RBCC Red Blood Cell Collection

CETP [Confidence: low (only semi-automatic identification from reviews)]
Cholesteryl ester transfer protein (Lipid transfer protein I; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P11597
ID CETP_HUMAN Reviewed; 493 AA.
AC P11597; Q13987; Q13988; Q53YZ1;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 19-JUL-2005, sequence version 2.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=Cholesteryl ester transfer protein;
DE AltName: Full=Lipid transfer protein I;
DE Flags: Precursor;
GN Name=CETP;
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] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, AND
RP VARIANT ILE-422.
RX PubMed=3600759; DOI=10.1038/327632a0;
RA Drayna D., Jarnagin A.S., McLean J., Henzel W., Kohr W., Fielding C.,
RA Lawn R.;
RT "Cloning and sequencing of human cholesteryl ester transfer protein
RT cDNA.";
RL Nature 327:632-634(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2334701; DOI=10.1021/bi00458a004;
RA Agellon L.B., Quinet E.M., Gillette T.G., Drayna D.T., Brown M.L.,
RA Tall A.R.;
RT "Organization of the human cholesteryl ester transfer protein gene.";
RL Biochemistry 29:1372-1376(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-422.
RA Rieder M.J., da Ponte S.H., Kuldanek S.A., Rajkumar N., Smith J.D.,
RA Toth E.J., Nickerson D.A.;
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ILE-422.
RC TISSUE=Pancreas, and Spleen;
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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-15.
RX PubMed=8943225; DOI=10.1074/jbc.271.50.31831;
RA Oliveira C.F.O., Chouinard R.A., Agellon L.B., Bruce C., Ma L.,
RA Walsh A., Breslow J.L., Tall A.R.;
RT "Human cholesteryl ester transfer protein gene proximal promoter
RT contains dietary cholesterol positive responsive elements and mediates
RT expression in small intestine and periphery while predominant liver
RT and spleen expression is controlled by 5'-distal sequences. Cis-acting
RT sequences mapped in transgenic mice.";
RL J. Biol. Chem. 271:31831-31838(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-27.
RX PubMed=9332354; DOI=10.1016/S0378-1119(97)00247-3;
RA Williams S., Hayes L., Elsenboss L., Williams A., Andre C.,
RA Abramson R., Thompson J.F., Milos P.M.;
RT "Sequencing of the cholesteryl ester transfer protein 5' regulatory
RT region using artificial transposons.";
RL Gene 197:101-107(1997).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-493 (ISOFORM 2), AND VARIANT ILE-422.
RC TISSUE=Liver;
RA Dinchuk J.E., Hart J.T., Wirak D.O.;
RL Submitted (FEB-1992) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-257 AND ASN-358, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [9]
RP GLYCOSYLATION AT ASN-105.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 19-493 IN COMPLEX WITH LIPID,
RP DISULFIDE BOND, AND MUTAGENESIS OF THR-155; VAL-215; ARG-218; SER-247;
RP PHE-282; PHE-287; PHE-309; LEU-313; TYR-392; LEU-399 AND VAL-433.
RX PubMed=17237796; DOI=10.1038/nsmb1197;
RA Qiu X., Mistry A., Ammirati M.J., Chrunyk B.A., Clark R.W., Cong Y.,
RA Culp J.S., Danley D.E., Freeman T.B., Geoghegan K.F., Griffor M.C.,
RA Hawrylik S.J., Hayward C.M., Hensley P., Hoth L.R., Karam G.A.,
RA Lira M.E., Lloyd D.B., McGrath K.M., Stutzman-Engwall K.J.,
RA Subashi A.K., Subashi T.A., Thompson J.F., Wang I.-K., Zhao H.,
RA Seddon A.P.;
RT "Crystal structure of cholesteryl ester transfer protein reveals a
RT long tunnel and four bound lipid molecules.";
RL Nat. Struct. Mol. Biol. 14:106-113(2007).
RN [11]
RP INVOLVEMENT IN HALP1.
RX PubMed=2215607;
RA Inazu A., Brown M.L., Hesler C.B., Agellon L.B., Koizumi J.,
RA Takata K., Maruhama Y., Mabuchi H., Tall A.R.;
RT "Increased high-density lipoprotein levels caused by a common
RT cholesteryl-ester transfer protein gene mutation.";
RL N. Engl. J. Med. 323:1234-1238(1990).
RN [12]
RP VARIANT HALP1 GLY-459.
RX PubMed=8408659; DOI=10.1172/JCI116802;
RA Takahashi K., Jiang X.-C., Sakai N., Yamashita S., Hirano K., Bujo H.,
RA Yamazaki H., Kusunoki J., Miura T., Kussie P., Matsuzawa Y., Saito Y.,
RA Tall A.;
RT "A missense mutation in the cholesteryl ester transfer protein gene
RT with possible dominant effects on plasma high density lipoproteins.";
RL J. Clin. Invest. 92:2060-2064(1993).
RN [13]
RP VARIANTS SER-331; PRO-390; ILE-422 AND MET-486.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [14]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [15]
RP VARIANTS HALP1 PRO-168 AND CYS-299, AND CHARACTERIZATION OF VARIANTS
RP HALP1 PRO-168 AND CYS-299.
RX PubMed=12091484; DOI=10.1194/jlr.M200024-JLR200;
RA Nagano M., Yamashita S., Hirano K., Ito M., Maruyama T., Ishihara M.,
RA Sagehashi Y., Oka T., Kujiraoka T., Hattori H., Nakajima N.,
RA Egashira T., Kondo M., Sakai N., Matsuzawa Y.;
RT "Two novel missense mutations in the CETP gene in Japanese
RT hyperalphalipoproteinemic subjects: high-throughput assay by Invader
RT assay.";
RL J. Lipid Res. 43:1011-1018(2002).
RN [16]
RP VARIANTS GLY-15; MET-385; PRO-390; ILE-422 AND GLN-468.
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).
CC -!- FUNCTION: Involved in the transfer of insoluble cholesteryl esters
CC in the reverse transport of cholesterol.
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P11597-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P11597-2; Sequence=VSP_023645;
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- POLYMORPHISM: Genetic variations in CETP define the high density
CC lipoprotein cholesterol level quantitative trait locus 10
CC (HDLCQ10) [MIM:143470].
CC -!- DISEASE: Hyperalphalipoproteinemia 1 (HALP1) [MIM:143470]: A
CC condition characterized by high levels of high density lipoprotein
CC (HDL) and increased HDL cholesterol levels. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the BPI/LBP/Plunc superfamily. BPI/LBP
CC family.
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;=CETP";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Cholesterylester transfer
CC protein entry;
CC URL="http://en.wikipedia.org/wiki/Cholesterylester_transfer_protein";
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DR EMBL; M30185; AAA51977.1; -; mRNA.
DR EMBL; M32998; AAA51978.1; -; Genomic_DNA.
DR EMBL; M32992; AAA51978.1; JOINED; Genomic_DNA.
DR EMBL; M32993; AAA51978.1; JOINED; Genomic_DNA.
DR EMBL; M32994; AAA51978.1; JOINED; Genomic_DNA.
DR EMBL; M32995; AAA51978.1; JOINED; Genomic_DNA.
DR EMBL; M32996; AAA51978.1; JOINED; Genomic_DNA.
DR EMBL; M32997; AAA51978.1; JOINED; Genomic_DNA.
DR EMBL; AY422211; AAR03500.1; -; Genomic_DNA.
DR EMBL; BC025739; AAH25739.1; -; mRNA.
DR EMBL; U71187; AAD14876.1; -; Genomic_DNA.
DR EMBL; AF027656; AAB86604.1; -; Genomic_DNA.
DR EMBL; M83573; AAB59388.1; -; mRNA.
DR PIR; A26941; A26941.
DR RefSeq; NP_000069.2; NM_000078.2.
DR UniGene; Hs.89538; -.
DR PDB; 2OBD; X-ray; 2.10 A; A=19-493.
DR PDB; 4EWS; X-ray; 2.59 A; A=19-493.
DR PDB; 4F2A; X-ray; 3.11 A; A=19-493.
DR PDBsum; 2OBD; -.
DR PDBsum; 4EWS; -.
DR PDBsum; 4F2A; -.
DR ProteinModelPortal; P11597; -.
DR SMR; P11597; 22-493.
DR IntAct; P11597; 3.
DR STRING; 9606.ENSP00000200676; -.
DR BindingDB; P11597; -.
DR ChEMBL; CHEMBL3572; -.
DR PhosphoSite; P11597; -.
DR DMDM; 71153497; -.
DR PaxDb; P11597; -.
DR PeptideAtlas; P11597; -.
DR PRIDE; P11597; -.
DR DNASU; 1071; -.
DR Ensembl; ENST00000200676; ENSP00000200676; ENSG00000087237.
DR Ensembl; ENST00000379780; ENSP00000369106; ENSG00000087237.
DR GeneID; 1071; -.
DR KEGG; hsa:1071; -.
DR UCSC; uc002eki.2; human.
DR CTD; 1071; -.
DR GeneCards; GC16P056996; -.
DR HGNC; HGNC:1869; CETP.
DR MIM; 118470; gene.
DR MIM; 143470; phenotype.
DR neXtProt; NX_P11597; -.
DR Orphanet; 79506; Cholesterol-ester transfer protein deficiency.
DR PharmGKB; PA108; -.
DR eggNOG; NOG252260; -.
DR HOGENOM; HOG000111553; -.
DR HOVERGEN; HBG005310; -.
DR InParanoid; P11597; -.
DR KO; K16835; -.
DR OMA; PKISCQN; -.
DR OrthoDB; EOG783MV4; -.
DR PhylomeDB; P11597; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; P11597; -.
DR GeneWiki; Cholesterylester_transfer_protein; -.
DR GenomeRNAi; 1071; -.
DR NextBio; 4472; -.
DR PRO; PR:P11597; -.
DR ArrayExpress; P11597; -.
DR Bgee; P11597; -.
DR CleanEx; HS_CETP; -.
DR Genevestigator; P11597; -.
DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0031982; C:vesicle; IDA:BHF-UCL.
DR GO; GO:0015485; F:cholesterol binding; IDA:BHF-UCL.
DR GO; GO:0017127; F:cholesterol transporter activity; IDA:BHF-UCL.
DR GO; GO:0031210; F:phosphatidylcholine binding; IDA:BHF-UCL.
DR GO; GO:0005548; F:phospholipid transporter activity; IDA:BHF-UCL.
DR GO; GO:0017129; F:triglyceride binding; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL.
DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IMP:BHF-UCL.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR GO; GO:0010745; P:negative regulation of macrophage derived foam cell differentiation; IC:BHF-UCL.
DR GO; GO:0046470; P:phosphatidylcholine metabolic process; IDA:BHF-UCL.
DR GO; GO:0055091; P:phospholipid homeostasis; IDA:BHF-UCL.
DR GO; GO:0006898; P:receptor-mediated endocytosis; TAS:Reactome.
DR GO; GO:0010874; P:regulation of cholesterol efflux; IMP:BHF-UCL.
DR GO; GO:0043691; P:reverse cholesterol transport; IC:BHF-UCL.
DR GO; GO:0070328; P:triglyceride homeostasis; IDA:BHF-UCL.
DR GO; GO:0006641; P:triglyceride metabolic process; IDA:BHF-UCL.
DR GO; GO:0034372; P:very-low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR InterPro; IPR017943; Bactericidal_perm-incr_a/b_dom.
DR InterPro; IPR017130; Cholesteryl_ester_transfer.
DR InterPro; IPR001124; Lipid-bd_serum_glycop_C.
DR InterPro; IPR017954; Lipid-bd_serum_glycop_CS.
DR InterPro; IPR017942; Lipid-bd_serum_glycop_N.
DR PANTHER; PTHR10504:SF12; PTHR10504:SF12; 1.
DR Pfam; PF01273; LBP_BPI_CETP; 1.
DR Pfam; PF02886; LBP_BPI_CETP_C; 1.
DR PIRSF; PIRSF037185; Cholesteryl_ester_transf; 1.
DR SMART; SM00328; BPI1; 1.
DR SMART; SM00329; BPI2; 1.
DR SUPFAM; SSF55394; SSF55394; 2.
DR PROSITE; PS00400; LBP_BPI_CETP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Atherosclerosis;
KW Cholesterol metabolism; Complete proteome; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Lipid metabolism;
KW Lipid transport; Polymorphism; Reference proteome; Secreted; Signal;
KW Steroid metabolism; Sterol metabolism; Transport.
FT SIGNAL 1 17
FT CHAIN 18 493 Cholesteryl ester transfer protein.
FT /FTId=PRO_0000017155.
FT CARBOHYD 105 105 N-linked (GlcNAc...) (complex).
FT CARBOHYD 257 257 N-linked (GlcNAc...).
FT CARBOHYD 358 358 N-linked (GlcNAc...).
FT CARBOHYD 413 413 N-linked (GlcNAc...) (Potential).
FT DISULFID 160 201
FT VAR_SEQ 251 310 Missing (in isoform 2).
FT /FTId=VSP_023645.
FT VARIANT 15 15 A -> G (in dbSNP:rs34065661).
FT /FTId=VAR_017018.
FT VARIANT 154 154 R -> W (in dbSNP:rs34716057).
FT /FTId=VAR_033098.
FT VARIANT 168 168 L -> P (in HALP1; reduced secretion into
FT plasma).
FT /FTId=VAR_033099.
FT VARIANT 299 299 R -> C (in HALP1; reduced secretion into
FT plasma).
FT /FTId=VAR_033100.
FT VARIANT 331 331 G -> S (in dbSNP:rs5881).
FT /FTId=VAR_013919.
FT VARIANT 385 385 V -> M (in dbSNP:rs34855278).
FT /FTId=VAR_017019.
FT VARIANT 390 390 A -> P (in dbSNP:rs5880).
FT /FTId=VAR_013920.
FT VARIANT 422 422 V -> I (in dbSNP:rs5882).
FT /FTId=VAR_013921.
FT VARIANT 455 455 V -> M (in dbSNP:rs2228667).
FT /FTId=VAR_031127.
FT VARIANT 459 459 D -> G (in HALP1; dbSNP:rs2303790).
FT /FTId=VAR_004172.
FT VARIANT 468 468 R -> Q (in dbSNP:rs1800777).
FT /FTId=VAR_013922.
FT VARIANT 486 486 V -> M (in dbSNP:rs5887).
FT /FTId=VAR_013923.
FT MUTAGEN 155 155 T->Y: Reduces triglyceride transfer and
FT cholesteryl ester transfer 5-fold.
FT MUTAGEN 215 215 V->W: Reduces triglyceride transfer 10-
FT fold. No effect on cholesteryl ester
FT transfer.
FT MUTAGEN 218 218 R->S: Reduces triglyceride transfer 10-
FT fold. Slight reduction of cholesteryl
FT ester transfer.
FT MUTAGEN 247 247 S->A: Reduces triglyceride transfer 5-
FT fold. Slight reduction of cholesteryl
FT ester transfer.
FT MUTAGEN 282 282 F->R: Not secreted.
FT MUTAGEN 287 287 F->R: Not secreted.
FT MUTAGEN 309 309 F->D: Not secreted.
FT MUTAGEN 313 313 L->Q: Reduces cholesteryl ester transfer
FT by 60%.
FT MUTAGEN 392 392 Y->S: Not secreted.
FT MUTAGEN 399 399 L->W: Not secreted.
FT MUTAGEN 433 433 V->R: Reduces activity by 60%.
FT STRAND 27 33
FT HELIX 34 40
FT HELIX 41 43
FT HELIX 44 54
FT STRAND 60 66
FT TURN 67 69
FT STRAND 70 94
FT TURN 95 97
FT STRAND 98 120
FT HELIX 122 124
FT STRAND 128 149
FT STRAND 152 171
FT HELIX 172 174
FT HELIX 180 187
FT HELIX 189 222
FT STRAND 228 231
FT STRAND 234 236
FT STRAND 242 249
FT STRAND 252 255
FT HELIX 269 271
FT STRAND 274 283
FT HELIX 284 296
FT STRAND 300 304
FT HELIX 306 315
FT HELIX 323 325
FT HELIX 326 329
FT HELIX 333 335
FT STRAND 337 344
FT STRAND 347 351
FT STRAND 354 367
FT HELIX 372 374
FT STRAND 378 393
FT STRAND 396 416
FT HELIX 420 432
FT HELIX 434 451
FT TURN 452 454
FT HELIX 455 457
FT STRAND 458 468
FT STRAND 471 479
FT HELIX 482 490
SQ SEQUENCE 493 AA; 54756 MW; CD7762766A9B062E CRC64;
MLAATVLTLA LLGNAHACSK GTSHEAGIVC RITKPALLVL NHETAKVIQT AFQRASYPDI
TGEKAMMLLG QVKYGLHNIQ ISHLSIASSQ VELVEAKSID VSIQNVSVVF KGTLKYGYTT
AWWLGIDQSI DFEIDSAIDL QINTQLTCDS GRVRTDAPDC YLSFHKLLLH LQGEREPGWI
KQLFTNFISF TLKLVLKGQI CKEINVISNI MADFVQTRAA SILSDGDIGV DISLTGDPVI
TASYLESHHK GHFIYKNVSE DLPLPTFSPT LLGDSRMLYF WFSERVFHSL AKVAFQDGRL
MLSLMGDEFK AVLETWGFNT NQEIFQEVVG GFPSQAQVTV HCLKMPKISC QNKGVVVNSS
VMVKFLFPRP DQQHSVAYTF EEDIVTTVQA SYSKKKLFLS LLDFQITPKT VSNLTESSSE
SVQSFLQSMI TAVGIPEVMS RLEVVFTALM NSKGVSLFDI INPEIITRDG FLLLQMDFGF
PEHLLVDFLQ SLS
//

MIM 118470
*RECORD*
*FIELD* NO
118470
*FIELD* TI
*118470 CHOLESTERYL ESTER TRANSFER PROTEIN, PLASMA; CETP
;;LIPID TRANSFER PROTEIN I
read more*FIELD* TX

DESCRIPTION

The cholesteryl ester transfer protein (CETP) mediates the exchange of
lipids between lipoproteins, resulting in the net transfer of
cholesteryl ester from high density lipoprotein (HDL) to other
lipoproteins and in the subsequent uptake of cholesterol by hepatocytes
(summary by Kuivenhoven et al., 1998).

CLONING

Using a partial amino acid sequence from purified CETP, Drayna et al.
(1987) cloned and sequenced cDNA encoding CETP from a human liver
library. They used the sequenced cDNA to detect CETP mRNA in a number of
human tissues. CETP is also known as lipid transfer protein I (Day et
al., 1994).

GENE FUNCTION

Because the role of CETP in atherosclerosis remained unclear, Okamoto et
al. (2000) attempted to develop a potent, specific CETP inhibitor. One
inhibitor, JTT-705, forms a disulfide bond with CETP and increases high
density lipoprotein (HDL) cholesterol, decreases non-HDL cholesterol,
and inhibits the progression of atherosclerosis in rabbits. These
observations suggested that CETP may be atherogenic in vivo and that
JTT-705 may be a potential antiatherogenic drug.

GENE STRUCTURE

Oliveira et al. (1996) used transgenic mice to map the cis-acting
sequences of the CETP gene. They localized a dietary cholesterol
positive response element to the interval between -370 bp and -138 bp in
the 5-prime proximal promoter region. Oliveira et al. (1996) found that
more distal 5-prime promoter regions are required for tissue-specific
expression in the liver, spleen, small intestine, adrenal gland, and
other tissues.

MAPPING

Sparkes et al. (1987) used a CETP probe against DNA from a human/mouse
somatic cell hybrid panel to assign the CETP gene to chromosome 16. In
situ hybridization of the same probe to metaphase chromosomes
regionalized the gene to 16q21. See also Lusis et al. (1987). This
contributes a new marker for chromosome 16 inasmuch as RFLPs of this
gene have been reported (Drayna and Lawn, 1987).

MOLECULAR GENETICS

For a discussion of the relationship between variation in the CETP gene
and HDL cholesterol levels, see 143470.

ANIMAL MODEL

The acceleration of atherosclerosis by polygenic (essential)
hypertension is well recognized in humans; however, the lack of an
animal model that simulates the human disease hinders elucidation of
pathogenic mechanisms. Herrera et al. (1999) reported a transgenic
atherosclerosis-polygenic hypertension model in Dahl salt-sensitive
hypertensive rats that overexpress the human cholesteryl ester transfer
protein. Male transgenic rats fed regular rat chow showed age-dependent
severe combined hyperlipidemia, atherosclerotic lesions, myocardial
infarctions, and decreased survival. These findings differed from
various mouse atherosclerosis models, demonstrating the necessity of
complex disease modeling in different species. The data demonstrated
that CETP can be proatherogenic.

To determine the relationship between apolipoprotein C-I (APOC1; 107710)
and CETP, Gautier et al. (2002) crossed transgenic mice expressing human
CETP with Apoc1 null mice. The HDLs of these crosses contained 50% less
cholesteryl esters and showed a decreased cholesteryl
ester-to-triglyceride ratio. The mean apparent diameter of LDLs from
these mice was also significantly reduced. In vitro, purified Apoc1
inhibited cholesteryl ester exchange when added to either total plasma
or to reconstituted HDL-free mixtures. Gautier et al. (2002) concluded
that APOC1 is a specific inhibitor of CETP.

*FIELD* AV
.0001
HYPERALPHALIPOPROTEINEMIA 1
CETP, IVS14DS, G-A, +1

Using monoclonal antibodies, Brown et al. (1989) showed that 2 Japanese
sibs with markedly increased and enlarged HDL had CETP deficiency
(143470). They were homozygous for a point mutation in the 5-prime
splice donor site of intron 14 of the CETP gene. The mutation was a
change of the strictly conserved G-T intron splice donor to A-T. The
family illustrates the key role of CETP in HDL metabolism. Plasma CETP
catalyzes the transfer of cholesteryl esters from HDL to other
lipoproteins.

Inazu et al. (1990) identified the same CETP mutation in 4 additional
Japanese families with increased HDL levels, including a family reported
by Saito (1984) with unusual longevity and increased HDL levels. The
lipoprotein phenotype of CETP deficiency, which is characterized by both
increased levels of HDL and decreased levels of low density lipoprotein
(LDL), appeared to have strong antiatherogenic potential. CETP
deficiency appears to be a frequent cause of increased HDL levels in the
population of Japan, possibly because of founder effect. A mutation in
the APOB gene (107730.0006) causing familial hypobetalipoproteinemia
(615558) is another antiatherogenic mutation.

The G-to-A mutation was found in homozygous state in 2 patients by
Yamashita et al. (1990). Heterozygosity for the mutation was found in 2
other probands who totally lacked CETP and whose lipoprotein patterns
were similar to those of the 2 homozygotes. They were presumably
compound heterozygotes. Compound heterozygotes associated with
hyperalphalipoproteinemia are described in 118470.0002.

.0002
HYPERALPHALIPOPROTEINEMIA 1
CETP, ASP442GLY

Takahashi et al. (1993) reported 2 unrelated, healthy females who were
heterozygous for a G-to-A transition in exon 15 of the CETP gene,
resulting in a substitution of gly for asp at amino acid 442. Both women
had 3-fold increases in HDL concentrations and markedly decreased plasma
CETP mass and activity (HALP1; 143470), suggesting that the mutation has
dominant effects on CETP and HDL in vivo. The dominant effect of the
CETP mutation raises the possibility that the active species of CETP is
multimeric. Inazu et al. (1994) found a heterozygote frequency of 7% for
the D442G mutation in a sample of 236 Japanese men. The heterozygote
frequency of the IVS14 splice mutation (118470.0001) was estimated to be
2%. The 2 mutations accounted for about 10% of the total variance of HDL
cholesterol values in the Japanese population studied.

Akita et al. (1994) found either the IVS14 splice mutation or the D442G
mutation, or both, in 44 out of 226 unrelated patients with
hyperalphalipoproteinemia. The IVS14 mutation was found in 15 patients,
including 4 compound heterozygotes for the 2 mutations; D442G was
identified in 33, including the 4 compound heterozygotes. Allelic
frequencies in the general population for the IVS14 and the D442G
mutations were 0.81% and 4.62%, respectively. The IVS14 mutation was
responsible for a more severe form of hyperalphalipoproteinemia.

Among 117 Japanese subjects with hyperalphalipoproteinemia without the
intron 14 splice defect, Sakai et al. (1995) found 3 homozygotes (2.5%)
and 34 heterozygotes (29.1%) for the D442G mutation. These results
suggested that this mutation is as common as the intron 14 splice defect
in Japanese hyperalphalipoproteinemic subjects. One of the homozygotes
was the patient previously described by Takahashi et al. (1993) as
having hyperalphalipoproteinemia with corneal opacity and coronary heart
disease. They had previously thought that this patient was heterozygous.

.0003
HYPERALPHALIPOPROTEINEMIA 1
CETP, 1-BP INS, T, IVS14, +3

Inazu et al. (1994) screened Japanese subjects with high density
lipoprotein cholesterol levels in excess of 100 mg/dl (143470) by PCR
single-strand conformation polymorphism analysis of the CETP gene. They
found a novel intron 14 splice donor site mutation caused by a T
insertion at position +3 from the exon 14/intron 14 boundary. The
phenotype of a genetic compound heterozygote for this mutation and the
IVS14 splice mutation (118470.0001) was similar to that of the
homozygote for the latter mutation: no detectable CETP and markedly
increased HDL cholesterol levels (see 143470).

.0004
HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
10
CETP, ILE405VAL

Barzilai et al. (2003) performed a case-control study of 213 Ashkenazi
Jewish probands with exceptional longevity (mean age, 98.2 years) and
their 216 offspring (mean age, 68.3 years) with an age-matched group of
258 Ashkenazi Jews and 589 participants from the Framingham Offspring
Study as controls. They found that high density lipoprotein (HDL) and
low density lipoprotein (LDL) particle sizes were significantly higher
(143470) in probands compared with both control groups (P of 0.001 for
both), independent of plasma levels of HDL and LDL cholesterol and
apolipoproteins A-I (107680) and B (107730). This phenotype was also
typical of the probands' offspring, but not of the age-matched controls.
The HDL and LDL particle sizes were significantly larger in offspring
and controls without hypertension or cardiovascular disease.
Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were
significantly higher in offspring and controls without the metabolic
syndrome. Probands and offspring had a 2.9- and 3.6-fold (in men) and
2.7- and 1.5-fold (in women) increased frequency, respectively, of
homozygosity for the val405 allele (VV genotype) of an ile405-to-val
(I405V; dbSNP rs5882) polymorphism in the CETP gene, respectively,
compared with controls. Probands with the VV genotype had increased
lipoprotein sizes and lower serum CETP concentrations. The findings
suggested that lipoprotein particle sizes are heritable and promote a
healthy aging phenotype.

Among 158 Ashkenazi Jewish individuals aged 95 to 107 years, Barzilai et
al. (2006) found that the val405 allele was significantly associated
with preserved cognitive function. Those with the V/V genotype were
twice as likely to have good cognitive function compared to those with
the I/I genotype. The findings were replicated in a second group of 173
individuals. The results also showed a link between better cognitive
function and low CETP levels, higher HDL cholesterol levels, and larger
lipoprotein size.

Sanders et al. (2010) performed a prospective cohort study of 523
community-dwelling adults without dementia aged 70 years or older.
Standardized neuropsychologic and neurologic measures were administered
annually from 1994 to 2009. Linear mixed-effects models adjusted for
sex, education, race, medical comorbidities, and APOE4 examined
associations of the val405 genotype with longitudinal performance on
cognitive tests of episodic memory, attention, and psychomotor speed.
The V405 genotype was the main predictor of incident dementia or
Alzheimer disease in similarly adjusted Cox proportional hazards models
with age as the time scale. The V405 allele frequency was 43.5%, and a
total of 40 cases of incident dementia occurred during follow-up.
Compared with isoleucine homozygotes, valine homozygotes had
significantly slower memory decline on the Free and Cued Selective
Reminding Test (0.43 points per year of age for isoleucine; 95% CI,
-0.58 to 0.29 vs. 0.21 points per year of age for valine; 95% CI, -0.39
to 0.04; difference in linear age slope, 0.22; 95% CI, 0.02 to 0.41; P =
0.03) and no significant differences on the Digit Span or Digit Symbol
Substitution tests. Valine homozygotes also had a lower risk of dementia
(hazard ratio, 0.28; 95% CI, 0.10-0.85; P - 0.02) and Alzheimer disease
(hazard ratio, 0.31; 95% CI, 0.10-0.95; P = 0.04). Sanders et al. (2010)
concluded that their preliminary report suggests that CETP V405 valine
homozygosity is associated with slower memory decline and lower incident
dementia and Alzheimer disease risk, and supports the observations of
Barzilai et al. (2006).

.0005
HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
10
CETP, C-T

In an association study of 7 HDL metabolism genes in participants in the
Dallas Heart Study and in 849 African American men and women from
Maywood, IL, Spirin et al. (2007) identified a SNP of the CETP gene,
dbSNP rs183130, that was associated with incremental changes in HDL
cholesterol levels (143470) in 3 independent samples. This SNP achieved
a P value of 4.73 x 10(-12) in analysis of covariance in the entire
sample in a model that included race, sex, age, and body mass index
(BMI). The C allele was associated with lowering of HDL cholesterol.

*FIELD* RF
1. Akita, H.; Chiba, H.; Tsuchihashi, K.; Tsuji, M.; Kumagai, M.;
Matsuno, K.; Kobayashi, K.: Cholesteryl ester transfer protein gene:
two common mutations and their effect on plasma high-density lipoprotein
cholesterol content. J. Clin. Endocr. Metab. 79: 1615-1618, 1994.

2. Barzilai, N.; Atzmon, G.; Derby, C. A.; Bauman, J. M.; Lipton,
R. B.: A genotype of exceptional longevity is associated with preservation
of cognitive function. Neurology 67: 2170-2175, 2006.

3. Barzilai, N.; Atzmon, G.; Schechter, C.; Schaefer, E. J.; Cupples,
A. L.; Lipton, R.; Cheng, S.; Shuldiner, A. R.: Unique lipoprotein
phenotype and genotype associated with exceptional longevity. JAMA 290:
2030-2040, 2003.

4. Brown, M. L.; Inazu, A.; Hesler, C. B.; Agellon, L. B.; Mann, C.;
Whitlock, M. E.; Marcel, Y. L.; Milne, R. W.; Koizumi, J.; Mabuchi,
H.; Takeda, R.; Tall, A. R.: Molecular basis of lipid transfer protein
deficiency in a family with increased high-density lipoproteins. Nature 342:
448-451, 1989.

5. Day, J. R.; Albers, J. J.; Lofton-Day, C. E.; Gilbert, T. L.; Ching,
A. F. T.; Grant, F. J.; O'Hara, P. J.; Marcovina, S. M.; Adolphson,
J. L.: Complete cDNA encoding human phospholipid transfer protein
from human endothelial cells. J. Biol. Chem. 269: 9388-9391, 1994.

6. Drayna, D.; Jarnagin, A. S.; McLean, J.; Henzel, W.; Kohr, W.;
Fielding, C.; Lawn, R.: Cloning and sequencing of human cholesteryl
ester transfer protein cDNA. Nature 327: 632-634, 1987.

7. Drayna, D.; Lawn, R. M.: Multiple RFLPs at the human cholesteryl
ester transfer protein (CETP) locus. Nucleic Acids Res. 15: 4698
only, 1987.

8. Gautier, T.; Masson, D.; Jong, M. C.; Duverneuil, L.; Le Guern,
N.; Deckert, V.; Pais de Barros, J.-P.; Dumont, L.; Bataille, A.;
Zak, Z.; Jiang, X.-C.; Tall, A. R.; Havekes, L. M.; Lagrost, L.:
Apolipoprotein CI deficiency markedly augments plasma lipoprotein
changes mediated by human cholesteryl ester transfer protein (CETP)
in CETP transgenic/ApoCI-knocked out mice. J. Biol. Chem. 277: 31354-31363,
2002.

9. Herrera, V. L. M.; Makrides, S. C.; Xie, H. X.; Adari, H.; Krauss,
R. M.; Ryan, U. S.; Ruiz-Opazo, N.: Spontaneous combined hyperlipidemia,
coronary heart disease and decreased survival in Dahl salt-sensitive
hypertensive rats transgenic for human cholesteryl ester transfer
protein. Nature Med. 5: 1383-1389, 1999.

10. Inazu, A.; Brown, M. L.; Hesler, C. B.; Agellon, L. B.; Koizumi,
J.; Takata, K.; Maruhama, Y.; Mabuchi, H.; Tall, A. R.: Increased
high-density lipoprotein levels caused by a common cholesteryl-ester
transfer protein gene mutation. New Eng. J. Med. 323: 1234-1238,
1990.

11. Inazu, A.; Jiang, X.-C.; Haraki, T.; Yagi, K.; Kamon, N.; Koizumi,
J.; Mabuchi, H.; Takeda, R.; Takata, K.; Moriyama, Y.; Doi, M.; Tall,
A.: Genetic cholesteryl ester transfer protein deficiency caused
by two prevalent mutations as a major determinant of increased levels
of high density lipoprotein cholesterol. J. Clin. Invest. 94: 1872-1882,
1994.

12. Kuivenhoven, J. A.; Jukema, J. W.; Zwinderman, A. H.; de Knijff,
P.; McPherson, R.; Bruschke, A. V. G.; Lie, K. I.; Kastelein, J. J.
P.: The role of a common variant of the cholesteryl ester transfer
protein gene in the progression of coronary atherosclerosis. New
Eng. J. Med. 338: 86-93, 1998.

13. Lusis, A. J.; Zollman, S.; Sparkes, R. S.; Klisak, I.; Mohandas,
T.; Drayna, D.; Lawn, R. M.: Assignment of the human gene for cholesteryl
ester transfer protein to chromosome 16q12-16q21. Genomics 1: 232-242,
1987.

14. Okamoto, H.; Yonemori, F.; Wakitani, K.; Minowa, T.; Maeda, K.;
Shinkai, H.: A cholesteryl ester transfer protein inhibitor attenuates
atherosclerosis in rabbits. Nature 406: 203-207, 2000.

15. Oliveira, H. C. F.; Chouinard, R. A.; Agellon, L. B.; Bruce, C.;
Ma, L.; Walsh, A.; Breslow, J. L.; Tall, A. R.: Human cholesteryl
ester transfer protein gene proximal promoter contains dietary cholesterol
positive responsive elements and mediates expression in small intestine
and periphery while predominant liver and spleen expression is controlled
by 5-prime-distal sequences. J. Biol. Chem. 271: 31831-31838, 1996.

16. Saito, F.: A pedigree of homozygous familial hyperalphalipoproteinemia. Metabolism 33:
629-633, 1984.

17. Sakai, N.; Yamashita, S.; Hirano, K.; Menju, M.; Arai, T.; Kobayashi,
K.; Ishigami, M.; Yoshida, Y.; Hoshino, T.; Nakajima, N.; Kameda-Takemura,
K.; Matsuzawa, Y.: Frequency of exon 15 missense mutation (442D:G)
in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic
Japanese subjects. Atherosclerosis 114: 139-145, 1995.

18. Sanders, A. E.; Wang, C.; Katz, M.; Derby, C. A.; Barzilai, N.;
Ozelius, L.; Lipton, R. B.: Association of a functional polymorphism
in the cholesteryl ester transfer protein (CETP) gene with memory
decline and incidence of dementia. JAMA 303: 150-158, 2010.

19. Sparkes, R. S.; Drayna, D.; Mohandas, T.; Klisak, I.; Heinzmann,
C.; Lawn, R.; Lusis, A. J.: Assignment of cholesterol ester transfer
protein (CETP) gene to human 16q21. (Abstract) Cytogenet. Cell Genet. 46:
696 only, 1987.

20. Spirin, V.; Schmidt, S.; Pertsemlidis, A.; Cooper, R. S.; Cohen,
J. C.; Sunyaev, S. R.: Common single-nucleotide polymorphisms act
in concert to affect plasma levels of high-density lipoprotein cholesterol. Am.
J. Hum. Genet. 81: 1298-1303, 2007.

21. Takahashi, K.; Jiang, X.-C.; Sakai, N.; Yamashita, S.; Hirano,
K.; Bujo, H.; Yamazaki, H.; Kusunoki, J.; Miura, T.; Kussie, P.; Matsuzawa,
Y.; Saito, Y.; Tall, A.: A missense mutation in the cholesteryl ester
transfer protein gene with possible dominant effects on plasma high
density lipoproteins. J. Clin. Invest. 92: 2060-2064, 1993.

22. Yamashita, S.; Hui, D. Y.; Sprecher, D. L.; Matsuzawa, Y.; Sakai,
N.; Tarui, S.; Kaplan, D.; Wetterau, J. R.; Harmony, J. A.: Total
deficiency of plasma cholesteryl ester transfer protein in subjects
homozygous and heterozygous for the intron 14 splicing defect. Biochem.
Biophys. Res. Commun. 170: 1346-1351, 1990.

*FIELD* CN
Ada Hamosh - updated: 9/27/2010
Ada Hamosh - updated: 1/26/2010
Ada Hamosh - updated: 1/21/2010
George E. Tiller - updated: 12/8/2008
Ada Hamosh - updated: 4/1/2008
Cassandra L. Kniffin - updated: 1/30/2008
Victor A. McKusick - updated: 11/28/2007
John A. Phillips, III - updated: 5/22/2007
Marla J. F. O'Neill - updated: 12/28/2005
George E. Tiller - updated: 10/26/2004
Victor A. McKusick - updated: 5/10/2004
Victor A. McKusick - updated: 10/22/2003
Patricia A. Hartz - updated: 10/25/2002
Ada Hamosh - updated: 7/12/2000
John A. Phillips, III - updated: 3/22/2000
Victor A. McKusick - updated: 2/3/2000
Victor A. McKusick - updated: 7/30/1998
Jennifer P. Macke - updated: 5/12/1998

*FIELD* CD
Victor A. McKusick: 6/30/1987

*FIELD* ED
carol: 12/09/2013
terry: 6/17/2011
alopez: 6/8/2011
alopez: 9/27/2010
alopez: 2/2/2010
terry: 1/26/2010
alopez: 1/21/2010
alopez: 3/25/2009
wwang: 12/8/2008
alopez: 6/2/2008
carol: 4/1/2008
wwang: 1/31/2008
ckniffin: 1/30/2008
alopez: 12/13/2007
terry: 11/28/2007
alopez: 5/22/2007
wwang: 1/3/2006
terry: 12/28/2005
terry: 2/9/2005
carol: 2/2/2005
tkritzer: 11/2/2004
terry: 10/26/2004
carol: 10/21/2004
tkritzer: 5/26/2004
terry: 5/10/2004
mgross: 2/16/2004
tkritzer: 10/24/2003
terry: 10/22/2003
mgross: 10/25/2002
alopez: 7/13/2000
terry: 7/12/2000
mgross: 4/17/2000
terry: 3/22/2000
mcapotos: 2/17/2000
mcapotos: 2/16/2000
terry: 2/3/2000
terry: 8/21/1998
alopez: 8/2/1998
terry: 7/30/1998
dholmes: 5/12/1998
mark: 9/19/1996
marlene: 8/15/1996
mark: 6/29/1995
carol: 11/29/1994
mimadm: 6/25/1994
carol: 10/29/1993
carol: 10/28/1992
carol: 4/28/1992

MIM 143470
*RECORD*
*FIELD* NO
143470
*FIELD* TI
#143470 HYPERALPHALIPOPROTEINEMIA 1; HALP1
;;CHOLESTEROL ESTER TRANSFER PROTEIN DEFICIENCY;;
read moreCETP DEFICIENCY
HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
10, INCLUDED;;
HDLCQ10, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because variation in high
density lipoprotein (HDL) cholesterol levels, including
hyperalphalipoproteinemia, can result from mutation in the cholesteryl
ester transfer protein gene (CETP; 118470) on chromosome 16q21.

Another form of hyperalphalipoproteinemia (HALP2; 614028) results from
loss-of-function mutations in the apolipoprotein C-III gene (APOC3;
107720).

CLINICAL FEATURES

Glueck et al. (1975) described a family in which 3 generations contained
persons with elevated levels of alpha-lipoprotein (HDL, the molecule
deficient in Tangier disease (205400), or hypoalphalipoproteinemia).
They referred to preliminary studies of 11 other kindreds. There was no
instance of male-to-male transmission in the pedigree described in
detail. The 'affected' persons showed no xanthomata or vascular or
neurologic disease. On further studies in 18 kindreds, Glueck et al.
(1975) found segregation among 84 offspring of 22 hyper-alpha X
normo-alpha matings consistent with autosomal dominant inheritance.
However, the distribution of alpha-lipoprotein cholesterol (HDLC) did
not show bimodality in the kindreds and no parent-offspring correlation
was found. The authors concluded that an environmental cause common to
sibships might be responsible. Longevity analysis showed prolongation of
life and a rarity of premature 'atherosclerotic events.' The last
finding makes it particularly important to identify the postulated
environmental factors. Glueck et al. (1977) identified a kindred with 4
affected generations through measurement of elevated levels of cord
blood high-density lipoproteins in neonates.

In a study of 11 black and 15 white kindreds, Siervogel et al. (1980)
found bimodality for HDL cholesterol only in whites: one mode at 46 mg
per dl and the second at 69.

Koizumi et al. (1985) and Kurasawa et al. (1985) described 2 Japanese
families with CETP deficiency. Koizumi et al. (1985) found a 58-year-old
male and his 55-year-old sister with HDL cholesterol levels of 301 and
174 mg/dl, respectively. Both were asymptomatic without signs of
atherosclerosis, and there was no unusual amount of cardiovascular
disease in the family. Two other sibs and 4 offspring had levels of HDL
cholesterol in the range of 54 to 83 mg/dl. Low density lipoprotein
(LDL) cholesterol and triglyceride levels were low in the affected
brother and sister. Both were shown to have a defect in the transfer of
labeled cholesteryl ester from HDL to VLDL plus LDL. Studies of a
35-year-old Japanese male by Kurasawa et al. (1985) demonstrated an
abnormally low triglyceride level in HDL, consistent with the concept
that CETP exchanges cholesteryl ester in HDL for triglyceride in LDL or
VLDL. Rats, dogs, and pigs with plasma CETP deficiency have been found
to be relatively resistant to atherosclerosis.

Kronenberg et al. (2002) performed segregation analysis of HDLC values
in 3,755 individuals from 560 randomly recruited Caucasian families and
522 Caucasian families with high family risk of coronary heart disease
(CHD) in the NHLBI Family Heart Study. There was no evidence for an
allele at a major gene locus responsible for low HDLC levels (604091).
The best model for low HDLC was the environmental model. However, there
was evidence for a major allele leading to higher-than-average HDLC
values in the CHD group after adjustment for triglyceride
concentrations. The environmental and dominant models were rejected,
while the codominant and recessive models were not rejected. In both
models, the means of those individuals inferred to be homozygous for the
high HDLC allele and those without the high HDLC allele were separated
by about 25 mg/dl HDLC. Because these results were unexpected,
segregation analysis was repeated using data of 2,013 individuals from
85 large Utah pedigrees ascertained for early CHD deaths, early stroke
deaths, and early hypertension. Similar results were obtained supporting
the evidence for a major allele for high HDLC level in subjects
ascertained for CHD risk.

MOLECULAR GENETICS

- CETP Deficiency/Hyperalphalipoproteinemia

Saito (1984) described a family in which both parents were
hyperlipoproteinemic. Among their progeny, 2 individuals showed
extremely high levels of HDL-cholesterol (more than 150 mg/dl),
suggesting that the affected parents were heterozygous and the
exceptional progeny homozygous. The family reported by Saito (1984) was
found by Inazu et al. (1990) to have deficiency of plasma
cholesteryl-ester transfer protein; see 118470.0002.

In 3,469 men of Japanese ancestry in the Honolulu Heart Program, Zhong
et al. (1996) found a high prevalence of 2 different CETP gene
mutations: 5.1% for D442G (118470.0002) and 0.5% for the G-to-A
substitution in the intron 14 donor site (118470.0001). The mutations
were associated with decreased CETP (-35%) and increased HDL cholesterol
levels (+10% for D442G). However, the overall prevalence of definite
coronary heart disease was 21% in men with mutations and 16% in men
without mutations.

Because the CETP-mediated cholesteryl ester transfer out of HDL is
stimulated by high triglycerides, Borggreve et al. (2005) hypothesized
that triglycerides modify the effect of the CETP -629C-A promoter
polymorphism on HDL cholesterol. In 7083 nondiabetic subjects, the HDL
cholesterol-raising effect of the CETP -629A allele was diminished with
higher triglycerides, which may be explained by a predominant effect of
triglyceride-rich lipoproteins over circulating CETP itself on
cholesteryl ester transfer out of HDL with rising triglycerides. Neither
central obesity nor insulin resistance modified the influence of the
-629C-A polymorphism on HDL cholesterol.

Large-scale clinical trials in which inhibitors of
3-hydroxy-3-methylglutaryl-co enzyme A reductase (HMGCR; 142910)
(statins) were used to reduce LDL cholesterol levels have shown marked
improvements in clinical outcomes (Schaefer and Brousseau, 2000).
Despite the favorable effects of statins on the risk of coronary heart
disease, many cardiovascular events are not prevented by statin therapy.
Brousseau et al. (2004) noted that decreased HDL cholesterol levels
constitute a major risk factor for coronary heart disease, and
investigated the effect of a novel CETP inhibitor, torcetrapib, on
plasma lipoproteins in patients with low HDL cholesterol levels. They
found that in patients with low HDL cholesterol levels, CETP inhibition
with torcetrapib markedly increased HDL cholesterol levels and also
decreased LDL cholesterol levels, both when administered as monotherapy
and when administered in combination with a statin.

- High Density Lipoprotein Cholesterol Level Quantitative
Trait Locus 10

In an evaluation of the hypothesis that multiple HDL cholesterol levels
reflect the cumulative contributions of multiple common DNA sequence
variants, each of which has a small effect, Spirin et al. (2007)
identified a single-nucleotide polymorphism (SNP) of the CETP gene
(118470.0005) that acts in concert with other SNPs in the PLTP
(172425.0001) and LPL (118470.0042) genes to affect plasma levels of HDL
cholesterol.

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 rs1800775 of CETP, 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.

Aulchenko et al. (2009) reported the first genomewide association (GWA)
study of loci affecting total cholesterol, LDL cholesterol, HDL
cholesterol, and triglycerides sampled randomly from 16 population-based
cohorts and genotyped using mainly the Illumina HumanHap300-Duo
platform. This study included a total of 17,797 to 22,562 individuals
aged 18 to 104 years from geographic regions spanning from the Nordic
countries to Southern Europe. Aulchenko et al. (2009) established 22
loci associated with serum lipid levels at a genomewide significance
level (P less than 5 x 10(-8)), including 16 loci that were identified
by previous GWA studies. The area near the CETP gene identified by dbSNP
rs1532624 was significantly associated with HDL cholesterol levels (P =
9.4 x 10(-94)).

Teslovich et al. (2010) performed a genomewide association study for
plasma lipids in more than 100,000 individuals of European ancestry and
reported 95 significantly associated loci (P = less than 5 x 10(-8)),
with 59 showing genomewide significant association with lipid traits for
the first time. The newly reported associations included SNPs near known
lipid regulators (e.g., CYP7A1, 118455; NPC1L1, 608010; SCARB1, 601040)
as well as in scores of loci not previously implicated in lipoprotein
metabolism. The 95 loci contributed not only to normal variation in
lipid traits but also to extreme lipid phenotypes and had an impact on
lipid traits in 3 non-European populations (East Asians, South Asians,
and African Americans). Teslovich et al. (2010) identified several novel
loci associated with plasma lipids that are also associated with
coronary artery disease. Teslovich et al. (2010) identified dbSNP
rs3764261 near the CETP gene as having an effect on HDL cholesterol
concentrations with an effect size of +3.39 mg per deciliter and a P
value of 7 x 10(-380).

- TaqI Polymorphism

Kondo et al. (1989) demonstrated an association between 1 allele of the
CETP locus, as demonstrated by a TaqI polymorphism (dbSNP rs708272), and
plasma apoA-I concentrations. The effect of the CETP alleles was limited
to nonsmokers in this study.

HDL cholesterol concentration is inversely related to the risk of
coronary artery disease. CETP has a central role in the metabolism of
this lipoprotein and might therefore alter the susceptibility to
atherosclerosis. For this reason, Kuivenhoven et al. (1998) studied the
DNA of 807 men with angiographically documented coronary atherosclerosis
for the presence of a polymorphism in the CETP gene. The specific
polymorphism studied was a restriction polymorphism TaqIB in intron 1 of
the CETP gene (Kuivenhoven et al., 1997). The TaqIB polymorphism had
been shown to be associated with an effect on lipid-transfer activity
(Hannuksela et al., 1994) and on HDL cholesterol concentrations (Freeman
et al., 1994). The presence of the DNA variation was referred to as B1
and its absence as B2. All 807 patients in the study participated in a
cholesterol-lowering trial designed to induce the regression of coronary
atherosclerosis and were randomly assigned to treatment with either
pravastatin or placebo for 2 years. The B1 variant of CETP was
associated with both higher plasma CETP concentrations and lower HDL
cholesterol concentrations. In addition, Kuivenhoven et al. (1998)
observed a significant dose-dependent association between this marker
and the progression of coronary atherosclerosis in the placebo group.
This association was abolished by pravastatin. Pravastatin therapy
slowed the progression of coronary atherosclerosis in B1B1 carriers but
not in B2B2 carriers. This common DNA variant appeared to predict
whether men with coronary artery disease will benefit from treatment
with pravastatin to delay the progression of coronary atherosclerosis.
In the total cohort, the B1 and B2 alleles were found at frequencies of
0.594 and 0.406, respectively. The observed frequencies were in
Hardy-Weinberg equilibrium.

In commenting on the report by Kuivenhoven et al. (1998), Altshuler et
al. (1998) expressed caution concerning the interpretation of studies of
association between allelic variants and common diseases. The 2 issues
they raised in urging caution were, first, population admixture, which
can cause an artificial association if a study includes genetically
distinct subpopulations, one of which coincidentally displays a higher
frequency of disease and allelic variants. Consideration of the ethnic
backgrounds of subjects and the use of multiple, independent populations
can help avoid this problem. The most persuasive tests, however, such as
the transmission disequilibrium test, involve family-based controls. In
this test, if a given allele contributes to disease, then the
probability that an affected person has inherited the allele from a
heterozygous parent should vary from the expected mendelian ratio of
50:50; the association of a neutral polymorphism due to admixture
displays no such deviation. A second source of concern is
multiple-hypothesis testing, aggravated by publication bias. Authors who
test a single genetic variant for an association with a single phenotype
base statistical thresholds for significance on a single hypothesis.
However, many laboratories search for associations using different
variants. Each test represents an independent hypothesis, but only
positive results are reported, leading to an overestimate of the
significance of any positive associations. Statistical correction for
multiple testing is possible, but the application of such thresholds
result in loss of statistical power.

Fumeron et al. (1995) reported that alcohol intake modulates the effect
of the TaqIB polymorphism on plasma HDL and the risk of myocardial
infarction. They found that HDL cholesterol was increased in subjects
with the B2B2 genotype only when they ingested at least 25 g of alcohol
per day. The cardioprotective effect of the B2B2 CETP genotype was
restricted to subjects who consumed the highest amounts of alcohol. In a
study of patients with insulin-dependent diabetes, Dullaart et al.
(1997) found that the ratio of very low density lipoprotein cholesterol
plus LDL cholesterol to HDL cholesterol fell in response to a linoleic
acid-enriched, low-cholesterol diet in B1B1 homozygotes but not in B1B2
heterozygotes.

In 276 unrelated patients with statin-treated familial
hypercholesterolemia, Mohrschladt et al. (2005) found that the relative
risk for cardiovascular disease events was 1.8 for B2B2 carriers
compared to B1 allele carriers, despite the fact that B2B2 patients had
higher baseline HDL cholesterol levels. Mohrschladt et al. (2005) noted
that their findings were consistent with those of Kuivenhoven et al.
(1998).

Durlach et al. (1999) studied the B polymorphism of the CETP gene in 406
type II diabetic (125853) patients aged 59.5 +/- 10.8 years, with a body
mass index of 28.9 +/- 5.3 kg/m2, and glycosylated hemoglobin of 8.2 +/-
1.9%. Patients were separated into 2 groups, 231 males (78 B1B1, 108
B1B2, and 45 B2B2) and 175 females (48 B1B1, 94 B1B2, and 33 B2B2), and
were compared on the basis of their lipid parameters (total cholesterol,
triglycerides, HDL cholesterol (HDLC), APOA1 (107680)/APOB (107730), and
LDL cholesterol) and their micro- and macrovascular complications. HDLC
was significantly higher in men with the B2B2 genotype, together with a
lower incidence of coronary heart disease. Women displayed a higher HDLC
than men and an equally high incidence of coronary heart disease in B2
homozygotes as in other genotypes. The authors concluded that in type II
diabetic patients, the B polymorphism exerts a modulating role in males
only and that this may contribute to the loss of macrovascular
protection in type II diabetic females.

- CETP Promoter Polymorphisms

In 709 males with coronary artery disease (CAD), Klerkx et al. (2003)
investigated phenotypic associations of 5 tightly linked polymorphisms
in the CETP gene: -2708G-A, 784CCC-A, -971G-A, -629C-A, and TaqIB. All
polymorphisms were associated with CETP concentration and HDL
cholesterol, except for the -971G-A polymorphism with HDL cholesterol.
Detailed haplotype analysis revealed that a 3-polymorphism haplotype
model consisting of the -2708G-A, -629C-A, and -971G-A polymorphisms
best explained the variation in CETP concentration.

Frisdal et al. (2005) reported that a -1337C-T polymorphism in CETP (C
allele frequency, 0.684), was significantly associated with plasma HDL
cholesterol and CETP levels (P = 0.0001 and P less than 0.0001,
respectively). Transient transfection of liver cells with a reporter
gene construct containing the CETP promoter from nucleotides -1707 to
+28 revealed that the -1337T allele was expressed to a significantly
lower degree (34%, P less than 0.0001) than the -1337C allele. The
-971G-A polymorphism was functional, and its functionality was
intimately linked to the presence of the -1337C-T SNP. In vitro
evaluation of potential interaction between -1337C-T and the variants
-971G-A and -629C-A demonstrated that these 3 functional CETP promoter
polymorphisms could interact to determine the overall activity of the
CETP gene and thus contribute significantly to variation in plasma CETP
mass concentration.

ANIMAL MODEL

Paigen et al. (1987) described a mouse mutation, Ath1, which
phenotypically resembles the human disorder familial
hyperalphalipoproteinemia. In the mouse, HDL-cholesterol levels and
susceptibility to atherosclerosis appear to be determined by the same
gene (or by two closely linked genetic factors that could not be more
than 1.7 cM apart). Ath1 was found to map on mouse chromosome 1 near
Alp2 (APOA2; 107670), a gene that determines the structure of
apolipoprotein A-II, one of the 2 major proteins found in HDL. The 2
loci were separated by a distance of about 6.0 cM.

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*FIELD* CS
INHERITANCE:
Autosomal dominant

LABORATORY ABNORMALITIES:
Cholesteryl ester transfer protein deficiency;
Elevated HDL (2-6x normal) in homozygotes;
Mildly elevated HDL in heterozygotes;
Elevated apoA-I (1.8x normal) in homozygotes;
Normal apoA-II levels in homozygotes

MISCELLANEOUS:
Heterozygous mutation present in 5-7% of the Japanese population

MOLECULAR BASIS:
Caused by mutation in the plasma cholesteryl ester transfer protein
gene (CETP, 118470.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 11/7/2002

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

*FIELD* ED
joanna: 06/08/2011
joanna: 11/7/2002
joanna: 10/25/2002

*FIELD* CN
Michael B. Petersen - updated: 3/12/2003
Victor A. McKusick - updated: 7/25/2000

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

*FIELD* ED
terry: 06/17/2011
alopez: 6/8/2011
carol: 1/12/2009
carol: 7/21/2006
carol: 2/2/2005
cwells: 3/12/2003
carol: 8/4/2000
alopez: 9/17/1998
mark: 4/7/1995
mimadm: 9/24/1994
supermim: 3/16/1992
carol: 3/4/1992
carol: 12/4/1990
supermim: 3/20/1990