater than 0.01). Within-family association was
observed in the APOE gene for SNP1 and PFM (p = 0.001) and for the CGTC
haplotype with both fat mass (p = 0.012) and PFM (p = 0.006). For the
TGFB1 gene, within-family association was found between lean mass and
SNP5 (p = 0.003), haplotype C+C (p = 0.12), and haplotype T+C (p =
0.012). Long et al. (2003) concluded that the large study size,
analytical method, and inclusion of the lean mass phenotype improved the
power of their study and explained discrepancies in previous studies,
and that both APOE and TGFB1 are associated with obesity phenotypes in
their population.

In a review of genetic determinants of human longevity, Christensen et
al. (2006) pointed out that polymorphism in the APOE gene has
consistently been found to be associated with survival and longevity
(Gerdes et al., 2000).

Price et al. (2006) noted that hepatitis C virus (HCV; see 609532) RNA
is associated with low and very low density lipoproteins, and that HCV
uptake through LDLR into hepatocyte cell lines can be blocked by
anti-APOB and anti-APOE. They evaluated APOE genotypes in 420 Northern
Europeans with evidence of HCV exposure. Both APOE2 and APOE4 alleles
were associated with reduced likelihood of chronic infection, and no
APOE2 homozygotes were HCV seropositive. Price et al. (2006) concluded
that APOE2 and APOE4 alleles favor HCV clearance.

Burt et al. (2008) examined a large cohort of human immunodeficiency
virus (HIV; see 609423)-positive European and African American subjects
and found that those homozygous for APOE4 had an accelerated disease
course and progression to death compared with those homozygous for
APOE3. The increased risk was independent of CD4 (186940)-positive
T-cell count, delayed-type hypersensitivity reactivity, and CCL3L1
(601395)-CCR5 (601373) type. APOE4 alleles showed a weak association
with higher viral load. No association was observed with APOE4
homozygosity and HIV-associated dementia or with an increased risk of
acquiring HIV infection. Expression of recombinant APOE4 or APOE3 in
HeLa cells also expressing CD4 and CCR5 revealed that the presence of
APOE4 enhanced HIV fusion/cell entry of both R5 (macrophage-tropic) and
X4 (T lymphocyte-tropic) HIV strains in vitro. Burt et al. (2008)
concluded that APOE4 is a determinant of AIDS pathogenesis.

MAPPING

Olaisen et al. (1982) found linkage of C3 (120700) and apoE with a lod
score of 3.00 in males at a recombination fraction of 13%. Since the C3
locus is on chromosome 19, apoE can be assigned to that chromosome also.
The authors stated that preliminary evidence suggested that the apoE
locus is close to the secretor locus (182100). Berg et al. (1984)
studied apoE-C3 linkage with a C3 restriction fragment length
polymorphism. Low positive lod scores were found when segregation was
from a male (highest score at recombination fraction 0.17). Using DNA
probes, Das et al. (1985) mapped the apoE gene to chromosome 19 by
Southern blot analysis of DNA from human-rodent somatic cell hybrids.
Humphries et al. (1984) used a common TaqI RFLP near the APOC2 gene to
demonstrate close linkage to APOE in 7 families segregating for APOE
protein variants. No recombination was observed in 20 opportunities.
Apparent linkage disequilibrium was observed. On the other hand,
Houlston et al. (1989), using a robust PCR-based method for apoE
genotyping, found no strong linkage disequilibrium between the APOE and
APOC2 loci. Gedde-Dahl et al. (1984) found linkage between Se and APOE
with a peak lod score of 3.3 at recombination fraction of 0.08 in males
and 1.36 at 0.22 in females, and linkage between APOE and Lu with a lod
score 4.52 at zero recombination (sexes combined). The C3-APOE linkage
gave lod score 4.00 at theta 0.18 in males and 0.04 at theta 0.45 in
females. Triply heterozygous families confirmed that APOE is on the Se
side and on the Lu side of C3. Lusis et al. (1986) used a reciprocal
whole arm translocation between the long arm of 19 and the short arm of
chromosome 1 to map APOC1, APOC2, APOE and GPI to the long arm and LDLR,
C3 and PEPD to the short arm. Furthermore, they isolated a single lambda
phage that carried both APOC1 and APOE separated by about 6 kb of
genomic DNA. Since family studies indicate close linkage of APOE and
APOC2, the 3 must be in a cluster on 19q.

Fullerton et al. (2000) studied sequence haplotype variation in 5.5 kb
of genomic DNA encompassing the whole of the APOE locus and adjoining
flanking regions in 96 individuals from 4 populations (48 chromosomes
from each group): blacks from Jackson, Mississippi, Mayans from
Campeche, Mexico, Finns from North Karelia, Finland, and non-Hispanic
whites from Rochester, Minnesota. They identified 22 diallelic sites
defining 31 distinct haplotypes. Sequence analysis of the chimpanzee
APOE gene showed that it is most closely related to human E4-type
haplotypes. The evolutionary history of allelic divergence within humans
was inferred from the pattern of haplotype relationships. Sequence
analysis suggested that haplotypes defining the E3 and E2 alleles were
derived from the ancestral E4 and that the E3 group of haplotypes had
increased in frequency, relative to E4, in the past 200,000 years.
Substantial heterogeneity was found within all 3 classes of sequence
haplotypes, and there were important interpopulation differences in the
sequence variation underlying the protein isoforms that may be relevant
to interpreting conflicting reports of phenotypic associations with
variation in the common protein isoforms.

POPULATION GENETICS

Corbo and Scacchi (1999) analyzed the APOE allele distribution in the
world. They pointed out that the APOE3 allele is the most frequent in
all human groups, especially in populations with a long-established
agricultural economy such as those of the Mediterranean basin, where the
allele frequency is 0.849-0.898. The frequency of the APOE4 allele, the
ancestral allele, remains higher in populations such as Pygmies (0.407)
and Khoi San (0.370), aborigines of Malaysia (0.240) and Australia
(0.260), Papuans (0.368), some Native Americans (0.280), and Lapps
(0.310) where an economy of foraging still exists, or food supply is (or
was until shortly before the time of the report) scarce and sporadically
available. The APOE2 frequency fluctuates with no apparent trend
(0.145-0.02) and is absent in Native Americans. Corbo and Scacchi (1999)
suggested that the APOE4 allele, based on some functional properties,
may be a 'thrifty' allele. The exposure of APOE4 to the environmental
conditions at the time of the report (Western diet, longer life spans)
may have rendered it a susceptibility allele for coronary artery disease
and Alzheimer disease. The absence of the association of APOE4 with
either disorder in sub-Saharan Africans, and the presence of the
association in African Americans, seems to confirm this hypothesis.

ANIMAL MODEL

Because apolipoprotein E is a ligand for receptors that clear remnants
of chylomicrons and very low density lipoproteins, lack of apoE would be
expected to cause accumulation in plasma of cholesterol-rich remnants
whose prolonged circulation should be atherogenic. Zhang et al. (1992)
demonstrated that this was indeed the case: apoE-deficient mice
generated by gene targeting (Piedrahita et al., 1992) had 5 times normal
plasma cholesterol and developed foam cell-rich depositions in their
proximal aortas by age 3 months. These spontaneous lesions progressed
and caused severe occlusion of the coronary artery ostium by 8 months.
Plump et al. (1992) independently found the same in apoE-deficient mice
created by homologous recombination in ES cells. The findings in the
mouse model are comparable to those in 3 human kindreds with inherited
apoE deficiency (Ghiselli et al., 1981; Mabuchi et al., 1989; Kurosaka
et al., 1991). Commenting on the articles of Plump et al. (1992) and
Zhang et al. (1992), Brown and Goldstein (1992) pointed out that
molecular genetics has given us the opportunity to satisfy Koch's
postulates for multifactorial metabolic diseases. Further use of the
apoE gene-targeted mice was made by Linton et al. (1995), who showed
that the severe hyperlipidemia and atherosclerosis in these mice could
be prevented by bone marrow transplantation. Although the majority of
apoE in plasma is of hepatic origin, the protein is synthesized by a
variety of cell types, including macrophages. Because macrophages derive
from hematopoietic cells, bone marrow transplantation seemed a possible
therapeutic approach. ApoE-deficient mice given transplants of normal
bone marrow showed apoE in the serum and a normalization of serum
cholesterol levels. Furthermore, they showed virtually complete
protection from diet-induced atherosclerosis.

To unravel the metabolic relationship between apoE and apoC1 in vivo,
van Ree et al. (1995) generated mice deficient in both apolipoproteins.
This enabled subsequent production of transgenic mice with variable
ratios of normal and mutant apoE and apoC1 on a null background. They
found that double inactivation of the ApoE and ApoC1 (107710) loci in
mice, as well as single inactivations at either one of these loci, also
affected the levels of RNA expression of other members of the Apoe-c1-c2
cluster. Homozygous Apoe-c1 knockout mice were hypercholesterolemic and,
with serum cholesterol levels more than 4 times the control value,
resembled mice solely deficient in apoE.

Kashyap et al. (1995) noted that apolipoprotein E-deficient mice,
generated using homologous recombination for targeted gene disruption in
embryonic stem cells, developed marked hyperlipidemia as well as
atherosclerosis. Kashyap et al. (1995) found that intravenous infusion
of a recombinant adenovirus containing the human APOE gene resulted in
normalization of the lipid and lipoprotein profile with markedly
decreased total cholesterol, VLDL, IDL, and LDL, as well as increased
HDL. A marked reduction in the extent of aortic atherosclerosis was
observed after one month.

Plump et al. (1992) and Zhang et al. (1992) created apoE-deficient mice
by gene targeting in embryonic stem cells. These mice displayed severe
hypercholesterolemia even on a low-fat, low cholesterol diet. A key
regulator of cholesterol-rich lipoprotein metabolism, apoE, is
synthesized by numerous extrahepatic tissues. It is synthesized, for
example, in macrophages. To assess the contribution of
macrophage-derived apoE to hepatic clearance of serum cholesterol,
Boisvert et al. (1995) performed bone marrow transplantation on
hypercholesterolemic apoE-deficient 'knockout' mice. Serum cholesterol
levels dropped dramatically in the bone marrow-treated mice largely due
to a reduction in VLDL cholesterol. The extent of atherosclerosis in the
treated mice was also greatly reduced. Wildtype apoE mRNA was detected
in the liver, spleen, and brain of the treated mice indicating that gene
transfer was successfully achieved through bone marrow transplantation.
Masliah et al. (1995) observed an age-dependent loss of
synaptophysin-immunoreactive nerve terminals and microtubule-associated
protein 2-immunoreactive dendrites in the neocortex and hippocampus of
apoE-deficient (knockout) mice. They suggested that apoE may play a role
in maintaining the stability of the synapto-dendritic apparatus.

Sullivan et al. (1997) found that when the mouse apolipoprotein E gene
was replaced by the human APOE3 gene in transgenic mice, diet-induced
hypercholesterolemia and atherosclerosis were considerably enhanced.

To assess the effects of human APOE isoforms on deposition of
amyloid-beta protein in vivo, Holtzman et al. (1999) bred apoE3 and
apoE4 hemizygous (+/-) transgenic mice expressing human APOE by
astrocytes to mice homozygous (+/+) for a mutant amyloid precursor
protein, V717F (104760.0003), transgene that developed age-dependent
Alzheimer disease neuropathology. All mice had a mouse apoE null (-/-)
background. By 9 months of age, the mice heterozygous for the human
V717F mutant had developed deposition of amyloid-beta protein, but the
quantity of amyloid-beta deposits was significantly less than that seen
in heterozygous mice expressing mouse apoE. In contrast to effects of
mouse apoE, similar levels of human apoE3 and apoE4 markedly suppressed
early amyloid-beta deposition at 9 months of age in the V717F
heterozygous transgenic mice, even when compared with mice lacking apoE.
These findings suggested that human APOE isoforms decrease amyloid-beta
aggregation or increase amyloid-beta clearance relative to an
environment in which mouse apoE or no apoE is present.

To determine the effect of APOE on deposition of amyloid-beta and
Alzheimer disease pathology, Holtzman et al. (2000) compared APP(V717F)
transgenic mice expressing mouse, human, or no APOE. A severe,
plaque-associated neuritic dystrophy developed in the transgenic mice
expressing mouse or human APOE. Although significant levels of
amyloid-beta deposition also occurred in APP(V717F) transgenics that
completely lacked APOE, neuritic degeneration was virtually absent.
Expression of APOE3 and APOE4 in APP(V717F) transgenics who had knockout
of APOE resulted in fibrillar amyloid-beta deposits and neuritic plaques
by 15 months of age, and more than 10-fold more fibrillar deposits were
observed in APOE4-expressing APP(V717F) transgenic mice. The data
demonstrated a critical and isoform-specific role for APOE in neuritic
plaque formation, a pathologic hallmark of Alzheimer disease.

Raber et al. (2000) tested the spatial memory of transgenic mice
carrying human forms of amyloid precursor protein and either apoE3 or
apoE4 and found that it was impaired in mice with apoE4 but not in those
with apoE3, even though the levels of beta-amyloid in their brains were
comparable. As no plaques were detectable in APP and APP/apoE mice at 6
months of age, Raber et al. (2000) concluded that the differential
effects of apoE isoforms on human amyloid precursor protein/amyloid
beta-induced cognitive impairments are independent of plaque formation.
Learning deficits were more significant in female than in male mice.
These sex-dependent differences may relate to the increased
susceptibility of women to APOE4-associated cognitive deficits.

Mitchell et al. (2000) investigated the therapeutic efficacy of liver
repopulation in ApoE knockout mice. Knockout mice were transplanted with
Fas/CD95-resistant hepatocytes, which constitutively express ApoE, and
were subsequently submitted to weekly injections of nonlethal doses of
the Fas agonist antibody Jo2. After 8 weeks of treatment, mice exhibited
up to 30% of the normal level of plasma ApoE. ApoE secretion was
accompanied by a drastic and significant decrease in total plasma
cholesterol and a markedly reduced progression of atherosclerosis.

Mice homozygous for human APOE2 (107741.0001), regardless of age or
gender, develop type III hyperlipoproteinemia (HLP; 606945.0001),
whereas homozygosity for APOE2 results in HLP in no more than 10% of
humans, predominantly in adult males. By generating mice homozygous for
human APOE2 and heterozygous for human LDLR and mouse Ldlr, Knouff et
al. (2001) detected increased stability of mRNA in liver associated with
a truncation of the 3-prime-UTR of LDLR. Plasma lipoprotein levels were
normal in the LDLR heterozygotes. Knouff et al. (2001) concluded that
moderate and controlled overexpression of the LDLR completely
ameliorates the type III HLP phenotype of APOE2 homozygous mice.

Tangirala et al. (2001) determined that human APOE3 expressed in
Ldlr-null mice accumulated in artery walls. Expression induced
significant regression of advanced pre-existing atherosclerotic lesions.
Regression of lesions was accompanied by the loss of macrophage-derived
foam cells and a trend toward increased extracellular matrix of lesions,
but there was no change in plasma total cholesterol levels or
lipoprotein composition. APOE also had antioxidant properties as
measured by reduced levels of isoprostanes in urine, LDLs, and artery
walls.

Lesuisse et al. (2001) investigated whether increased expression of apoE
can, in a dominant fashion, influence amyloid deposition. They expressed
human apoE4 via the mouse prion protein promoter, resulting in high
expression in both astrocytes and neurons; only astrocytes efficiently
secreted human apoE4 (at least 5-fold more than endogenous). Mice
hyperexpressing human apoE4 developed normally and lived normal life
spans. The coexpression of human apoE4 with a mutant APP or mutant APP
and mutant presenilin did not lead to proportional changes in the age of
appearance, relative burden, character, or distribution of amyloid-beta
deposits. The authors concluded that the mechanisms by which apoE
influences amyloid-beta deposition may involve an aspect of its normal
function that is not augmented by hyperexpression.

Yamauchi et al. (2003) crossed ApoE-deficient mice with mice carrying a
transgene for the globular domain of adiponectin (605441). When
expressed on the ApoE-deficient background, the globular domain of
adiponectin reduced the atherosclerotic lesions even though plasma
glucose and lipid levels remained the same. The protection from
atherosclerosis was associated with decreased expression of class A
scavenger receptor (see 153622) and tumor necrosis factor alpha
(191160).

Chen et al. (2001) determined that ApoE is expressed in mouse kidneys,
specifically in the mesangial cells and at lower levels in glomerular
epithelial cells. They found that ApoE-null mice showed increased
mesangial cell proliferation and matrix formation compared with wildtype
mice. ApoE-null mice also had reduced levels of perlecan (142461), the
major heparin sulfate proteoglycan (HSPG) of the mesangial matrix. The
addition of ApoE3 to isolated mouse mesangial cells in culture
completely blocked mesangial cell proliferation stimulated by serum,
PDGF (190040), or LDL. ApoE3 also induced HSPG formation and inhibited
mesangial cell apoptosis induced by oxidized LDL. ApoE2 and ApoE4 were
less effective.

To study lipoprotein metabolism, Magoori et al. (2003) generated mice
lacking both apoE and Lrp5 (603506). On a normal diet, the double
knockout mice older than 4 months of age had 60% higher plasma
cholesterol levels than the levels observed with apoE deficiency alone.
LRP5 deficiency alone had no significant effects on the plasma
cholesterol levels. Analysis showed that the VLDL and low LDL fractions
were markedly increased in the double knockout mice. Atherosclerotic
lesions in the double knockout mice at age 6 months were severe, with
destruction of the internal elastic lamina.

Huang et al. (2001) found that apoE undergoes proteolytic cleavage in AD
brains and in cultured neuronal cells, resulting in the accumulation of
C-terminal-truncated fragments of apoE that are neurotoxic. Harris et
al. (2003) showed that this fragmentation is caused by proteolysis of
apoE by a chymotrypsin-like serine protease that cleaves apoE4 more
efficiently than apoE3. They found that transgenic mice expressing the
C-terminal-cleaved product, apoE4 (del272-299), at high levels in the
brain died at 2 to 4 months of age. The cortex and hippocampus of these
mice displayed AD-like neurodegenerative alterations, including
abnormally phosphorylated tau and silver-positive neurons that contained
cytosolic straight filaments with diameters of 15 to 20 nm, resembling
preneurofibrillary tangles. Transgenic mice expressing lower levels of
the truncated apoE4 survived longer but showed impaired learning and
memory at 6 to 7 months of age. Thus, C-terminal-truncated fragments of
apoE4, which occur in AD brains, are sufficient to elicit AD-like
neurodegeneration and behavioral deficits in vivo. Harris et al. (2003)
concluded that inhibiting their formation might inhibit apoE4-associated
neuronal deficits. Using various truncation and mutant constructs, Chang
et al. (2005) demonstrated that the neurotoxicity associated with ApoE4
fragments was mediated by both the lipid-binding region, spanning amino
acids 241-272, and the receptor-binding region, spanning amino acids
135-150, which caused mitochondrial dysfunction and neurotoxicity.

Lund et al. (2004) found aberrant DNA methylation patterns prior to the
onset of atherosclerosis in Apoe null mice. Both hyper- and
hypomethylation were found in aortas and peripheral blood mononuclear
cells of 4-week-old mutant mice with no detectable atherosclerotic
lesions. Sequencing and expression analysis of 60 leukocyte
polymorphisms revealed that epigenetic changes involved transcribed
genes as well as repeated interspersed elements. Furthermore, Lund et
al. (2004) showed that atherogenic lipoproteins promoted global DNA
hypermethylation in a human monocyte cell line.

Ricci et al. (2004) showed that atherosclerosis-prone ApoE-null mice
simultaneously lacking Jnk2 (602896) (ApoE -/- Jnk2 -/- mice), but not
ApoE -/- Jnk1 (601158) -/- mice, developed less atherosclerosis than do
ApoE-null mice. Pharmacologic inhibition of Jnk activity efficiently
reduced plaque formation. Macrophages lacking Jnk2 displayed suppressed
foam cell formation caused by defective uptake and degradation of
modified lipoproteins and showed increased amounts of the modified
lipoprotein-binding and -internalizing scavenger receptor A (see
153622), whose phosphorylation was markedly decreased.
Macrophage-restricted deletion of Jnk2 was sufficient to decrease
atherogenesis. Thus, Ricci et al. (2004) concluded that JNK2-dependent
phosphorylation of SRA promotes uptake of lipids in macrophages, thereby
regulating foam cell formation, a critical step in atherogenesis.

DeMattos et al. (2004) generated transgenic mice with a mutation in the
amyloid precursor protein (APP) (V717F; 104760.0003) that were also null
for apoE, apoJ (185430), or null for both apo genes. The double apo
knockout mice showed early-onset beta-amyloid deposition beginning at 6
months of age and a marked increase in amyloid deposition compared to
the other mice. The amyloid plaques were compact and diffuse, were
thioflavine S-positive (indicating true fibrillar amyloid), and were
distributed throughout the hippocampus and some parts of the cortex,
contributing to neuritic plaques. The findings suggested that apoE and
apoJ are not required for amyloid fibril formation. The double apo
knockout mice also had increased levels of intracellular soluble
beta-amyloid compared to the other mice. Insoluble beta-42 was similar
to the apoE-null mice, suggesting that ApoE has a selective effect on
beta-42. As APP is produced and secreted by neurons in the CNS and apoE
and clusterin are produced and secreted primarily by astrocytes in the
CNS, the interaction between the apolipoproteins and beta-amyloid occurs
in the interstitial fluid of the brain, an extracellular compartment
that is continuous with the CSF. DeMattos et al. (2004) found that
apoE-null and apoE/apoJ-null mice had increased levels of beta-amyloid
in the CSF and interstitial space, suggesting that apoE, and perhaps
apoJ, play a role in regulating extracellular CNS beta-amyloid clearance
independent of beta-amyloid synthesis. The data suggested that, in the
mouse, apoE and apoJ cooperatively suppress beta-amyloid deposition.

Steffens et al. (2005) investigated the effects of
delta-9-tetrahydrocannabinol (THC) in a mouse model of established
atherosclerosis. Oral administration of THC (1 mg/kg(-1) per day)
resulted in significant inhibition of disease progression. This
effective dose is lower than the dose usually associated with
psychotropic effects of THC. Furthermore, Steffens et al. (2005)
detected CB2 receptor (605051) (the main cannabinoid receptor expressed
on immune cells) in both human and mouse atherosclerotic plaques.
Lymphoid cells isolated from THC-treated mice showed diminished
proliferation capacity and decreased interferon-gamma (147570)
secretion. Macrophage chemotaxis, which is a crucial step for the
development of atherosclerosis, was also inhibited in vitro by THC. All
these effects were completely blocked by a specific CB2 receptor
antagonist. Steffens et al. (2005) concluded that oral treatment with a
low dose of THC inhibited atherosclerosis progression in the
apolipoprotein E knockout mouse model, through pleiotropic
immunomodulatory effects on lymphoid and myeloid cells, and that THC or
cannabinoids with activity at the CB2 receptor may be valuable targets
for treating atherosclerosis.

In cultured rat neuroblastoma cells, Ye et al. (2005) found that
lipid-poor Apoe4 increased beta-amyloid production to a greater extent
than lipid-poor Apoe3 due to more pronounced stimulation of APP
recycling by Apoe4 compared to Apoe3. The difference in beta-amyloid
production was abolished by blocking the LDL receptor (606945) protein
pathway. The findings indicated that there are isoform-specific effects
of ApoE on beta-amyloid production.

Dodart et al. (2005) generated mice carrying the APP V717F mutation
(104760.0003) and found that intracerebral hippocampal delivery of the
human ApoE E4 gene in V717F-mutant mice that lacked mouse Apoe resulted
in increased beta-amyloid deposition compared to similar mice that
received human ApoE E3 or E4. In V717F-mutant mice expressing mouse
Apoe, administration of human ApoE E4 did not result in increased
beta-amyloid burden, and administration of human ApoE E2 resulted in
decreased beta-amyloid burden, reflecting the dominant effect of the
human E2 isoform. Dodart et al. (2005) noted that the findings were
consistent with ApoE isoform-dependent human neuropathologic findings.
However, the lentiviral vectors used to deliver ApoE isoforms appeared
to result in a loss of hippocampal granule neurons, suggesting a
neurotoxic effect.

Malek et al. (2005) described a mouse model that combined 3 known ARMD
(603075) risk factors: advanced age, high fat cholesterol-rich (HF-C)
diet, and apoE genotype. Eyes of aged, targeted replacement mice
expressing human apoE2, apoE3, or apoE4 and maintained on an HF-C diet
showed apoE isoform-dependent pathologies of differential severity:
apoE4 mice were the most severely affected. They developed a
constellation of changes that mimicked the pathology associated with
human ARMD. These alterations included diffuse subretinal pigment
epithelial deposits, drusenoid deposits, thickened Bruch membrane, and
atrophy, hypopigmentation, and hyperpigmentation of the retinal pigment
epithelium. In extreme cases, apoE4 mice also developed choroidal
neovascularization, a hallmark of exudative ARMD. Neither age nor HF-C
diet alone was sufficient to elicit these changes. The findings
implicated the human apoE4 allele as a susceptibility gene for ARMD.

Seitz et al. (2005) reported that, in addition to the transcript (ApoE
S1) that translates into ApoE, there are 3 additional transcripts in
mice. Two of these transcripts, ApoE S2 and ApoE S3, which are predicted
to be transmembrane proteins, were transcribed from the sense strand.
ApoE AS1 was transcribed from the antisense strand and was complementary
to exon 4 of ApoE S1. The antisense transcript fell within the region of
the human APOE*E4 allele that has been linked to the familial onset form
of Alzheimer disease. Although ApoE S3 and ApoE AS1 were transcribed in
ApoE-knockout mice, ApoE S1 and ApoE S2 were not transcribed. In spinal
cord-injured C57BL/6 mice, both ApoE S1 and ApoE S3 transcripts were
upregulated 10-fold, and the antisense ApoE AS1 was upregulated 100-fold
compared with normal levels. Seitz et al. (2005) suggested that these
alternate transcripts may be involved in the molecular pathogenesis of
CNS disease and perhaps in ApoE expression in general, since ApoE S2 and
AS1 are also transcribed in humans.

In mouse hybrid cells and cultured rat hippocampal cells in vitro, Wang
et al. (2006) found that ApoE expression was differentially regulated by
estrogen receptor (ESR)-alpha (ESR1; 133430) and ESR-beta (ESR2;
601663). Pharmacologic activation of ESR1 significantly upregulated ApoE
mRNA and protein expression, whereas ESR2 activation resulted in
significant downregulation. Similar results were observed in the
hippocampus of ovariectomized rats in vivo.

Using different Apoe transgenic mice, including mice with ablation
and/or inhibition of cyclophilin A (CypA; 123840), Bell et al. (2012)
showed that expression of Apoe4 and lack of murine Apoe, but not Apoe2
and Apoe3, leads to blood-brain barrier breakdown by activating a
proinflammatory CypA-Nfkb (164011)-Mmp9 (120361) pathway in pericytes.
This, in turn, leads to neuronal uptake of multiple blood-derived
neurotoxic proteins, and microvascular and cerebral blood flow
reductions. Bell et al. (2012) showed that the vascular defects in
Apoe-deficient and Apoe4-expressing mice precede neuronal dysfunction
and can initiate neurodegenerative changes. Astrocyte-secreted Apoe3,
but not Apoe4, suppressed the CypA-Nfkb-Mmp9 pathway in pericytes
through a lipoprotein receptor. Bell et al. (2012) concluded that CypA
is a key target for treating APOE4-mediated neurovascular injury and the
resulting neuronal dysfunction and degeneration.

Dutta et al. (2012) showed that after myocardial infarction or stroke,
Apoe-null mice developed larger atherosclerotic lesions with a more
advanced morphology. This disease acceleration persisted over many weeks
and was associated with markedly increased monocyte recruitment. Seeking
the source of surplus monocytes in plaques, Dutta et al. (2012) found
that myocardial infarction liberated hematopoietic stem and progenitor
cells from bone marrow niches via sympathetic nervous system signaling.
The progenitors then seeded the spleen, yielding a sustained boost in
monocyte production.

*FIELD* AV
.0001
APOE2 ISOFORMS
HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL RECESSIVE
APOE, ARG158CYS

Apolipoprotein E2 exists in 2 main isoforms, arg158 and cys158 (Rall et
al., 1982; Gill et al., 1985). The second isoform (arg158-to-cys) was
found in 98 of 100 E2 alleles by Emi et al. (1988). The other isoforms
that give a band at the E2 position with isoelectric focusing include
E2(lys146-to-gln) and E2(arg145-to-cys). Type III hyperlipoproteinemia
is typically associated with homozygosity for a change in apolipoprotein
E2 from arg158 to cys.

By generating mice with a human APOE*2 allele in place of the mouse Apoe
gene via targeted gene replacement in embryonic stem cells, Sullivan et
al. (1998) demonstrated that a single amino acid difference (arg158 to
cys) in the APOE protein is sufficient to cause type III
hyperlipoproteinemia and spontaneous atherosclerosis in mice. Mice
expressing human APOE2 (2/2) had virtually all the characteristics of
type III hyperlipoproteinemia. Both their plasma cholesterol and
triglyceride levels were 2 to 3 times those in normolipidemic mice that
expressed human APOE3 (3/3) generated in an identical manner. The 2/2
mice were markedly defective in clearing beta-migrating VLDL particles
and spontaneously developed atherosclerotic plaques, even on a regular
diet. An atherogenic diet, high in fat and cholesterol, exacerbated
development of atherosclerosis and xanthomas in the 2/2 mice.

In 72 patients with type III hyperlipidemia and the APOE 2/2 genotype,
Evans et al. (2005) found a significantly higher frequency for at least
1 minor allele of the APOA5 -1131T-C and S19W (606368.0002) SNPs in
patients than in controls (53% vs 19.7%, respectively; p = 0.0001).
Evans et al. (2005) concluded that genetic variation in the APOA5 gene
is an important cofactor in the development of type III hyperlipidemia.

.0002
HYPERLIPOPROTEINEMIA AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5
APOE, GLU3LYS

This change was identified in Japanese by Tajima et al. (1988). Using
isoelectric focusing with immunoblotting in the study of blood specimens
from 1,269 Japanese subjects, Matsunaga et al. (1995) found that the
epsilon-5 allele had a frequency of 0.001.

.0003
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-CHRISTCHURCH
APOE, ARG136SER

This variant was described by Wardell et al. (1987) and Emi et al.
(1988). Wardell et al. (1987) studied the primary structure of apoE in 7
type III hyperlipoproteinemic patients with the apoE2/E2 phenotype. Six
of the patients had identical 2-dimensional tryptic peptide maps; these
differed from the normal by the altered mobility of a single peptide.
Amino acid analysis and sequencing showed that these patients had the
most common form of apoE2 (158 arg-to-cys). The seventh patient had a
unique peptide map with the new peptide resulting from a substitution of
136 arginine-to-serine. He was heterozygous for this and for the common
158 arg mutation; thus, he was a genetic compound.

.0004
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2
FAMILIAL DYSBETALIPOPROTEINEMIA
APOE, ARG145CYS

This variant was described by Rall et al. (1982) and Emi et al. (1988).
Rall et al. (1982) demonstrated heterogeneity in type III
hyperlipoproteinemia. They studied 3 subjects who were phenotypically
homozygous for apoE2 but showed considerable differences in the binding
activity to the fibroblast receptor. The subject with the poorest
binding apoE2 was genotypically homozygous for an apoE allele (epsilon
2); cysteine was found at sites A and B. The subject with the most
actively binding apoE2 was genotypically homozygous for an apoE allele
(epsilon 2*); cysteine was found at site A and at a new site, site C,
residue 145, which in apoE2 has arginine. Epsilon 2*, furthermore,
specifies a protein with arginine at site B (residue 158). The third
subject, whose apoE2 displayed binding activity intermediate between the
activities of the other 2, was genotypically heterozygous, having 1
epsilon 2 allele and 1 epsilon 2* allele.

.0005
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY
APOE, IVS3AS, A-G, -1

Cladaras et al. (1987) showed that one form of familial apoE deficiency
results from a point mutation in the 3-prime splice junction of the
third intron of the APOE gene. The change, an A-to-G substitution in the
penultimate 3-prime nucleotide of the third intron, abolished the
correct 3-prime splice site, thus creating 2 abnormally spliced mRNA
forms. Both mRNAs contain chain termination codons within the intronic
sequence. The clinical features of the patient were described by
Ghiselli et al. (1981) and Schaefer et al. (1986).

.0006
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE LEIDEN
APOE, 21-BP INS, DUP CODONS 121-127

Havekes et al. (1986) found type III hyperlipoproteinemia (HLP) in a
dominant pedigree pattern in a family with a variant of E3 they called
E3(Leiden). By isoelectric focusing, the affected persons appeared to be
homozygous for normal apoE3, but the variant E3 showed defective binding
to LDL receptor, and on sodium dodecyl sulfate polyacrylamide gel
electrophoresis showed mobility intermediate to those of normal E3 and
normal E2. The mother and 5 of 8 sibs had type III HLP; 4 of the 5 had
xanthomatosis. The affected persons were heterozygotes E3/E3(Leiden).
Wardell et al. (1989) demonstrated a 7-amino acid insertion that is a
tandem repeat of residues 121-127. In a screening of patients with
familial dysbetalipoproteinemia, de Knijff et al. (1991) found 5
probands showing heterozygosity for the APOE*3-Leiden allele.
Genealogical studies revealed that these probands shared common ancestry
in the 17th century. In 1 large kindred spanning 3 generations, 37
additional heterozygotes were detected. Although severity varied, all
carriers showed characteristics of dysbetalipoproteinemia such as: (a)
elevated levels of cholesterol in VLDL and IDL fractions; (b) elevated
ratios of cholesterol levels in these density fractions over total
plasma levels of triglycerides; and (c) strongly increased plasma levels
of apoE. Multiple linear regression analysis showed that most of the
variability in expression of familial dysbetalipoproteinemia in
APOE*3-Leiden allele carriers can be explained by age.

In a discussion of mouse models of atherosclerosis, Breslow (1996)
referred to the development of a transgenic mouse carrying the
APOE-Leiden mutation. When fed a very high cholesterol diet containing
cholic acid, these mice had cholesterol levels of 1,600 to 2,000 mg/dl
and developed fatty streak and fibrous plaque lesions.

.0007
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE7
APOE-SUITA
APOE, GLU244LYS AND GLU245LYS

Maeda et al. (1989) and Tajima et al. (1989) found that 2 contiguous
glutamic acid residues, glu244 and glu245, are changed to lysine
residues, lys244 and lys245. This involved a change from GAC-GAG to
AAC-AAG. Using isoelectric focusing with immunoblotting in the study of
blood specimens from 1,269 Japanese subjects, Matsunaga et al. (1995)
found that the epsilon-7 allele had a frequency of 0.007.

.0008
HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT
FAMILIAL DYSBETALIPOPROTEINEMIA
APOE, CYS112ARG AND ARG142CYS

In a family reported by Havel et al. (1983), Rall et al. (1989) found
that the members with type III hyperlipoproteinemia (HLP) were compound
heterozygotes for 2 different APOE alleles, one coding for the normal
APOE3 and one for a previously undescribed variant APOE3 with 2 changes:
arginine replacing cysteine at residue 112 and cysteine replacing
arginine at residue 142. The variant APOE3 was defective in its ability
to bind to lipoprotein receptors, a functional defect probably
contributing to expression of type III HLP in this kindred. Type III HLP
typically is associated with homozygosity for apolipoprotein E2
(arg158-to-cys); see 107741.0001. Dominant expression of type III HLP
associated with apoE phenotype E3/3 is caused by heterozygosity for a
common apoE variant, apoE3 (cys112-to-arg; arg142-to-cys). To determine
the functional characteristics of the variant protein, Horie et al.
(1992) used recombinant DNA techniques to produce the variant in
bacteria. They also produced a non-naturally occurring variant,
apoE(arg142cys), that had only the cysteine substituted at residue 142.
They demonstrated that the cys142 variant was responsible for the
defective binding to lipoprotein receptors because both showed the same
defect. The arg112,cys142 variant predominates 3:1 over normal apoE3 in
the very low density lipoproteins of plasma from an affected subject.
Horie et al. (1992) concluded that unique properties of the
arg112,cys142 variant provided an explanation for its association with
dominant expression of type III HLP.

.0009
APOLIPOPROTEINEMIA E1
APOE, GLY127ASP AND ARG148CYS

Weisgraber et al. (1984) found an electrophoretic variant of apoE in a
Finnish hypertriglyceridemic subject. The variant was designated E1
(gly127-to-asp, arg148-to-cys). Family studies showed 'vertical
transmission.' The relation of E1 to hypertriglyceridemia was unclear.

.0010
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG
APOE, LYS146GLU

Mann et al. (1989) described this mutation as the basis of familial
dysbetalipoproteinemia.

The mutation led to the dominant expression of type III
hyperlipoproteinemia in all 5 affected patients heterozygous for the
mutant allele in this family. A second family with type III
hyperlipoproteinemia due to the identical mutation was reported by
Moriyama et al. (1992). Mann et al. (1995) determined the structural
defect in the ApoE-1 molecule resulting from this mutation and studied
its functional implications using in vivo kinetic studies in the
original proband and in normal subjects, and using in vitro binding
assays with human fibroblasts and the proteoglycan heparin. They
concluded that the functional dominance of the mutation resulted from
the abnormal in vitro binding characteristics and the altered in vivo
metabolism of the mutant protein.

.0011
DYSBETALIPOPROTEINEMIA DUE TO APOE2
APOE, LYS146GLN

As in APOE1-Harrisburg, a mutation at position 146 leads to
dysbetalipoproteinemia, suggesting that this residue plays a crucial
role in removal of chylomicrons and VLDL in vivo. In the Netherlands,
Smit et al. (1990) found that all 40 patients with familial
dyslipoproteinemia and the E2E2 phenotype were homozygous for the
E2(arg158-to-cys) mutation. On the other hand, all 3 unrelated patients
with the E3E2 phenotype showed the rare E2(lys146-to-gln) mutation due
to an A-to-C substitution at nucleotide 3847 of the APOE gene. This
mutation was not found in 13 normolipidemic persons with the E2E2
phenotype or 120 with the E3E2 phenotype selected from a random
population sample. Family studies showed predisposition to type III
hyperlipoproteinemia with high penetrance. Thus, this is a highly
penetrant dominant form of the disease; E2(arg158-to-cys) is a low
penetrant, recessive form. Dominant inheritance has been observed also
with E1(Harrisburg), E3(Leiden), and E3(cys112-to-arg; arg142-to-cys).
Some of the reduced penetrance of the E2 allele in causing familial
dysbetalipoproteinemia is based on the fact that all E2 as phenotyped by
isoelectric focusing is not genetically a single entity.

.0012
APOE2-DUNEDIN
APOE, ARG228CYS

In identical twin brothers with the E2/2 phenotype but with type IV/V
hyperlipoproteinemia, Wardell et al. (1990) found compound
heterozygosity for the arg158-to-cys mutation and a second unusual
mutation representing a substitution of cysteine for arginine at
position 228.

.0013
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA
APOE, GLU13LYS AND ARG145CYS

In a 24-year-old white female with severe type III hyperlipoproteinemia
(HLP), Lohse et al. (1991) found 2 rare point mutations. One was a
C-to-T mutation which converted arginine (CGT) at position 145 of the
mature protein to cysteine (TGT), thus creating the APOE-2* variant
(107741.0004). A second G-to-A substitution at amino acid 13 led to the
exchange of lysine (AAG) for glutamic acid (GAG), thereby adding 2
positive charge units to the protein and producing the APOE-5 variant.
Both mutations resulted in loss of restriction enzyme cleavage sites.
The proband was homozygous for both mutations. Lohse et al. (1992)
extended their analyses to include 9 additional family members of the
Philadelphia kindred spanning 4 generations. DNA and protein analysis
demonstrated that the originally described proposita, called by them
propositus, was a true homozygote for the apolipoprotein
E4(Philadelphia) allele and that 6 of the 9 family members were
heterozygous for the mutant allele and the normal E3 allele or, in 1
case, the E4 allele. Heterozygosity led to the expression of a moderate
form of type III HLP without clinical manifestations. The simultaneous
presence of unaffected persons, heterozygotes, and a homozygote makes it
possible to conclude that the mutation shows incomplete dominance.

.0014
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY
APOE3-WASHINGTON
APOE, TRP210TER

Lohse et al. (1992) studied a kindred with apolipoprotein E deficiency
and a truncated low molecular weight apoE mutant, designated
apoE-3(Washington). Gel electrophoresis demonstrated complete absence of
the normal apoE isoproteins and the presence of a small quantity of a
lower molecular weight apoE. Plasma apoE levels in the proband were
approximately 4% of normal. This marked deficiency of apoE resulted in
delayed uptake of chylomicron and very low density lipoprotein (VLDL)
remnants by the liver, elevated plasma cholesterol levels, mild
hypertriglyceridemia, and the development of type III
hyperlipoproteinemia. Sequence analysis demonstrated a G-to-A transition
which converted amino acid 210 of the mature protein, tryptophan (TGG),
to a premature chain termination codon (TAG), thus leading to the
synthesis of a truncated E apolipoprotein of 209 amino acids with a
molecular mass of 23.88 kD. The nucleotide substitution also resulted in
the formation of a new restriction site for MaeI. Using this enzyme,
they were able to establish that the proband was a homozygote and that
her 2 offspring were heterozygotes. They stated that only a single
kindred with apoE deficiency had been reported previously. This was the
kindred reported by Ghiselli et al. (1981) and elucidated at the
molecular level by Cladaras et al. (1987); see 107741.0005.

.0015
APOE3 ISOFORM
APOE, CYS112 AND ARG158

Weisgraber et al. (1981) and Rall et al. (1982) identified one of the 3
major apolipoprotein E isoforms, apolipoprotein E3. The variant has
cys112 and arg158. This is the most common variant, with frequencies of
40% to 90% in various populations.

.0016
ALZHEIMER DISEASE 2, DUE TO APOE4 ISOFORM
APOE, CYS112ARG

Weisgraber et al. (1981), Das et al. (1985), and Paik et al. (1985)
identified the apolipoprotein E4 (apoE4) isoform, in which there is a
cys112-to-arg (C112R) substitution. This variant is found in 6 to 37% of
individuals from different populations. Individuals carrying the
apolipoprotein E4 allele display low levels of apolipoprotein E and high
levels of plasma cholesterol, low density lipoprotein-cholesterol,
apolipoprotein B, lipoprotein (a), and are at higher risk for coronary
artery disease than other individuals.

Saunders et al. (1993) reported an increased frequency of the E4 allele
in a small prospective series of possible-probable AD patients
presenting to the memory disorders clinic at Duke University, in
comparison with spouse controls. Corder et al. (1993) found that the
APOE*E4 allele is associated with the late-onset familial and sporadic
forms of Alzheimer disease. In 42 families with the late-onset form of
Alzheimer disease (AD2; 104310), the gene had been mapped to the same
region of chromosome 19 as the APOE gene. Corder et al. (1993) found
that the risk for AD increased from 20 to 90% and mean age of onset
decreased from 84 to 68 years with increasing number of APOE*E4 alleles.
Homozygosity for APOE*E4 was virtually sufficient to cause AD by age 80.

Myers et al. (1996) examined the association of apolipoprotein E4 with
Alzheimer disease and other dementias in 1,030 elderly individuals in
the Framingham Study cohort. They found an increased risk for Alzheimer
disease as well as other dementias in patients who were homozygous or
heterozygous for E4. However they pointed out that most apoE4 carriers
do not develop dementia and about one-half of Alzheimer disease is not
associated with apoE4.

Tang et al. (1996) compared relative risks by APOE genotypes in a
collection of cases and controls from 3 ethnic groups in a New York
community. The relative risk for Alzheimer disease associated with APOE4
homozygosity was increased in all ethnic groups: African American RR =
3.0; Caucasian RR = 7.3; and Hispanic RR = 2.5 (compared with the RR
with APOE3 homozygosity). The risk was also increased for APOE4
heterozygous Caucasians and Hispanics, but not for African Americans.
The age distribution of the proportion of Caucasian and Hispanics
without AD was consistently lower for APOE4 homozygous and APOE4
heterozygous individuals than for those with other APOE genotypes. In
African Americans this relationship was observed only in APOE4
homozygotes. Differences in risk among APOE4 heterozygous African
Americans suggested to the authors that other genetic or environmental
factors may modify the effect of APOE4 in some populations.

In a longitudinal study of 55 patients with Alzheimer disease, Mori et
al. (2002) determined that the rate of hippocampal atrophy was
significantly greater in those with an APOE4 allele, and that the rate
became more severe as the number of E4 alleles increased. However, their
data did not support the findings of previous studies that the E4 allele
is associated with an increased rate of cognitive decline.

In a cohort of 180 asymptomatic individuals with a mean age of 60 years,
Caselli et al. (2004) found that carriers of an E4 allele showed greater
declines in memory performance over a median period of 33 months
compared to those without an E4 allele. Among 494 individuals with mild
cognitive impairment, Farlow et al. (2004) found an association between
the E4 allele and worse scores on cognition tests as well as smaller
total hippocampal volume. Among 6,202 Caucasian middle-aged individuals
(47 to 68 years), Blair et al. (2005) found that carriers of the E4
allele had greater cognitive decline over a 6-year period compared to
those without an E4 allele. Results for 1,693 African American patients
were inconclusive.

Enzinger et al. (2004) noted that decreases in brain size and volume in
patients with multiple sclerosis (126200) are related to neuroaxonal
injury and loss, and are a useful surrogate marker of tissue damage and
disease progression. In a study of 99 patients with MS, the authors
found that patients who carried an E4 allele had more relapses during
the study period and had a 5-fold higher rate of annual brain volume
loss compared to patients without the E4 allele. Over time, E4 carriers
also had an increase in individual lesions on MRI, termed 'black holes.'
Among all genotype groups, the lowest annual loss of brain volume
occurred in patients with an E2 allele. Among 76 patients with
relapsing-remitting MS, de Stefano et al. (2004) found that carriers of
the E4 allele showed significantly lower total brain volumes compared to
MS patients without the E4 alleles. There was no difference in lesion
volume between the 2 groups. The authors suggested that the E4 allele is
linked to impaired mechanisms of cell repair and severe tissue
destruction in MS.

Among 89 patients with head injury, Teasdale et al. (1997) found that
patients with the E4 allele were more likely than those without the E4
allele to have an unfavorable outcome 6 months after head injury. The
authors discussed the role of the apoE protein in response to acute
brain injury. In a prospective study of 69 patients with severe blunt
trauma to the head, Friedman et al. (1999) found an odds ratio of 5.69
for more than 7 days of unconsciousness and 13.93 for a suboptimal
neurologic outcome at 6 months for individuals with an APOE4 allele
compared to those without that allele.

In 110 patients with traumatic brain injury (TBI), Crawford et al.
(2002) tested memory and other cognitive variables and found that
patients with the APOE4 allele had more difficulty with memory than
matched patients without the E4 allele. In those with the E4 allele,
performance was poor regardless of severity of injury, whereas in those
without the E4 allele, performance worsened with more severe injury.
Crawford et al. (2002) noted that TBI may result in greater damage to
the medial temporal lobe structures involved in memory and suggested a
role for the APOE protein in neuronal repair.

In 87 patients with mild to moderate TBI, Liberman et al. (2002) used
neuropsychologic testing to examine whether the APOE4 genotype affected
short-term recovery. At 6 weeks, E4-positive patients had lower mean
scores on 11 of 13 tests, but the differences from the E4-negative group
were smaller than the differences observed at 3 weeks. Although Liberman
et al. (2002) stated that the findings are consistent with delayed
recovery among E4-positive TBI patients, perhaps due to interactions
with beta-amyloid, they cautioned against the generalizability of the
results.

Among 60 patients with TBI with a mean follow-up of 31 years, Koponen et
al. (2004) found that presence of the E4 allele increased the risk for
dementia, but there was no association between the E4 allele and
development of other psychiatric illnesses, including depression,
anxiety, psychosis, or personality disorders.

To pursue mechanisms by which APOE4 affects human brain physiology and
modifies late-onset Alzheimer disease risk, Rhinn et al. (2013) analyzed
whole-transcriptome cerebral cortex gene expression data in unaffected
APOE4 carriers and late-onset Alzheimer disease patients. APOE4 carrier
status was associated with a consistent transcriptomic shift that
broadly resembled the late-onset Alzheimer disease profile. Differential
coexpression correlation network analysis of the APOE4 and late-onset
Alzheimer disease transcriptomic changes identified a set of candidate
core regulatory mediators. Several of these, including APBA2 (602712),
FYN (137025), RNF219, and SV2A (185860), encode modulators of late-onset
Alzheimer disease-associated amyloid beta A4 precursor protein (APP;
104760) endocytosis and metabolism. Furthermore, a genetic variant
within RNF219 was found to affect amyloid deposition in human brain and
late-onset Alzheimer disease age of onset.

.0017
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY, AUTOSOMAL
RECESSIVE
APOE, 1-BP DEL, 2919G DEL, FS60TER

Feussner et al. (1992) identified in German subjects with autosomal
recessive familial dysbetalipoproteinemia a 1-bp deletion (G) at the
last nucleotide of codon 30 at position 2919 of exon 3 (or the first 2
nucleotides of codon 31 at nucleotide positions 2920 or 2921). This
frameshift mutation (called APOE0) creates a termination at codon 60
resulting in a truncated protein. Individuals heterozygous for this
mutation display reduced plasma apolipoprotein E levels. Subjects
homozygous for this allele have undetectable plasma apolipoprotein E
levels concomitant with severe forms of familial dysbetalipoproteinemia.

.0018
HYPERLIPOPROTEINEMIA, TYPE III
APOE3(-)-KOCHI
APOE, ARG145HIS

This arg145-to-his amino acid change was identified in a Japanese
subject with familial dysbetalipoproteinemia by Suehiro et al. (1990).
The variant was designated E3(-) because it is slightly more acidic than
apolipoprotein E3 (107741.0015).

.0019
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2-FUKUOKA
APOE2-FUKUOKA
APOE, ARG158CYS AND ARG224GLN

In Japanese subjects with familial dysbetalipoproteinemia, Moriyama et
al. (1992) identified compound heterozygosity for the arg158-to-cys
(ApoE2; 107741.0001) mutation and a G-to-A transition at exon 4 leading
to a change from arginine-224 to glutamine.

.0020
HYPERCHOLESTEROLEMIA AND HYPERTRIGLYCERIDEMIA, TYPE III
APOE, GLU3LYS AND GLU13LYS

In French-Canadian subjects with hypercholesterolemia and
hypertriglyceridemia, Mailly et al. (1991) identified an apolipoprotein
E5 (107741.0002) with a glu13-to-lys substitution.

.0021
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2
APOE, ARG158CYS AND VAL236GLU

Van den Maagdenberg et al. (1993) identified in Dutch subjects with
hypertriglyceridemia T-to-A transition leading to a substitution of
glutamic acid for valine-236 in an APOE2 allele.

.0022
HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE4
APOE, CYS112ARG AND ARG251GLY

Van den Maagdenberg et al. (1993) identified in Dutch subjects with
hypertriglyceridemia 2 substitutions in an APOE3 allele: cys112arg and
arg251gly.

.0023
APOE4(-)-FREIBURG
APOE, LEU28PRO AND CYS112ARG

Wieland et al. (1991) identified an apolipoprotein E4 variant in
German-Caucasian subjects not associated with hyperlipidemia. The
variant was designated E4(-) because it is slightly more acidic than E4
(107741.0016). This variant has a leu28-to-pro substitution
(CTG-to-CCG).

.0024
APOE3(-)-FREIBURG
APOE, THR42ALA

In German-Caucasian subjects, Wieland et al. (1991) identified an
apolipoprotein E3 variant designated E3(-) that is slightly more acidic
than E3. This variant has a thr42-to-ala substitution (ACA-to-GCA) and
was not associated with hyperlipidemia.

.0025
APOE4 VARIANT
APOE, PRO84ARG AND CYS112ARG

In American-white subjects, Ordovas et al. (1987) and Wardell et al.
(1991) identified an apolipoprotein E4 variant not associated with
hyperlipidemia. This variant has a pro84-to-arg substitution
(CCG-to-CGG).

In a metaanalysis of 1,500 cases of schizophrenia versus 2,702 controls,
Allen et al. (2008) found that the odds ratio for the APOE4 versus the
APOE3 genotype was 1.16 (95% CI, 1.00-1.34; p = 0.043).

.0026
APOE3 VARIANT
APOE, ALA99THR AND ALA152PRO

In American subjects, McLean et al. (1984) identified an apolipoprotein
E3 variant not associated with hyperlipidemia. This variant has
ala99-to-thr and ala152-to-pro substitutions (GCG-to-ACG and GCC-to-CCC,
respectively).

In a metaanalysis of 1,500 cases of schizophrenia versus 2,702 controls,
Allen et al. (2008) found that the odds ratio for the APOE4 versus the
APOE3 genotype was 1.16 (95% CI, 1.00-1.34; p = 0.043).

.0027
APOE2 VARIANT
APOE, ARG134GLN

De Knijff et al. (1994) cited unpublished data identifying an
apolipoprotein E2 variant in Dutch subjects with no hyperlipidemia. This
variant has an arg134-to-gln substitution (CGG-to-CAG). The mutation is
located in the receptor-binding domain.

.0028
APOE4 VARIANT
APOE, ARG274HIS

In Dutch subjects, Van den Maagdenberg et al. (1993) identified an
apolipoprotein E4 variant not associated with hyperlipidemia. This
variant has an arg274-to-his substitution (TGC-to-CGC).

.0029
APOE4(+)
APOE, SER296ARG

In Dutch subjects, Van den Maagdenberg et al. (1993) identified an
apolipoprotein E4 variant not associated with hyperlipidemia. The
variant was designated E4(+) because it is slightly more basic than E4.
This variant has a ser296-to-arg substitution (AGC-to-CGC).

.0030
MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO
CORONARY ARTERY DISEASE, SEVERE, SUSCEPTIBILITY TO, INCLUDED
APOE, -219G-T (dbSNP rs405509)

In a large multicenter case-control study of myocardial infarction using
567 cases and 678 controls, Lambert et al. (2000) identified an
increased risk of myocardial infarction among patients carrying the
-219T allele, a promoter polymorphism. The odds ratio was 1.29, with a
95% confidence interval of 1.09 to 1.52 and a P value of less than
0.003. The effect of the allele was independent of the presence of other
promoter polymorphisms or mutations including the APOE
epsilon-2/epsilon-3/epsilon-4 polymorphism. Moreover, the -219T allele
greatly decreased the APOE plasma concentrations in a dose-dependent
manner (P less than 0.008). Lambert et al. (2000) concluded that the
-219G-T polymorphism of the APOE regulatory region is a genetic
susceptibility risk factor for myocardial infarction and constitutes
another common risk factor for both neurodegenerative and cardiovascular
diseases.

In a large cohort of patients with angiographically documented coronary
artery disease, Ye et al. (2003) found that the APOE -219T allele and
the E4 allele had independent effects on CAD severity. The frequency of
the E4 allele and the -219T allele both increased linearly with
increasing number of diseased vessels. The -219T/T genotype conferred an
odds ratio of 1.598 in favor of increased disease severity, and the
-219T/T haplotype in combination with the E4 haplotype conferred an odds
ratio of 1.488. The findings suggested that the -219T and E4
polymorphisms, which may affect the quantity and quality of apoE,
respectively, have independent and possibly additive effects on CAD
severity.

.0031
SEA-BLUE HISTIOCYTE DISEASE
APOE, 3-BP DEL, 499CTC

Nguyen et al. (2000) reported 2 kindreds in which the sea-blue
histiocyte syndrome (269600) was associated with an apoE variant in the
absence of severe dyslipidemia. Both patients presented with mild
hypertriglyceridemia and splenomegaly. After splenectomy both patients
developed severe hypertriglyceridemia. Pathologic evaluation of the
spleen revealed the presence of sea-blue histiocytes. An APOE mutation
was found: a 3-bp deletion resulting in the loss of leucine-149 in the
receptor-binding region of APOE (delta149 leu). Although the probands
were unrelated, they were of French Canadian ancestry, suggesting the
possibility of a founder effect.

In 2 brothers with splenomegaly, thrombocytopenia, and
hypertriglyceridemia, Faivre et al. (2005) identified the delta149 leu
mutation in the APOE gene. Their mother, who also had the mutation, had
only isolated hypertriglyceridemia. One brother had a large beta band in
the VLDL fraction and an elevated VLDL cholesterol-to-plasma
triglyceride ratio; Faivre et al. (2005) suggested that the more severe
phenotype might be explained by the presence of an APOE2 allele
(107741.0001) in this patient.

.0032
LIPOPROTEIN GLOMERULOPATHY
APOE SENDAI
APOE, ARG145PRO

In 3 Japanese patients with lipoprotein glomerulopathy (LPG; 611771),
Oikawa et al. (1997) identified heterozygosity for a G-to-C transversion
in exon 4 of the APOE gene that resulted in substitution of proline for
arginine at codon 145 (R145P). Two of the patients were related as
parent and child; the third patient was unrelated to them. Oikawa et al.
(1997) termed the mutation 'APOE Sendai' for the proband's city of
origin.

Ishigaki et al. (2000) introduced APOE Sendai into ApoE-deficient
hypercholesterolemic mice using adenovirus-mediated gene transfer and
observed insufficient correction of hypercholesterolemia and a marked
and temporal induction of plasma triglyceride levels. In vitro binding
studies demonstrated reduced affinity of APOE-Sendai for the low density
lipoprotein receptor (LDLR; 606945), suggesting that
dysbetalipoproteinemia in LPG is caused by the APOE mutation. Histologic
examination revealed marked intraglomerular depositions of
APOE-containing lipoproteins.

.0033
LIPOPROTEIN GLOMERULOPATHY
APOE KYOTO
APOE, ARG25CYS

In a Japanese man with lipoprotein glomerulopathy (LPG; 611771),
Matsunaga et al. (1999) detected a heterozygous C-to-T transition in
exon 3 of the APOE gene that resulted in substitution of cysteine for
arginine at codon 25 of the mature protein (R25C). The authors
designated the mutation APOE Kyoto. The proband's mother, who also
carried the mutation, was clinically unaffected.

Rovin et al. (2007) identified APOE Kyoto in 2 American males of
European descent with LPG.

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Amatruda et al. (1974); Blum et al. (1982); Borresen and Berg (1981);
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Psychiat. 6: 413-419, 2001.

321. Zwemmer, J.; Uitdehaag, B.; van Kamp, G.; Barkhof, F.; Polman,
C.: Association of APOE polymorphisms with disease severity in MS
is limited to women. (Letter) Neurology 63: 1139 only, 2004.

*FIELD* CS

Skin:
Xanthomatosis (tuberous, tuberoeruptive, planar and/or tendon)

Cardiac:
Premature coronary disease;
Angina pectoris

Vascular:
Premature peripheral vascular disease

Metabolic:
Abnormal glucose tolerance

Neuro:
APOE*E4 allele associated with late-onset familial and sporadic forms
of Alzheimer disease

Misc:
Primary dysbetalipoproteinemia a monogenic variant (APOE1-HARRISBURG
.0010, APOE3 LEIDEN .0006, APOE2 .0011);
Incompletely dominant type III hyperlipoproteinemia without clinical
manifestations (APOE4-PHILADELPHIA .0013);
Age dependent, rarely evident before the third decade;
Hyperlipidemia exacerbated by carbohydrate, hypothyroidism and obesity

Lab:
Apolipoprotein E;
Increased plasma cholesterol;
Increased triglycerides;
Impaired clearance of chylomicron and VLDL remnants;
Type III hyperlipoproteinemia with some alleles;
Defective apoE3 binding to LDL receptor (APOE LEIDEN .0006, APOE .0008);
Mild hypertriglyceridemia (APOE3-WASHINGTON .0014)

Inheritance:
Autosomal recessive with pseudodominance due to high gene frequency
(e.g. APOE .0009)

*FIELD* CN
Ada Hamosh - updated: 11/13/2013
Ada Hamosh - updated: 10/7/2013
Ada Hamosh - updated: 8/10/2012
Ada Hamosh - updated: 6/5/2012
Ada Hamosh - updated: 5/15/2012
Cassandra L. Kniffin - updated: 4/18/2011
Cassandra L. Kniffin - updated: 6/25/2010
Cassandra L. Kniffin - updated: 1/6/2010
Paul J. Converse - updated: 8/27/2009
Paul J. Converse - updated: 8/6/2009
Cassandra L. Kniffin - updated: 7/21/2009
Cassandra L. Kniffin - updated: 6/17/2009
Marla J. F. O'Neill - updated: 2/12/2009
Ada Hamosh - updated: 8/6/2008
Cassandra L. Kniffin - updated: 6/19/2008
Jane Kelly - updated: 6/5/2008
Ada Hamosh - updated: 4/1/2008
Cassandra L. Kniffin - updated: 2/7/2008
Victor A. McKusick - updated: 12/20/2007
Victor A. McKusick - updated: 11/12/2007
Jane Kelly - updated: 10/29/2007
Cassandra L. Kniffin - updated: 9/20/2007
Cassandra L. Kniffin - updated: 6/15/2007
George E. Tiller - updated: 5/22/2007
Cassandra L. Kniffin - updated: 1/4/2007
Jane Kelly - updated: 10/6/2006
Marla J. F. O'Neill - updated: 9/8/2006
Victor A. McKusick - updated: 7/12/2006
Victor A. McKusick - updated: 6/6/2006
Cassandra L. Kniffin - updated: 4/24/2006
Cassandra L. Kniffin - updated: 4/18/2006
Cassandra L. Kniffin - updated: 1/4/2006
Marla J. F. O'Neill - updated: 11/30/2005
Marla J. F. O'Neill - updated: 11/15/2005
Cassandra L. Kniffin - updated: 11/7/2005
Ada Hamosh - updated: 11/2/2005
Cassandra L. Kniffin - updated: 9/1/2005
Cassandra L. Kniffin - updated: 7/12/2005
Ada Hamosh - updated: 6/2/2005
Cassandra L. Kniffin - updated: 3/4/2005
Ada Hamosh - updated: 12/10/2004
Marla J. F. O'Neill - updated: 11/3/2004
Cassandra L. Kniffin - updated: 9/17/2004
Marla J. F. O'Neill - updated: 9/13/2004
Patricia A. Hartz - updated: 8/16/2004
Jane Kelly - updated: 7/26/2004
Natalie E. Krasikov - updated: 7/7/2004
Cassandra L. Kniffin - updated: 6/21/2004
Natalie E. Krasikov - updated: 3/30/2004
Cassandra L. Kniffin - updated: 1/29/2004
Victor A. McKusick - updated: 12/8/2003
Victor A. McKusick - updated: 10/7/2003
Cassandra L. Kniffin - updated: 9/5/2003
Jane Kelly - updated: 8/19/2003
Michael B. Petersen - updated: 7/2/2003
Cassandra L. Kniffin - updated: 6/20/2003
Victor A. McKusick - updated: 5/23/2003
Cassandra L. Kniffin - updated: 5/15/2003
Patricia A. Hartz - updated: 4/28/2003
Cassandra L. Kniffin - updated: 3/4/2003
Cassandra L. Kniffin - updated: 2/11/2003
Cassandra L. Kniffin - updated: 1/8/2003
Cassandra L. Kniffin - updated: 9/6/2002
Cassandra L. Kniffin - updated: 6/13/2002
Victor A. McKusick - updated: 6/12/2002
Cassandra L. Kniffin - updated: 6/12/2002
Cassandra L. Kniffin - updated: 5/28/2002
George E. Tiller - updated: 5/7/2002
Sonja A. Rasmussen - updated: 4/18/2002
Jane Kelly - updated: 4/3/2002
Victor A. McKusick - updated: 8/10/2001
John A. Phillips, III - updated: 8/8/2001
Victor A. McKusick - updated: 6/21/2001
Paul J. Converse - updated: 5/16/2001
Ada Hamosh - updated: 4/26/2001
George E. Tiller - updated: 11/14/2000
Victor A. McKusick - updated: 10/20/2000
Victor A. McKusick - updated: 9/15/2000
Ada Hamosh - updated: 9/13/2000
Victor A. McKusick - updated: 5/1/2000
Victor A. McKusick - updated: 4/18/2000
Ada Hamosh - updated: 3/27/2000
Ada Hamosh - updated: 2/1/2000
Orest Hurko - updated: 12/2/1999
Michael J. Wright - updated: 8/18/1999
Victor A. McKusick - updated: 4/16/1999
Orest Hurko - updated: 3/23/1999
Ada Hamosh - updated: 3/19/1999
Victor A. McKusick - updated: 1/5/1999
Orest Hurko - updated: 12/3/1998
Victor A. McKusick - updated: 11/5/1998
Victor A. McKusick - updated: 7/27/1998
Victor A. McKusick - updated: 5/11/1998
Victor A. McKusick - updated: 10/9/1997
Victor A. McKusick - updated: 6/12/1997
Victor A. McKusick - updated: 4/8/1997
Stylianos E. Antonarakis - updated: 3/20/1997
Iosif W. Lurie - updated: 1/8/1997
Orest Hurko - edited: 12/19/1996
Orest Hurko - updated: 12/16/1996
Lori M. Kelman - updated: 11/15/1996
Cynthia K. Ewing - updated: 9/6/1996
Orest Hurko - updated: 5/14/1996
Orest Hurko - updated: 5/8/1996
Orest Hurko - updated: 4/3/1996
Orest Hurko - updated: 3/6/1996
Orest Hurko - updated: 2/22/1996
Orest Hurko - updated: 2/7/1996
Orest Hurko - updated: 1/25/1996
Orest Hurko - updated: 11/13/1995

*FIELD* CD
Victor A. McKusick: 1/26/1990

*FIELD* ED
alopez: 11/13/2013
alopez: 10/7/2013
carol: 9/30/2013
joanna: 9/23/2013
alopez: 9/12/2013
alopez: 3/11/2013
terry: 10/10/2012
carol: 8/17/2012
carol: 8/10/2012
terry: 8/10/2012
terry: 7/13/2012
terry: 7/5/2012
alopez: 6/7/2012
terry: 6/6/2012
terry: 6/5/2012
terry: 5/24/2012
alopez: 5/15/2012
terry: 5/15/2012
carol: 3/6/2012
wwang: 8/9/2011
wwang: 4/22/2011
ckniffin: 4/18/2011
alopez: 1/24/2011
wwang: 7/7/2010
ckniffin: 6/25/2010
terry: 5/12/2010
wwang: 1/20/2010
ckniffin: 1/19/2010
ckniffin: 1/6/2010
mgross: 9/4/2009
terry: 8/27/2009
mgross: 8/17/2009
terry: 8/6/2009
wwang: 8/5/2009
wwang: 7/31/2009
ckniffin: 7/21/2009
wwang: 7/17/2009
ckniffin: 6/17/2009
terry: 6/3/2009
carol: 3/17/2009
carol: 2/13/2009
carol: 2/12/2009
terry: 1/8/2009
carol: 8/13/2008
terry: 8/6/2008
terry: 7/3/2008
wwang: 7/1/2008
ckniffin: 6/19/2008
carol: 6/5/2008
carol: 4/2/2008
carol: 4/1/2008
wwang: 2/25/2008
ckniffin: 2/7/2008
alopez: 2/6/2008
terry: 12/20/2007
alopez: 11/12/2007
carol: 10/29/2007
wwang: 9/25/2007
ckniffin: 9/20/2007
wwang: 6/27/2007
ckniffin: 6/15/2007
wwang: 5/30/2007
terry: 5/22/2007
alopez: 1/29/2007
wwang: 1/26/2007
ckniffin: 1/4/2007
wwang: 11/8/2006
carol: 10/6/2006
terry: 10/6/2006
wwang: 9/12/2006
terry: 9/8/2006
terry: 8/24/2006
alopez: 7/18/2006
terry: 7/12/2006
alopez: 6/12/2006
terry: 6/6/2006
wwang: 6/2/2006
wwang: 5/10/2006
ckniffin: 4/24/2006
wwang: 4/24/2006
ckniffin: 4/18/2006
alopez: 2/16/2006
terry: 2/15/2006
wwang: 2/1/2006
ckniffin: 1/4/2006
alopez: 12/12/2005
wwang: 11/30/2005
wwang: 11/15/2005
ckniffin: 11/7/2005
alopez: 11/4/2005
terry: 11/2/2005
terry: 10/12/2005
wwang: 9/19/2005
ckniffin: 9/1/2005
carol: 8/29/2005
wwang: 7/27/2005
ckniffin: 7/12/2005
tkritzer: 6/6/2005
terry: 6/2/2005
terry: 3/11/2005
tkritzer: 3/9/2005
ckniffin: 3/4/2005
alopez: 12/14/2004
terry: 12/10/2004
tkritzer: 11/11/2004
tkritzer: 11/4/2004
terry: 11/3/2004
tkritzer: 10/4/2004
ckniffin: 9/17/2004
tkritzer: 9/13/2004
mgross: 8/31/2004
terry: 8/16/2004
tkritzer: 7/28/2004
terry: 7/26/2004
carol: 7/7/2004
tkritzer: 7/6/2004
ckniffin: 6/21/2004
carol: 6/17/2004
terry: 3/30/2004
carol: 3/17/2004
tkritzer: 2/4/2004
ckniffin: 1/29/2004
tkritzer: 12/9/2003
terry: 12/8/2003
carol: 11/5/2003
tkritzer: 10/7/2003
tkritzer: 9/11/2003
ckniffin: 9/5/2003
carol: 8/19/2003
cwells: 7/2/2003
carol: 6/23/2003
ckniffin: 6/20/2003
carol: 6/11/2003
mgross: 6/2/2003
ckniffin: 5/28/2003
terry: 5/23/2003
cwells: 5/21/2003
carol: 5/20/2003
ckniffin: 5/15/2003
cwells: 5/2/2003
terry: 4/28/2003
tkritzer: 4/8/2003
tkritzer: 4/7/2003
ckniffin: 3/13/2003
ckniffin: 3/4/2003
carol: 2/25/2003
ckniffin: 2/11/2003
cwells: 1/14/2003
ckniffin: 1/8/2003
terry: 1/6/2003
carol: 9/9/2002
ckniffin: 9/6/2002
carol: 6/18/2002
ckniffin: 6/13/2002
terry: 6/12/2002
carol: 6/12/2002
ckniffin: 6/12/2002
ckniffin: 6/5/2002
carol: 5/28/2002
ckniffin: 5/28/2002
cwells: 5/17/2002
cwells: 5/7/2002
carol: 4/19/2002
terry: 4/18/2002
mgross: 4/3/2002
mcapotos: 10/26/2001
mgross: 8/10/2001
alopez: 8/8/2001
mcapotos: 7/5/2001
mcapotos: 6/27/2001
terry: 6/21/2001
cwells: 6/21/2001
cwells: 5/16/2001
mcapotos: 5/4/2001
mcapotos: 5/3/2001
mcapotos: 4/27/2001
terry: 4/26/2001
carol: 4/6/2001
mgross: 4/5/2001
mcapotos: 11/14/2000
mcapotos: 11/9/2000
mcapotos: 11/6/2000
mcapotos: 10/30/2000
terry: 10/20/2000
alopez: 10/3/2000
terry: 9/15/2000
terry: 9/13/2000
mcapotos: 5/11/2000
mcapotos: 5/10/2000
terry: 5/1/2000
terry: 4/18/2000
alopez: 3/30/2000
terry: 3/27/2000
mcapotos: 3/22/2000
mcapotos: 3/7/2000
alopez: 2/3/2000
terry: 2/1/2000
carol: 12/3/1999
terry: 12/2/1999
alopez: 8/18/1999
terry: 7/7/1999
carol: 6/28/1999
carol: 4/19/1999
terry: 4/16/1999
carol: 3/23/1999
alopez: 3/19/1999
carol: 1/6/1999
terry: 1/5/1999
carol: 12/3/1998
carol: 11/15/1998
dkim: 11/13/1998
terry: 11/5/1998
alopez: 7/31/1998
alopez: 7/30/1998
terry: 7/27/1998
carol: 5/28/1998
terry: 5/11/1998
terry: 10/9/1997
terry: 9/15/1997
alopez: 7/10/1997
jenny: 7/9/1997
joanna: 6/23/1997
carol: 6/23/1997
mark: 6/18/1997
terry: 6/12/1997
mark: 5/8/1997
terry: 4/10/1997
jenny: 4/8/1997
terry: 4/4/1997
jenny: 3/31/1997
jenny: 3/25/1997
jenny: 3/21/1997
jenny: 3/20/1997
jenny: 3/18/1997
mark: 3/10/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 2/24/1997
jenny: 1/21/1997
jenny: 1/8/1997
mark: 12/19/1996
mark: 12/16/1996
terry: 12/9/1996
jamie: 11/15/1996
jamie: 11/6/1996
jamie: 11/1/1996
terry: 10/22/1996
mark: 7/22/1996
mark: 6/21/1996
mark: 6/20/1996
terry: 5/17/1996
terry: 5/14/1996
mark: 5/10/1996
terry: 5/10/1996
mark: 5/8/1996
terry: 5/2/1996
mark: 4/25/1996
terry: 4/19/1996
mark: 4/12/1996
terry: 4/5/1996
mark: 4/3/1996
terry: 3/23/1996
mark: 3/6/1996
terry: 2/23/1996
mark: 2/22/1996
terry: 2/9/1996
mark: 2/7/1996
mark: 2/2/1996
terry: 1/27/1996
mark: 1/25/1996
terry: 1/19/1996
mark: 10/12/1995
jason: 6/14/1994
warfield: 4/7/1994
pfoster: 4/1/1994
mimadm: 2/21/1994

MIM 143890
*RECORD*
*FIELD* NO
143890
*FIELD* TI
#143890 HYPERCHOLESTEROLEMIA, FAMILIAL
;;FHC; FH;;
HYPERLIPOPROTEINEMIA, TYPE II;;
read moreHYPERLIPOPROTEINEMIA, TYPE IIA;;
HYPER-LOW-DENSITY-LIPOPROTEINEMIA;;
HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL;;
LDL RECEPTOR DISORDER
LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
2, INCLUDED; LDLCQ2, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because familial
hypercholesterolemia can be caused by heterozygous mutation in the low
density lipoprotein receptor gene (LDLR; 606945) on chromosome 19p13.
Other forms of this disorder include type B hypercholesterolemia
(144010), caused by ligand-defective apolipoprotein B-100 (see APOB,
107730), and HCHOLA3 (603776), caused by mutation in the PCSK9 gene
(607786).

In individuals with the LDLR mutation IVS14+1G-A (606945.0063), the
phenotype can be altered by a SNP in the APOA2 gene (107670.0002), a SNP
in the EPHX2 gene (132811.0001), or a SNP in the GHR gene (600946.0028).
A SNP in the promoter region of the G-substrate gene (GSBS; 604088.0001)
correlates with elevated plasma total cholesterol levels. A SNP in
intron 17 of the ITIH4 gene (600564.0001) was associated with
hypercholesterolemia susceptibility in a Japanese population.

DESCRIPTION

Familial hypercholesterolemia is an autosomal dominant disorder
characterized by elevation of serum cholesterol bound to low density
lipoprotein (LDL).

CLINICAL FEATURES

Heterozygotes develop tendinous xanthomas, corneal arcus, and coronary
artery disease; the last usually becomes evident in the fourth or fifth
decade (Hobbs et al., 1992). Homozygotes develop these features at an
accelerated rate in addition to planar xanthomas, which may be evident
at birth in the web between the first 2 digits.

The ranges of serum cholesterol and LDL-cholesterol are, in mg per dl,
250-450 and 200-400 in heterozygotes, greater than 500 and greater than
450 in homozygous affecteds, and 150-250 and 75-175 in homozygous
unaffecteds, with some positive correlation with age (Khachadurian,
1964; Kwiterovich et al., 1974).

In homozygous familial hypercholesterolemia, the aortic root is prone to
develop atherosclerotic plaque at an early age. Such plaques can
accumulate in unusual sites, such as the ascending aorta and around the
coronary ostia. Summers et al. (1998) evaluated the aortic root using
MRI imaging in a blinded, prospective study of 17 homozygous FH patients
and 12 healthy controls. When patient age and body mass index were taken
into account, 53% of patients with homozygous FH had increased aortic
wall thickness compared to controls; this was thought to result from a
combination of medial hyperplasia and plaque formation. Supravalvular
aortic stenosis was seen in 41% of patients.

Houlston et al. (1988) studied the relationship of lipoprotein(a)
(152200) levels and coronary heart disease in patients with familial
hypercholesterolemia. Individuals with coronary artery disease had a
significantly higher mean lipoprotein(a) concentration than those
without coronary heart disease, suggesting that lipoprotein(a)
measurements may help predict the risk of coronary heart disease in
individuals with familial hypercholesterolemia.

Deramo et al. (2003) investigated the relationship between nonarteritic
ischemic optic neuropathy (NAION; 258660) and serum lipid levels in 37
consecutive patients diagnosed with NAION at or below age 50 years and
74 age- and gender-matched controls. They found that
hypercholesterolemia was a risk factor in these patients and suggested
that NAION might be the first manifestation of a previously unrecognized
lipid disorder. The patients had experienced a focal, microvascular
central nervous system ischemic event at a relatively young age. Deramo
et al. (2003) suggested that aggressive treatment of lipid abnormalities
might be warranted in these patients.

PATHOGENESIS

By studies of cultured fibroblasts from homozygotes, Goldstein and Brown
(1973) and Brown and Goldstein (1974) showed that the basic defect
concerns the cell membrane receptor for LDL. Normally, LDL is bound at
the cell membrane and taken into the cell ending up in lysosomes where
the protein is degraded and the cholesterol is made available for
repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A
(HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In
familial hypercholesterolemia, there is a binding defect due to a
dysfunctional receptor. At the same time, a reciprocal stimulation of
cholesterol ester synthesis takes place. Harders-Spengel et al. (1982)
presented evidence that the receptor defect is present on liver
membranes.

To determine the influences of intrauterine and genetic factors on
atherogenic lipid profiles in later life, Ijzerman et al. (2001)
investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They
found an association between low birth weight and high levels of total
cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the
intrapair analysis in dizygotic twin pairs but was reversed within
monozygotic twin pairs. Furthermore, they found that the association
between low birth weight and low levels of HDL cholesterol tended to
persist in the intrapair analysis in both dizygotic and monozygotic
twins. These data suggested that genetic factors may account for the
association of low birth weight with high levels of total cholesterol,
LDL cholesterol, and apolipoprotein B, whereas intrauterine factors
possibly play a role in the association of low birth weight with low
levels of HDL cholesterol.

Garcia-Otin et al. (2007) determined serum noncholesterol sterols in
normolipidemic control subjects and in well-phenotyped patients with
dyslipidemias, including autosomal dominant hypercholesterolemia (ADH)
with and without known genetic defects and familial combined
hyperlipidemia (FCHL; 144250). Intestinal cholesterol absorption was
highest in ADH without known defect, followed by ADH with known defect,
then controls, and then FCHL. Garcia-Otin et al. (2007) concluded that
intestinal cholesterol absorption might play a role in the lipid
abnormalities of patients with autosomal dominant hypercholesterolemia
without identified genetic defects. They suggested that serum
noncholesterol sterols are a useful tool for the differential diagnosis
of genetic hypercholesterolemias.

DIAGNOSIS

Humphries et al. (1985) found a RFLP of the LDL receptor gene using the
restriction enzyme PvuII. About 30% of persons are heterozygous for the
polymorphism which is, therefore, useful in family studies and early
diagnosis of FHC. Schuster et al. (1989) also used RFLPs of the LDLR
gene in the diagnosis of FH.

Bhatnagar et al. (2000) reported a case-finding experience in the UK
among relatives of patients with familial hypercholesterolemia by a
nurse-led genetic register. By performing cholesterol tests on 200
relatives, 121 new patients with familial hypercholesterolemia were
discovered. The newly diagnosed patients were younger than the probands
and were generally detected before they had clinically overt
atherosclerosis. A case was made for organizing a genetic register
approach, linking lipid clinics nationally.

Umans-Eckenhausen et al. (2001) found that in the Netherlands targeted
family screening with DNA analysis proved to be highly effective in
identifying patients with hypercholesterolemia. Most of the identified
patients sought treatment and were successfully started on
cholesterol-lowering treatment to lower the risk of premature
cardiovascular disease.

Newson and Humphries (2005) discussed cascade testing in familial
hypercholesterolemia. They questioned whether and how family members
should be contacted for testing. The implications of the test results
for life planning, employment, or ability to obtain life insurance are
concerns. The pros and cons of cascade testing were reviewed by de Wert
(2005).

- Prenatal Diagnosis

Vergotine et al. (2001) demonstrated the feasibility of prenatal
diagnosis of homozygous familial hypercholesterolemia in the Afrikaner
population.

CLINICAL MANAGEMENT

Starzl et al. (1984) performed both heart transplant and liver
transplant in a 6.75-year-old girl with homozygous familial
hypercholesterolemia.

Tonstad et al. (1996) conducted a double-blind placebo-controlled trial
over 1 year using 8 grams of cholestyramine in prepubertal children
(aged 6-11 years) with familial hypercholesterolemia. After 1 year of a
low-fat, low-cholesterol diet, children with a family history of
premature cardiovascular disease had LDL cholesterol levels at or
greater than 4.9 mmol/liter, while children without such a family
history had LDL cholesterol levels at or greater than 4.1 mmol/liter.
The LDL cholesterol levels in the test group lowered by 16.9% (95%
confidence interval), compared with a 1.4% increase in the placebo
group. Growth velocity was not adversely affected in the treatment
group, although folate and 25-hydroxyvitamin D deficiency were noted
among a small number of treated children. Additionally, a boy who had an
appendectomy 3 months before the study required surgery for intestinal
obstruction after he had taken the first 2 cholestyramine doses. Given
the number of gastrointestinal side effects, Tonstad et al. (1996)
recommended caution in starting cholestyramine after abdominal surgery
in children.

Cuchel et al. (2007) treated 6 patients with homozygous familial
hypercholesterolemia with an inhibitor of microsomal triglyceride
transfer protein (157147). A reduction of LDL cholesterol levels was
observed, owing to reduced production of apolipoprotein B. However, the
therapy was associated with elevated liver aminotransferase levels and
hepatic fat accumulation.

- Statin Therapy

The 'statin' drugs are potent competitive inhibitors of
3-hydroxy-3-methylglutaryl coenzyme-A reductase and have proven useful
in the treatment of hypercholesterolemia (Betteridge et al., 1978;
Goldstein and Brown, 1987; Hoeg and Brewer, 1987). Brorholt-Petersen et
al. (2001) tested the hypothesis that the cholesterol lowering effect of
statin therapy is a function of the particular type of LDLR mutation.
They studied the response to treatment with fluvastatin in 28 patients
with heterozygous FH as a result of a receptor-negative mutation (trp23
to ter; 606945.0060) and in 30 patients with a receptor-binding
defective mutation (trp66 to gly; 606945.0003). They found no
statistically significant differences. A tabulation of the results of
this and earlier studies suggested that differences in treatment
response as an apparent function of LDLR gene mutation type occur mainly
in populations with recent genetic admixture. The authors suggested that
in such populations persons with the same mutation in the LDLR gene are
also more likely to share other but undetermined genetic variations
affecting the pharmacology of statins.

Chaves et al. (2001) examined the presence of mutations in the LDLR gene
among subjects clinically diagnosed with FH and analyzed whether the
molecular diagnosis helped to predict the response to simvastatin
treatment in their FH population. They conducted a randomized clinical
trial with simvastatin in 42 genetically diagnosed subjects with FH,
with 22 classified as carriers of null mutations and 20 with defective
mutations. A mutation causing FH was identified in 46 probands (84%). In
41 of them (89%), a total of 28 point mutations were detected, 13 of
which had not been previously described. FH with null mutations showed a
poor response to simvastatin treatment. The mean percentage reduction of
plasma total and LDL cholesterol levels in these subjects was
significantly lower than in subjects with defective mutations. Subjects
with FH with null mutations (class I) showed lower plasma HDL
cholesterol values and a poor LDL cholesterol response to simvastatin
treatment.

Hedman et al. (2005) studied the efficacy and safety for up to 2 years
of pravastatin treatment in 19 girls and 11 boys with autosomal dominant
familial hypercholesterolemia. Pravastatin was started at 10 mg/d, with
a forced titration by 10 mg at 2, 4, 6, and 12 months until the target
cholesterol level of less than 194 mg/dl was reached. By 2, 4, 6, 12,
and 24 months of treatment, the total cholesterol levels had,
respectively, decreased by 19, 20, 23, 27 and 26%, and the LDL
cholesterol levels had decreased by 25, 27, 29, 33, and 32% compared
with the dietary baseline values. The side effects were mild, and no
clinically significant elevations in alanine aminotransferase, creatine
kinase, or creatinine were seen. The authors concluded that the efficacy
in children with slight or moderate hypercholesterolemia was
satisfactory, but in children with severe hypercholesterolemia it was
insufficient.

GENE THERAPY

Wilson et al. (1992) presented a detailed clinical protocol for the ex
vivo gene therapy of familial hypercholesterolemia. The approach, which
they proposed to use to treat homozygous FH patients with symptomatic
coronary artery disease who have a relatively poor prognosis but can
tolerate a noncardiac surgical procedure with acceptable risks, involves
recovery of hepatocytes from the patient and reimplanting them after
genetic correction by a retrovirus-mediated gene transfer. Not only were
the technical details of vectors and viruses, transduction and delivery
of hepatocytes, evaluation of engraftment and rejection, etc.,
discussed, but also assessment of risks versus benefits and informed
consent for both adult and child patients.

Grossman et al. (1994) reported a 29-year-old woman with FH caused by
mutation in the LDLR gene (606945.0003) who underwent
hepatocyte-directed ex vivo gene therapy with LDLR-expressing
retroviruses. She tolerated the procedures well, liver biopsy after 4
months showed engraftment of the transgene, and there was no clinical or
pathologic evidence for autoimmune hepatitis. The patient showed an
improvement in serum lipids up to 18 months after the treatment.

MAPPING

Three independent linkage studies, by Ott et al. (1974), Berg and
Heiberg (1976), and Elston et al. (1976), strongly suggested loose
linkage between familial hypercholesterolemia and the third component of
complement; C3 (120700) has been mapped to chromosome 19 by somatic cell
hybridization. Donald et al. (1984) presented further data on HC-C3
linkage, bringing the combined male-female lod score to a maximum of
3.79 at theta 0.25. C3 and FHC are about 20 cM apart; APOE (107741) and
C3 are about 15 cM apart. FHC is not closely linked to APOE, suggesting
that these 2 loci are on opposite sides of C3. The LDLR gene was
regionalized to 19p13.1-p13.3 by in situ hybridization (Lindgren et al.,
1985). Judging by the sequence of loci suggested by linkage data
(pter--FHC--C3--APOE/APOC2), the location of FHC (LDLR) is probably
19p13.2-p13.12 and of C3, 19p13.2-p13.11.

Leppert et al. (1986) found tight linkage between a RFLP of the LDL
receptor gene and dominantly inherited hypercholesterolemia;
specifically, no exception to cosegregation was found between high-LDL
cholesterol phenotype and a unique allele at the LDLR locus. The maximum
lod score was 7.52 at theta = 0.

In 3 adult Dutch, Swedish, and Australian twin samples totaling 410
dizygotic twin pairs, Beekman et al. (2003) found consistent evidence
for linkage between chromosome 19 and LDL cholesterol levels, with
maximum lod scores of 4.5, 1.7, and 2.1, respectively. No linkage was
observed in an adolescent Dutch twin sample of 83 dizygotic twin pairs.
Combined analysis of the adult samples increased the maximum lod to 5.7
at 60 cM from pter. Beekman et al. (2003) concluded that there is strong
evidence for the presence of a QTL on chromosome 19 with a major effect
on LDL cholesterol levels.

MOLECULAR GENETICS

Horsthemke et al. (1987) analyzed DNA from 70 patients in the UK with
heterozygous familial hypercholesterolemia. In most, the restriction
fragment pattern of the LDLR gene was indistinguishable from the normal;
however, 3 patients were found to have a deletion of about 1 kb in the
central portion of the gene. In 2 patients, the deletion included all or
part of exon 5 (606945.0027); in the third, the deletion included exon 7
(606945.0033). Including a previously described patient with a deletion
in the 3-prime part of the gene, these results indicated that 4 of 70
patients, or 6%, have deletions.

Hobbs et al. (1990) reviewed the many mutations found in the LDLR gene
as the cause of familial hypercholesterolemia.

Varret et al. (2008) reviewed 17 published studies of autosomal dominant
hypercholesterolemia and evaluated the contribution of mutations in the
LDLR, APOB, and PCSK9 genes. They noted that the proportion of subjects
without an identified mutation ranged from 12% to 72%, suggesting the
existence of further genetic heterogeneity.

In a patient diagnosed with probable heterozygous FH, Bourbon et al.
(2007) analyzed the LDLR gene and identified a novel variant initially
assumed to be a silent polymorphism (R385R; 606945.0065); however,
analysis of mRNA from the patient's cells showed that the mutation
introduces a new splice site predicted to cause premature truncation of
the protein. The R385R mutation was also found in a Chinese homozygous
FH patient.

Defesche et al. (2008) analyzed the LDLR gene in 1,350 patients
clinically diagnosed with familial hypercholesterolemia who were
negative for functional DNA variation in the LDLR, APOB (107730), and
PCSK9 (607786) genes. The authors examined the effects of 128 seemingly
neutral exonic and intronic DNA variants and identified 2 synonymous
variants in LDLR, R385R and G186G (606945.0066), that clearly affected
splice sites and segregated with hypercholesterolemia in all families
examined. The R385R variant was found in 2 probands of Chinese origin,
whereas G186G was found in 35 Dutch probands, 2 of whom were homozygous
for the variant and had a more severe phenotype, with myocardial
infarction occurring in both before the age of 20 years.

Kulseth et al. (2010) performed RNA analysis in 30 unrelated patients
with clinically defined hypercholesterolemia but without any LDLR
mutations detected by standard DNA analysis; sequencing of RT-PCR
products from an index patient revealed an insertion of 81 bp from the
5-prime end of intron 14 of LDLR, and DNA sequencing of exons 13 and 14
detected an splice site mutation in intron 14 (606945.0067). Twelve of
23 family members tested were heterozygous for the mutation, and
carriers had significantly increased total cholesterol levels compared
to noncarriers. Kulseth et al. (2010) analyzed an additional 550 index
patients and identified the same splice site mutation in 3 more
probands. In 1 proband's family, the mutation was found in 6 of 7 tested
family members, who all had LDL cholesterol levels above the 97th
percentile.

GENOTYPE/PHENOTYPE CORRELATIONS

Goldstein et al. (1977) found that both receptor-absent and
receptor-defective mutants occur and they concluded that some of the
'homozygotes' are in fact genetic compounds. An internalization mutant
of the LDL receptor binds LDL but is unable to facilitate passage of LDL
to the inside of the cell. A patient was found to be a genetic compound,
having inherited the internalization mutant from the father and the
binding mutant from the mother. From the fact that an individual was
shown by family studies to be a genetic compound and that
complementation did not occur, Goldstein et al. (1977) concluded that
the gene for binding of LDL and the gene for internalization of LDL are
allelic mutations at the structural locus for the LDL receptor. Miyake
et al. (1981) found homozygosity for the internalization defect.

The LDL receptor is synthesized as a 120-kD glycoprotein precursor that
undergoes change to a 160-kD mature glycoprotein through the covalent
addition of a 40-kD protein. Tolleshaug et al. (1982) reported a
heterozygous child who inherited one allele from his mother which
produced an abnormal 120-kD protein that could not be further processed,
and one allele from his father which produced an elongated 170-kD
precursor that underwent an increase in molecular weight to form an
abnormally large receptor of 210 kD.

Levy et al. (1986) reported 2 brothers with a unique genetic compound
form of 'homozygous' hypercholesterolemia in which the mother had
typical FHC and the father and 3 of his close relatives had what they
termed the HMWR (high molecular weight receptor) trait. In these persons
2 types of functional LDL receptors were found in cultured skin
fibroblasts: one with molecular weight of 140,000 and one with molecular
weight of 176,000. Curiously and puzzlingly, the compound heterozygotes
and the regular heterozygotes for the HMWR showed increased cholesterol
synthesis, which the authors suggested may play a significant role in
the pathology of the disease.

Funahashi et al. (1988) studied 16 Japanese kindreds with homozygous
FHC. Ten had a receptor-negative form of the disease; 5 had a
receptor-defective form; and 1 represented an internalization defect.
The receptor-defective group, in which residual amounts of functional
receptors were produced, showed a lower tendency to coronary artery
disease than the receptor-negative group.

- Modifiers

Feussner et al. (1996) described a 20-year-old man with a combination of
heterozygous FH caused by splice mutation (606945.0054) and type III
hyperlipoproteinemia (107741). He presented with multiple xanthomas of
the elbows, interphalangeal joints and interdigital webs of the hands.
Active lipid-lowering therapy caused regression of the xanthomas and
significant decrease of cholesterol and triglycerides. Flat xanthomas of
the interdigital webs were described in 3 of 4 formerly reported
patients with a combination of these disorders of lipoprotein
metabolism. Feussner et al. (1996) proposed that the presence of these
xanthomas should suggest compound heterozygosity (actually double
heterozygosity) for FH and type III hyperlipoproteinemia.

Sass et al. (1995) described a 4-generation French-Canadian kindred with
familial hypercholesterolemia in which 2 of the 8 heterozygotes for a
5-kb deletion (exons 2 and 3) in the LDLR gene were found to have normal
LDL-cholesterol levels. Analyses showed that it was unlikely that
variation in the genes encoding apolipoprotein B (107730), HMG-CoA
reductase (HMGCR; 142910), apoAI-CIII-AIV (see APOA1; 107680), or
lipoprotein lipase was responsible for the cholesterol-lowering effect.
Expression of the LDL receptor, as assessed in vitro with measurements
of activity and mRNA levels, was similar in normolipidemic and
hyperlipidemic subjects carrying the deletion. Analysis of the apoE
isoforms (107741), on the other hand, revealed that most of the E2
allele carriers in this family, including the 2 normolipidemic 5-kb
deletion carriers, had LDL cholesterol levels substantially lower than
subjects with the other apoE isoforms. Thus, this kindred provided
evidence for the existence of a gene or genes, including the apoE2
allele, with profound effects on LDL-cholesterol levels.

Vergopoulos et al. (1997) presented findings suggesting the existence of
a xanthomatosis susceptibility gene in a consanguineous Syrian kindred
containing 6 individuals with homozygous FH (see 602247). Half of the
homozygotes had giant xanthomas, while half did not, even though their
LDL-cholesterol concentrations were elevated to similar degrees (more
than 14 mmol/l). Heterozygous FH individuals in this family were also
clearly distinguishable with respect to xanthoma size. By DNA analysis
they identified a hitherto undescribed mutation in the LDLR gene in this
family: a T-to-C transition at nucleotide 1999 in codon 646 of exon 14,
resulting in an arginine for cysteine substitution. Segregation analysis
suggested that a separate susceptibility gene may explain the formation
of giant xanthomas.

In a 13-year-old girl with severe hypercholesterolemia, Ekstrom et al.
(1999) demonstrated compound heterozygosity for a cys240-to-phe mutation
(606945.0059) and a tyr167-to-ter mutation (606945.0045) in the LDLR
gene. Her 2 heterozygous sibs also carried the C240F mutation, but only
one of them was hypercholesterolemic. The authors concluded that there
may be cholesterol-lowering mechanisms that are activated by mutations
in other genes.

Knoblauch et al. (2000) studied an Arab family that carried the
tyr807-to-cys substitution (606945.0019). In this family, some
heterozygous persons had normal LDL levels, while some homozygous
individuals had LDL levels similar to those persons with heterozygous
FH. The authors presented evidence for the existence of a
cholesterol-lowering gene on 13q (604595).

Takada et al. (2002) demonstrated that a SNP of the promoter of the
APOA2 gene, -265T-C (107670.0002), influenced the level of total
cholesterol and low density lipoprotein (LDL) cholesterol in members
with the IVS14+1G-A mutation (606945.0063) in the LDLR gene causing
hypercholesterolemia. Strikingly lower total cholesterol and LDL
cholesterol values were observed among most of the LDLR mutation
carriers who were simultaneously homozygous for the -265C allele of the
APOA2 gene.

In the same large family reported by Takada et al. (2002), Takada et al.
(2003) found that a SNP in the GHR gene, resulting in a L526I
(600946.0028) substitution, influenced plasma levels of high density
lipoprotein (HDL) cholesterol in affected family members with the
IVS14+1G-A mutation. The lowest levels of plasma HDL were observed among
leu/leu homozygotes, highest levels among ile/ile homozygotes, and
intermediate levels among leu/ile heterozygotes. No such effect was
observed among noncarriers of the LDLR mutation.

In the pedigree reported by Takada et al. (2002), Sato et al. (2004)
demonstrated a significant modification of the phenotype of familial
hypercholesterolemia resulting from the IVS14+1G-A mutation by the
arg287 variation in the EPHX2 gene (132811.0001).

POPULATION GENETICS

In most populations the frequency of the homozygote is 1 in a million
(probably a minimal estimate, being a prevalence figure rather than
incidence at birth) and the frequency of heterozygotes not less than 1
in 500. Thus, heterozygous familial hypercholesterolemia is the most
frequent mendelian disorder, being more frequent than either cystic
fibrosis or sickle cell anemia which, in different populations, are
often given that distinction. Among survivors of myocardial infarction,
the frequency of heterozygotes is about 1 in 20.

Seftel et al. (1980) pointed to a high frequency of hypercholesterolemic
homozygotes in South Africa. In a 7-year period, 34 homozygotes were
seen in one clinic in Johannesburg. All were Afrikaners and most lived
in Transvaal Province. The authors calculated the frequency of
heterozygotes and homozygotes to be 1 in 100 and 1 in 30,000,
respectively. The oldest of their patients was a 46-year-old woman. Of
the 34, six were age 30 or older. The authors concluded that the high
frequency of the gene is attributable to founder effect, as in the case
of porphyria variegata (176200), lipoid proteinosis (247100), and
sclerosteosis (269500). Torrington and Botha (1981) found that 20 of 26
families with FHC (77%) belonged to the Gereformeerde Kerk, whereas
according to the 1970 census only 5% of the Afrikaans-speaking white
population of South Africa belonged to this religious group. Again, the
data were consistent with a founder effect. Using the LDLR activity of
lymphocytes, Steyn et al. (1989) calculated the prevalence of
heterozygous FHC in the permanent residents of a predominantly
Afrikaans-speaking community in South Africa to be 1 in 71--the highest
prevalence reported to date.

In the Saguenay-Lac-Saint-Jean region of Quebec Province, De Braekeleer
(1991) estimated the prevalence of familial hypercholesterolemia as
1/122, compared to the usually used frequency of 1/500 for European
populations.

Defesche and Kastelein (1998) stated that more than 350 different
mutations had been found in patients with familial hypercholesterolemia.
They tabulated the preferential geographic distribution that has been
demonstrated for some of the LDL receptor mutations. For example, in the
West of Scotland about half of the index cases of FH were found to have
the cys163-to-tyr mutation (606945.0058). Defesche and Kastelein (1998)
commented on the geographic associations of LDL receptor mutations
within the Netherlands.

Deletion of gly197 (606945.0005) is the most prevalent LDL receptor
mutation causing familial hypercholesterolemia in Ashkenazi Jewish
individuals. Studying index cases from Israel, South Africa, Russia, the
Netherlands, and the United States, Durst et al. (2001) found that all
traced their ancestry to Lithuania. A highly conserved haplotype was
identified in chromosomes carrying this deletion, suggesting a common
founder. When 2 methods were used for analysis of linkage disequilibrium
between flanking polymorphic markers and the disease locus and for the
study of the decay of LD over time, the estimated age of the deletion
was found to be 20 +/- 7 generations, so that the most recent common
ancestor of the mutation-bearing chromosomes would date to the 14th
century. This corresponds with the founding of the Jewish community of
Lithuania (1338 A.D.), as well as with the great demographic expansion
of Ashkenazi Jewish individuals in eastern Europe, which followed this
settlement. Durst et al. (2001) could find no evidence supporting a
selective evolutionary metabolic advantage. Therefore, the founder
effect in a rapidly expanding population from a limited number of
families remains a simple, parsimonious hypothesis explaining the spread
of this mutation in Ashkenazi Jewish individuals.

ANIMAL MODEL

Kingsley and Krieger (1984) identified 4 different types of mutant
Chinese hamster ovary cells with defective LDL receptor function. One
locus, called ldlA, apparently represents the structural gene for LDL
receptor, whereas the others--ldlB, ldlC, and ldlD--appear to have
defects involved in either regulation, synthesis, transport, recycling,
or turnover of LDL receptors.

The Watanabe heritable hyperlipidemic (WHHL) rabbit has a genetic
deficiency of LDL receptors and is therefore a superb experimental model
(Hornick et al., 1983). Kita et al. (1987) found that probucol prevented
the progression of atherosclerosis in the Watanabe rabbit by limiting
oxidative LDL modification and foam cell transformation of macrophages.
Probucol was originally developed as an antioxidant. Yamamoto et al.
(1986) showed that the defect in the Watanabe heritable hyperlipidemic
rabbit is a mutant receptor for LDL that is not transported to the cell
surface at a normal rate. Cloning and sequencing of complementary cDNAs
from normal and Watanabe rabbits showed that the defect arises from an
in-frame deletion of 12 nucleotides that eliminates 4 amino acids from
the cysteine-rich ligand binding domain of the LDL receptor. Yamamoto et
al. (1986) detected a similar mutation by S1 nuclease mapping of LDL
receptor mRNA from a patient with familial hypercholesterolemia whose
receptor also failed to be transported to the cell surface. These
findings suggested to Yamamoto et al. (1986) that animal cells may have
fail-safe mechanisms that prevent surface expression of improperly
folded proteins with unpaired or improperly bonded cysteine residues.

Scanu et al. (1988) investigated hypercholesterolemia due to deficiency
of the LDL receptor in a family of rhesus monkeys. Hummel et al. (1990)
used PCR to analyze the mutation carried by members of a family of
rhesus monkeys with spontaneous hypercholesterolemia and low density
lipoprotein receptor deficiency. Affected monkeys are heterozygous for a
nonsense mutation in exon 6, changing codon 284 from TGG to TAG. The
G-to-A transition creates a new SpeI restriction site. LDLR RNA is
reduced by about 50% on quantitative analysis of RNA obtained at liver
biopsy in affected animals.

Hofmann et al. (1988) found that overexpression of LDL receptors caused
elimination of both apoE and apoB, the 2 ligands, from the plasma in
transgenic mice derived from fertilized eggs injected with the LDLR gene
under control of the mouse metallothionein-I promoter. They speculated
that overexpression of other receptors, such as those for insulin
(147670) or transferrin (190000), might have pathologic effects leading
to a 'ligand steal' syndrome.

Roy Chowdhury et al. (1991) used the Watanabe rabbit for the development
of liver-directed gene therapy based on transplantation of autologous
hepatocytes that had been genetically corrected ex vivo with recombinant
retroviruses. Animals transplanted with LDLR-transduced autologous
hepatocytes demonstrated a 30 to 50% decrease in total serum cholesterol
that persisted for the duration of the experiment (122 days).
Recombinant-derived LDLR RNA was harvested from tissues with no
diminution for up to 6.5 months after transplantation. Ishibashi et al.
(1993) developed a new animal model for homozygous FH through targeted
disruption of the LDLR gene in mice. Homozygous LDL receptor-deficient
mice showed delayed clearance of VLDL, intermediate density lipoproteins
(IDL), and LDL from plasma. As a result, total plasma cholesterol level
rose from 108 mg/dl in wildtype mice to 236 mg/dl in homozygous
deficient mice. Adult mice did not exhibit gross evidence of
xanthomatosis, however, and the extent of aortic atherosclerosis was
minimal. On the other hand, Ishibashi et al. (1994) showed that in mice
homozygous for the targeted disruption of the LDLR gene who were fed a
diet high in cholesterol, total plasma cholesterol rose from 246 to more
than 1,500 mg/dl. In wildtype littermates fed the same diet, total
plasma cholesterol remained less than 160 mg/dl. After 7 months, the
homozygous deficient mice developed massive xanthomatous infiltration of
the skin and subcutaneous tissue. The aorta and coronary ostia exhibited
gross atheromata, and the aortic valve leaflets were thickened by
cholesterol-laden macrophages.

Mice homozygous for targeted replacement with human APOE2 (107741.0001),
regardless of age or gender, develop type III hyperlipoproteinemia,
whereas homozygosity for APOE2 results in HLP in no more than 10% in
humans, predominantly in adult males. By generating mice homozygous for
human APOE2 and heterozygous for human LDLR and mouse Ldlr, Knouff et
al. (2001) achieved increased stability of mRNA in liver associated with
a truncation of the 3-prime-UTR of LDLR. Plasma lipoprotein levels were
normal in the LDLR heterozygotes. Knouff et al. (2001) concluded that
moderate and controlled overexpression of LDLR completely ameliorates
the type III HLP phenotype of APOE2 homozygous mice.

Hasty et al. (2001) generated mice deficient in both the low density
lipoprotein receptor and leptin (ob/ob). These doubly mutant mice
exhibited striking elevations in both total plasma cholesterol and
triglyceride levels and had extensive atherosclerotic lesions throughout
the aorta by 6 months of age. Although fasting, diet restriction, and
low-level leptin treatment significantly lowered total plasma
triglyceride levels, they caused only slight changes in total plasma
cholesterol levels. Hepatic cholesterol and triglyceride contents as
well as mRNA levels of cholesterologenic and lipogenic enzymes suggested
that leptin deficiency increased production of hepatic triglycerides,
but not cholesterol, in the ob/ob mice regardless of their Ldlr
genotype. These data provided evidence that the hypertriglyceridemia and
hypercholesterolemia in the doubly mutant mice were caused by distinct
mechanisms, suggesting that leptin might have some impact on plasma
cholesterol metabolism, possibly through an LDLR-independent pathway.

HISTORY

Much of the early nosologic work that established the
hyperlipoproteinemia phenotype (Fredrickson et al., 1967) and suggested
familial occurrence (Hould et al., 1969; Schrott et al., 1972;
Kwiterovich et al., 1974) was done before the extensive genetic
heterogeneity of the phenotype was defined.

*FIELD* SA
Aalto-Setala et al. (1988); Berg and Heiberg (1978); Berg and Heiberg
(1979); Berger et al. (1978); Bilheimer et al. (1985); Bilheimer et
al. (1983); Bilheimer et al. (1978); Brink et al. (1987); Brown and
Goldstein (1976); Brown and Goldstein (1976); Brown and Goldstein
(1975); Brown and Goldstein (1986); Brown et al. (1981); Buja et al.
(1979); Cai et al. (1985); Cuthbert et al. (1986); Davis et al. (1986);
Deckelbaum et al. (1977); Edwards et al. (1978); Elston et al. (1975);
Epstein et al. (1959); Francke et al. (1984); Frank et al. (1989);
Fredrickson (1969); Goldstein et al. (1981); Goldstein and Brown
(1979); Goldstein and Brown (1978); Goldstein and Brown (1975); Goldstein
and Brown (1975); Goldstein et al. (1975); Goldstein et al. (1983);
Harlan et al. (1966); Heiberg (1976); Hobbs et al. (1986); Hobgood
et al. (1983); Horsthemke et al. (1980); Iselius (1979); King et
al. (1980); Knight et al. (1989); Komuro et al. (1987); Kotze et al.
(1987); Lehrman et al. (1985); Leitersdorf et al. (1989); Maartmann-Moe
and Berg-Johnsen (1981); Maartmann-Moe et al. (1981); Maartmann-Moe
et al. (1982); Mabuchi et al. (1981); Mabuchi et al. (1986); Mabuchi
et al. (1983); Mabuchi et al. (1978); Magnus et al. (1981); McNamara
et al. (1983); Mitchell (1983); Miyake et al. (1989); Nevin and Slack
(1968); Nora et al. (1985); Rose et al. (1982); Slack and Nevin (1968);
Stoffel et al. (1981); Tikkanen et al. (1978); Tolleshaug et al. (1983)
*FIELD* RF
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1382-1383, 1984. Note: Originally Volume I.

122. Steyn, K.; Weight, M. J.; Dando, B. R.; Christopher, K. J.; Rossouw,
J. E.: The use of low density lipoprotein receptor activity of lymphocytes
to determine the prevalence of familial hypercholesterolaemia in a
rural South African community. J. Med. Genet. 26: 32-36, 1989.

123. Stoffel, W.; Borberg, H.; Greve, V.: Application of specific
extracorporeal removal of low density lipoprotein in familial hypercholesterolaemia. Lancet II:
1005-1007, 1981.

124. Summers, R. M.; Andrasko-Bourgeois, J.; Feuerstein, I. M.; Hill,
S. C.; Jones, E. C.; Busse, M. K.; Wise, B.; Bove, K. E.; Rishforth,
B. A.; Tucker, E.; Spray, T. L.; Hoeg, J. M.: Evaluation of the aortic
root by MRI: insights from patients with homozygous familial hypercholesterolemia. Circulation 98:
509-518, 1998.

125. Takada, D.; Emi, M.; Ezura, Y.; Nobe, Y.; Kawamura, K.; Iino,
Y.; Katayama, Y.; Xin, Y.; Wu, L. L.; Larringa-Shum, S.; Stephenson,
S. H.; Hunt, S. C.; Hopkins, P. N.: Interaction between the LDL-receptor
gene bearing a novel mutation and a variant in the apolipoprotein
A-II promoter: molecular study in a 1135-member familial hypercholesterolemia
kindred. J. Hum. Genet. 47: 656-664, 2002.

126. Takada, D.; Ezura, Y.; Ono, S.; Iino, Y.; Katayama, Y.; Xin,
Y.; Wu, L. L.; Larringa-Shum, S.; Stephenson, S. H.; Hunt, S. C.;
Hopkins, P. M.; Emi, M.: Growth hormone receptor variant (L526I)
modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia:
intra-familial association study in an eight-generation hyperlipidemic
kindred. Am. J. Med. Genet. 121A: 136-140, 2003.

127. Tikkanen, M. J.; Nikkila, E. A.; Vartiainen, E.: Natural oestrogen
as an effective treatment for type-II hyperlipoproteinaemia in postmenopausal
women. Lancet 312: 490-491, 1978. Note: Originally Volume II.

128. Tolleshaug, H.; Goldstein, J. L.; Schneider, W. J.; Brown, M.
S.: Posttranslational processing of the LDL receptor and its genetic
disruption in familial hypercholesterolemia. Cell 30: 715-724, 1982.

129. Tolleshaug, H.; Hobgood, K. K.; Brown, M. S.; Goldstein, J. L.
: The LDL receptor locus in familial hypercholesterolemia: multiple
mutations disrupt transport and processing of a membrane receptor. Cell 32:
941-951, 1983.

130. Tonstad, S.; Knudtzon, J.; Sivertsen, M.; Refsum, H.; Ose, L.
: Efficacy and safety of cholestyramine therapy in peripubertal and
prepubertal children with familial hypercholesterolemia. J. Pediat. 129:
42-49, 1996.

131. Torrington, M.; Botha, J. L.: Familial hypercholesterolaemia
and church affiliation. (Letter) Lancet 318: 1120 only, 1981. Note:
Originally Volume II.

132. Umans-Eckenhausen, M. A. W.; Defesche, J. C.; Sijbrands, E. J.
G.; Scheerder, R. L. J. M.; Kastelein, J. J. P.: Review of first
5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357:
165-168, 2001.

133. Varret, M.; Abifadel, M.; Rabes, J.-P.; Boileau, C.: Genetic
heterogeneity of autosomal dominant hypercholesterolemia. Clin. Genet. 73:
1-13, 2008.

134. Vergopoulos, A.; Bajari, T.; Jouma, M.; Knoblauch, H.; Aydin,
A.; Bahring, S.; Mueller-Myhsok, B.; Dresel, A.; Joubran, R.; Luft,
F. C.; Schuster, H.: A xanthomatosis-susceptibility gene may exist
in a Syrian family with familial hypercholesterolemia. Europ. J.
Hum. Genet. 5: 315-323, 1997.

135. Vergotine, J.; Thiart, R.; Langenhoven, E.; Hillermann, R.; De
Jong, G.; Kotze, M. J.: Prenatal diagnosis of familial hypercholesterolemia:
importance of DNA analysis in the high-risk South African population. Genet.
Counsel. 12: 121-127, 2001.

136. Wilson, J. M.; Grossman, M.; Raper, S. E.; Baker, J. R., Jr.;
Newton, R. S.; Thoene, J. G.: Clinical protocol: ex vivo gene therapy
of familial hypercholesterolemia. Hum. Gene Therapy 3: 179-222,
1992.

137. Yamamoto, T.; Bishop, R. W.; Brown, M. S.; Goldstein, J. L.;
Russell, D. W.: Deletion in cysteine-rich region of LDL receptor
impedes transport to cell surface in WHHL rabbit. Science 232: 1230-1237,
1986.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Corneal arcus;
Xanthelasma

CARDIOVASCULAR:
[Heart];
Coronary artery disease presenting after age 30 years in heterozygotes,
in childhood in homozygotes

SKIN, NAILS, HAIR:
[Skin];
Tendinous xanthomas presenting after age 20 years in heterozygotes,
during first 4 years of life in homozygotes;
Planar xanthomas in homozygotes

LABORATORY ABNORMALITIES:
Hypercholesterolemia, 350-550 mg/L in heterozygotes, 650-1000 mg/L
in homozygotes

MISCELLANEOUS:
Incidence, 1 in 500 heterozygotes, 1 in 1,000,000 homozygotes

MOLECULAR BASIS:
Caused by mutations in the low density lipoprotein receptor gene (LDLR,
143890.0001)

*FIELD* CN
Michael J. Wright - revised: 6/21/1999
Ada Hamosh - revised: 6/21/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/06/2002
kayiaros: 6/24/1999
kayiaros: 6/21/1999

*FIELD* CN
Marla J. F. O'Neill - updated: 2/9/2012
Marla J. F. O'Neill - updated: 5/7/2009
John A. Phillips, III - updated: 3/9/2009
John A. Phillips, III - updated: 3/25/2008
Marla J. F. O'Neill - updated: 3/20/2008
Victor A. McKusick - updated: 5/31/2007
John A. Phillips, III - updated: 7/31/2006
Cassandra L. Kniffin - updated: 10/5/2005
Victor A. McKusick - updated: 4/26/2005
Cassandra L. Kniffin - updated: 3/1/2005
Marla J. F. O'Neill - updated: 5/14/2004
Marla J. F. O'Neill - updated: 2/19/2004
Victor A. McKusick - updated: 12/23/2003
Jane Kelly - updated: 8/29/2003
Cassandra L. Kniffin - reorganized: 6/5/2002
Cassandra L. Kniffin - updated: 6/5/2002
John A. Phillips, III - updated: 2/20/2002
Victor A. McKusick - updated: 10/11/2001
Victor A. McKusick - updated: 9/20/2001
Victor A. McKusick - updated: 8/3/2001
Victor A. McKusick - updated: 8/2/2001
Michael J. Wright - updated: 7/24/2001
Stylianos E. Antonarakis - updated: 6/19/2001
Victor A. McKusick - updated: 6/5/2001
Paul J. Converse - updated: 5/18/2001
Victor A. McKusick - updated: 7/26/2000
Carol A. Bocchini - updated: 6/9/2000
Victor A. McKusick - updated: 6/2/2000
Paul Brennan - updated: 3/8/2000
Victor A. McKusick - updated: 2/11/2000
Victor A. McKusick - updated: 11/10/1999
Victor A. McKusick - updated: 9/24/1999
Wilson H. Y. Lo - updated: 8/30/1999
Michael J. Wright - updated: 2/11/1999
Victor A. McKusick - updated: 1/25/1999
Victor A. McKusick -updated: 11/4/1998
John A. Phillips, III - updated: 10/1/1998
Victor A. McKusick - updated: 9/18/1998
Victor A. McKusick - updated: 8/17/1998
Victor A. McKusick - updated: 12/19/1997
Victor A. McKusick - updated: 8/26/1997
Victor A. McKusick - updated: 6/18/1997
Victor A. McKusick - updated: 3/21/1997
Iosif W. Lurie - updated: 1/8/1997
Cynthia K. Ewing - updated: 9/23/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 02/15/2012
carol: 2/13/2012
terry: 2/9/2012
terry: 10/26/2011
joanna: 9/1/2011
carol: 2/9/2011
terry: 6/3/2009
wwang: 5/18/2009
terry: 5/7/2009
alopez: 3/9/2009
terry: 1/29/2009
terry: 1/27/2009
terry: 1/21/2009
carol: 3/25/2008
terry: 3/20/2008
alopez: 6/4/2007
terry: 5/31/2007
alopez: 7/31/2006
wwang: 10/18/2005
wwang: 10/12/2005
ckniffin: 10/5/2005
tkritzer: 4/28/2005
terry: 4/26/2005
tkritzer: 3/9/2005
ckniffin: 3/1/2005
carol: 5/18/2004
terry: 5/14/2004
alopez: 4/7/2004
tkritzer: 2/24/2004
terry: 2/19/2004
tkritzer: 12/29/2003
terry: 12/23/2003
carol: 8/29/2003
alopez: 5/29/2003
alopez: 5/16/2003
alopez: 5/14/2003
tkritzer: 11/19/2002
carol: 6/5/2002
ckniffin: 6/5/2002
ckniffin: 6/3/2002
ckniffin: 5/17/2002
mgross: 4/8/2002
alopez: 2/20/2002
cwells: 10/29/2001
carol: 10/25/2001
mcapotos: 10/11/2001
mcapotos: 10/8/2001
mcapotos: 10/1/2001
terry: 9/20/2001
mcapotos: 8/15/2001
mcapotos: 8/13/2001
terry: 8/3/2001
terry: 8/2/2001
terry: 7/24/2001
mgross: 6/19/2001
cwells: 6/13/2001
cwells: 6/8/2001
terry: 6/5/2001
cwells: 5/18/2001
cwells: 5/14/2001
mcapotos: 7/26/2000
terry: 6/9/2000
carol: 6/9/2000
terry: 6/2/2000
carol: 4/27/2000
alopez: 3/8/2000
mgross: 2/23/2000
terry: 2/11/2000
carol: 11/17/1999
carol: 11/16/1999
terry: 11/10/1999
mgross: 10/1/1999
terry: 9/24/1999
carol: 9/8/1999
carol: 8/31/1999
carol: 8/30/1999
terry: 4/30/1999
carol: 4/20/1999
mgross: 3/16/1999
mgross: 2/22/1999
mgross: 2/17/1999
terry: 2/11/1999
carol: 2/8/1999
terry: 1/25/1999
carol: 11/12/1998
terry: 11/4/1998
carol: 10/1/1998
dkim: 9/23/1998
terry: 9/18/1998
carol: 8/20/1998
terry: 8/17/1998
alopez: 8/7/1998
dkim: 6/30/1998
terry: 6/18/1998
terry: 5/29/1998
alopez: 5/14/1998
carol: 3/28/1998
mark: 1/10/1998
terry: 12/19/1997
mark: 11/11/1997
terry: 11/10/1997
mark: 10/19/1997
terry: 9/15/1997
jenny: 9/5/1997
terry: 8/26/1997
alopez: 7/29/1997
alopez: 7/28/1997
terry: 7/7/1997
joanna: 7/7/1997
mark: 7/1/1997
mark: 6/30/1997
jenny: 6/27/1997
alopez: 6/25/1997
jenny: 6/23/1997
mark: 6/18/1997
terry: 3/21/1997
terry: 3/17/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 2/24/1997
jenny: 1/21/1997
jenny: 1/8/1997
mark: 9/23/1996
terry: 11/17/1995
mark: 10/2/1995
pfoster: 4/7/1995
mimadm: 4/19/1994
warfield: 4/8/1994
carol: 2/24/1994

MIM 269600
*RECORD*
*FIELD* NO
269600
*FIELD* TI
#269600 SEA-BLUE HISTIOCYTE DISEASE
;;SEA-BLUE HISTIOCYTOSIS;;
HISTIOCYTOSIS, SEA-BLUE
read more*FIELD* TX
A number sign (#) is used with this entry because primary sea-blue
histiocytosis can be caused by mutation in the APOE gene (107741).

CLINICAL FEATURES

This disorder is characterized by splenomegaly, mild thrombocytopenia,
and, in the bone marrow, numerous histiocytes containing cytoplasmic
granules which stain bright blue with the usual hematologic stains. The
name was coined by Silverstein et al. (1970). Holland et al. (1965)
suggested that the syndrome is the consequence of an inherited metabolic
defect analogous to Gaucher disease and other sphingolipidoses. Jones et
al. (1970) described an affected brother and sister. Parental
consanguinity was possible because both parents came from the same
restricted area of West Virginia. Lake et al. (1970) suggested that the
'sea-blue' designation be abandoned because the marrow contains a second
variety of abnormal cell which never stains 'sea-blue' and because they
had observed a 'malignant' disorder with 'sea-blue' cells and
progressive neurologic disease characterized by ataxia, dementia, and
seizures. Heterozygotes may have some sea-blue histiocytes in the bone
marrow (Zlotnick and Fried, 1970).

Wewalka (1970) gave a long-term follow-up on a case reported in 1950. He
commented on eye changes: a white ring surrounding the macula. Berman
(1972) described 2 sisters with this disorder in whom the initial
diagnosis was Gaucher disease. The qualitative test for excessive
mucopolysacchariduria was mildly positive in these patients. Sawitsky et
al. (1972) added 2 families. In one, 4 brothers and a sister out of 7
sibs with normal parents were affected. The family was from Trinidad. In
the second, an American black family, mother and daughter were affected.
The authors concluded that this disorder is a lipidosis. They presented
a pedigree of the family of Zlotnick and Fried (1970). The parents were
first cousins in their Iranian Jewish family and showed changes
consistent with carrier status.

Sea-blue histiocytes have been observed in Norum disease (245900)
(Jacobsen et al., 1972) and in Niemann-Pick disease type C1 (257220).
Chainuvati et al. (1977) described the disease in a Thai brother and
sister. The abnormal histiocytes were found in bone marrow and liver.
Cirrhosis and absence of axillary hair were found in both.

Blankenship et al. (1973) suggested the existence of a dominant variety,
which they called the Lewis type for the name of the family. Three sibs
had splenomegaly, peripheral neuropathy, cafe-au-lait spots and elevated
serum acid phosphatase levels. The father, who was not known to be
related to the mother, showed elevated bone marrow acid phosphatase and
abnormal histiocytes. The Lewis type of Blankenship et al. (1973)
subsequently was shown to be a form of Niemann-Pick disease (607616).
The findings in the father represented, presumably, heterozygote
manifestation.

A presumably dominant but different form of sea-blue histiocyte disease
was described by Swaiman et al. (1975), who found ceroid-lipofuscin
storage and varied neurologic changes, especially posterior column
degeneration, often beginning in the teens. Gait disturbance, positive
Romberg and Babinski tests, and diminished vibratory and position senses
were described.

Zina and Bundino (1983) reported an affected brother and sister. The
brother, aged 25 years, had skin lesions that contained sea-blue
histiocytes. Like her brother, the sister, aged 17 years, had
hepatosplenomegaly and pulmonary infiltrates; sea-blue histiocytes were
demonstrated in muscles and subcutaneous tissue. Viana et al. (1990)
reported sea-blue histiocytosis as a feature of 4 sibs in a Brazilian
kindred with nonneuropathic (presumably type B) Niemann-Pick disease.

MOLECULAR GENETICS

Nguyen et al. (2000) described 2 unrelated probands with primary
sea-blue histiocytosis who had normal or mildly elevated serum
triglyceride concentrations that markedly increased after splenectomy.
They provided evidence linking the syndrome to an inherited dominant
APOE mutation (delta149 leu; 107741.0031) that causes a derangement in
lipid metabolism and leads to splenomegaly in the absence of severe
hypertriglyceridemia.

In 2 brothers with splenomegaly, thrombocytopenia, and
hypertriglyceridemia, Faivre et al. (2005) identified the delta149 leu
mutation in the APOE gene. Their mother, who also had the mutation, had
only isolated hypertriglyceridemia. One brother had a large beta band in
the VLDL fraction and an elevated VLDL cholesterol-to-plasma
triglyceride ratio; Faivre et al. (2005) suggested that the more severe
phenotype might be explained by the presence of an APOE2 allele
(107741.0001) in this patient.

*FIELD* SA
Fried et al. (1978); Silverstein and Ellefson (1972); Tachibana et
al. (1979)
*FIELD* RF
1. Berman, E. R.: Personal Communication. Jerusalem, Israel 1972.

2. Blankenship, R. M.; Greenburg, B. R.; Lucas, R. N.; Reynolds, R.
D.; Beutler, E.: Familial sea-blue histiocytes with acid phosphatasemia:
a syndrome resembling Gaucher disease: the Lewis variant. JAMA 225:
54-56, 1973.

3. Chainuvati, T.; Piankijagum, A.; Viranuvatti, V.; Silverstein,
M. N.: Sea-blue histiocyte syndrome in Thai siblings. Acta Haemat. 58:
58-64, 1977.

4. Faivre, L.; Saugier-Veber, P.; Pais de Barros, J.-P.; Verges, B.;
Couret, B.; Lorcerie, B.; Thauvin, C.; Charbonnier, F.; Huet, F.;
Gambert, P.; Frebourg, T.; Duvillard, L.: Variable expressivity of
the clinical and biochemical phenotype associated with the apolipoprotein
E p.Leu149del mutation. Europ. J. Hum. Genet. 13: 1186-1191, 2005.

5. Fried, K.; Beer, S.; Drespin, H. I.; Leiba, H.; Djaldetti, M.;
Zitman, D.; Klibansky, C.: Biochemical, genetic and ultrastructural
study of a family with the sea-blue histiocyte syndrome--chronic non-neuronopathic
Niemann-Pick disease. Europ. J. Clin. Invest. 8: 249-253, 1978.

6. Holland, P.; Hug, G.; Schubert, W. K.: Chronic reticuloendothelial
cell storage disease. Am. J. Dis. Child. 110: 117-124, 1965.

7. Jacobsen, C. D.; Gjone, E.; Hovig, T.: Sea-blue histiocytes in
familial lecithin cholesterol acyltransferase deficiency. Scand.
J. Haemat. 9: 106-113, 1972.

8. Jones, B.; Gilbert, E. F.; Zugibe, F. T.; Thompson, H.: Sea-blue
histiocyte disease in siblings. Lancet 296: 73-75, 1970. Note: Originally
Volume II.

9. Lake, B. D.; Stephens, R.; Neville, B. G. R.: Syndrome of the
sea-blue histiocyte. (Letter) Lancet 296: 309 only, 1970. Note:
Originally Volume II.

10. Nguyen, T. T.; Kruckeberg, K. E.; O'Brien, J. F.; Ji, Z.-S.; Karnes,
P.S.; Crottgy, T. B.; Hay, I. D.; Mahley, R. W.; O'Brien, T.: Familial
splenomegaly: macrophage hypercatabolism of lipoproteins associated
with apolipoprotein E mutation [apolipoprotein E (delta149 leu)]. J.
Clin. Endocr. Metab. 85: 4354-4358, 2000.

11. Sawitsky, A.; Rosner, F.; Chodsky, S.: The sea-blue histiocyte
syndrome, a review: genetic and biochemical studies. Seminars Hemat. 9:
285-297, 1972.

12. Silverstein, M. N.; Ellefson, R. D.: The syndrome of the sea-blue
histiocyte. Seminars Hemat. 9: 299-308, 1972.

13. Silverstein, M. N.; Ellefson, R. D.; Ahern, E. J.: The syndrome
of the sea-blue histiocyte. New Eng. J. Med. 282: 1-4, 1970.

14. Swaiman, K. F.; Barg, B. P.; Lockman, L. A.: Sea-blue histiocyte
and posterior column dysfunction: a familial disorder. Neurology 25:
1084-1085, 1975.

15. Tachibana, F.; Hakozaki, H.; Takahashi, K.; Kojima, M.; Enomoto,
S.; Wada, J.: Syndrome of the sea-blue histiocyte: the first case
report in Japan and review of the literature. Acta Path. Jpn. 29:
73-97, 1979.

16. Viana, M. B.; Giugliani, R.; Leite, V. H. R.; Barth, M. L.; Lekhwani,
C.; Slade, C. M.; Fensom, A.: Very low levels of high density lipoprotein
cholesterol in four sibs of a family with non-neuropathic Niemann-Pick
disease and sea-blue histiocytosis. J. Med. Genet. 27: 499-504,
1990.

17. Wewalka, F. G.: Syndrome of the sea-blue histiocyte. (Letter) Lancet 296:
1248 only, 1970. Note: Originally Volume II.

18. Zina, A. M.; Bundino, S.: Familial sea-blue histiocytosis with
cutaneous involvement: a case report with ultrastructural findings. Brit.
J. Derm. 108: 355-361, 1983.

19. Zlotnick, A.; Fried, K.: Sea-blue-histiocyte syndrome. (Letter) Lancet 296:
776 only, 1970. Note: Originally Volume II.

*FIELD* CS

GI:
Splenomegaly;
Cirrhosis

Heme:
Mild thrombocytopenia

Eyes:
White ring surrounding the macula

Hair:
Absent axillary hair

Lab:
Numerous bone marrow histiocytes with cytoplasmic granules which stain
bright blue with the usual hematologic stains

Inheritance:
Autosomal recessive;
? same as the adult, chronic or B form of Niemann-Pick disease

*FIELD* CN
Marla J. F. O'Neill - updated: 11/30/2005
John A. Phillips, III - updated: 8/8/2001

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 06/03/2009
terry: 3/25/2009
carol: 12/12/2005
wwang: 11/30/2005
tkritzer: 10/15/2003
carol: 4/4/2003
alopez: 8/8/2001
davew: 6/7/1994
warfield: 4/20/1994
mimadm: 3/12/1994
supermim: 3/17/1992
carol: 2/21/1992
carol: 7/9/1991

MIM 611771
*RECORD*
*FIELD* NO
611771
*FIELD* TI
#611771 LIPOPROTEIN GLOMERULOPATHY; LPG
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morelipoprotein glomerulopathy can be caused by heterozygous mutation in the
APOE gene (107741).

DESCRIPTION

Lipoprotein glomerulopathy is an uncommon kidney disease characterized
by proteinuria, progressive kidney failure, and distinctive lipoprotein
thrombi in glomerular capillaries (Saito et al., 2006). It mainly
affects people of Japanese and Chinese origin; in these populations, it
is associated with mutations in the gene that encodes apolipoprotein E
(APOE; 107741). The disorder had rarely been described in Caucasians.

CLINICAL FEATURES

Lipoprotein glomerulopathy is characterized by abnormal lipoprotein
deposition in the glomeruli, usually with lipoprotein thrombi distending
and occluding the glomerular capillary lumina, a variable degree of
mesangial proliferation, dysbetalipoproteinemia, and high levels of APOE
and APOE2/3 phenotype in most cases (Matsunaga et al., 1999). It has
been described predominantly in Japanese and Chinese (Rovin et al.,
2007).

Rovin et al. (2007) described 2 European American families in each of
which a single male presented with edema and proteinuria in the
nephrotic range. In both, kidney biopsy showed an amorphous material
that stained positive for neutral lipids in almost all glomerular
capillaries. One clinically unaffected heterozygous female, an aunt of
one of the probands, showed in a nephrectomy specimen obtained for
therapy of renal cell carcinoma a glomerulus with dilated capillary
loops containing amorphous material similar to that found in the
patients with lipoprotein glomerulopathy.

MOLECULAR GENETICS

Oikawa et al. (1997) identified 3 Japanese patients with lipoprotein
glomerulopathy who were heterozygous for an arg145-to-pro mutation in
APOE (R145P; 107741.0032). The authors designated this variant 'APOE
Sendai.'

Matsunaga et al. (1999) reported a Japanese man with lipoprotein
glomerulopathy who carried an arg25-to-cys mutation in APOE (R25C;
107741.0033). The patient's mother, a heterozygous carrier, had
dysbetaliproteinemia but no lipoprotein glomerulopathy. Matsunaga et al.
(1999) termed this variant 'APOE Kyoto.'

In 2 unrelated American men of European ancestry with lipoprotein
glomerulopathy, Rovin et al. (2007) detected an R25C substitution in
APOE. Heterozygous female carriers were clinically unaffected. Rovin et
al. (2007) remarked that the APOE Kyoto mutation appears to be
sufficient to lead to glomerular lipoprotein deposition but not to
clinical lipoprotein glomerulopathy. Apolipoprotein E may accumulate in
glomerular capillaries because the mutation diminishes the capacity of
apolipoprotein E to bind to the low-density lipoprotein (LDL) receptor
and also decreases its uptake by endothelial cells. Impaired LPL binding
was also seen with APOE Sendai (Ishigaki et al., 2000). Rovin et al.
(2007) suggested that APOE Kyoto carriers in whom the disease develops
may have a second defect that reduces clearance of abnormal lipoprotein
through pathways that are independent of the LDL receptor.

*FIELD* RF
1. Ishigaki, Y.; Oikawa, S.; Suzuki, T.; Usui, S.; Magoori, K.; Kim,
DH.; Suzuki, H.; Sasaki, J.; Sasano, H.; Okazaki, M.; Toyota, T.;
Saito, T.; Yamamoto, T. T.: Virus-mediated transduction of apolipoprotein
E (ApoE)-Sendai develops lipoprotein glomerulopathy in ApoE-deficient
mice. J. Biol. Chem. 275(40): 31269-73, 2000.

2. Matsunaga, A.; Sasaki, J.; Komatsu, T.; Kanatsu, K.; Tsuji, E.;
Moriyama, K.; Koga, T.; Arakawa, K.; Oikawa, S.; Saito, T.; Kita,
T.; Doi, T.: A novel apolipoprotein E mutation, E2 (arg25cys), in
lipoprotein glomerulopathy. Kidney Int. 56(2): 421-427, 1999.

3. 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.; Sasaki, J.: Apolipoprotein
E Sendai (arginine 145--proline): a new variant associated with lipoprotein
glomerulopathy. J. Am. Soc. Nephrol. 8: 820-823, 1997.

4. Rovin, B. H.; Roncone, D.; McKinley, A.; Nadasdy, T.; Korbet, S.
M.; Schwartz, M. M.: APOE Kyoto mutation in European Americans with
lipoprotein glomerulopathy. (Letter) New Eng. J. Med. 357: 2522-2524,
2007.

5. Saito, T.; Matsunaga, A.; Oikawa, S.: Impact of lipoprotein glomerulopathy
on the relationship between lipids and renal diseases. Am. J. Kidney
Dis. 47: 199-211, 2006.

*FIELD* CD
Victor A. McKusick: 2/6/2008

*FIELD* ED
alopez: 02/06/2008

RBCC Red Blood Cell Collection

Full text data of APOE