title: Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism.
abstract: Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the [gaaa](n) repeat ("S" denotes [gaaa](n)=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, [gaaa](n), -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the [gaaa](n) repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa](n) repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.
authors.affiliation: Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, 920-8641, Kanazawa, Japan.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.forename: Yuri
authors.initials: Y
authors.lastname: Moriyama
authors.forename: Toshinori
authors.initials: T
authors.lastname: Higashikata
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Wenxin
authors.initials: W
authors.lastname: Yu
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Huang
authors.forename: Tomonori
authors.initials: T
authors.lastname: Okamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
mesh_terms: D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism*; D005787:Gene Frequency; D005838:Genotype; D006023:Glycoproteins; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid
chemical_list: C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D015252:Deoxyribonucleases, Type II Site-Specific; C027046:TCGA-specific type II deoxyribonucleases