title: Functional interaction between -629C/A, -971G/A and -1337C/T polymorphisms in the CETP gene is a major determinant of promoter activity and plasma CETP concentration in the REGRESS Study.
abstract: Cholesteryl ester transfer protein (CETP) plays a key role in the determination of high-density lipoprotein (HDL) levels via its action on intravascular HDL metabolism. The TaqIB polymorphism of the CETP gene is associated with plasma CETP and high-density lipoprotein cholesterol (HDL-C) levels and with premature coronary artery disease. Such associations appear to result from linkage disequilibrium between TaqIB and other functional polymorphisms. To date, only one functional promoter variant, which may explain the effects of TaqIB, has been identified at position -629 in the CETP gene. Here we describe a C/T polymorphism located at position -1337 in the human CETP gene (C allele frequency: 0.684), which is significantly associated with plasma HDL-C and CETP levels (P=0.0001 and P<0.0001, respectively). Transient transfection of a reporter gene construct containing the CETP promoter from -1707/+28 in liver cells (HepG2) revealed that the -1337T allele was expressed to a significantly lower degree (-34%, P<0.0001) than the -1337C allele. In addition, we clearly demonstrated that the -971G/A polymorphism is functional and that its functionality is intimately linked to the presence of the -1337 site. In vitro evaluation of potential interaction between -1337C/T and other functional variants of the CETP gene (-971G/A and -629C/A) demonstrated that these three functional CETP promoter polymorphisms can interact together to determine the overall activity of the CETP gene and thus contribute significantly to variation in plasma CETP mass concentration.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM Unité 551, Dyslipoproteinemia and Atherosclerosis, Paris Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Frisdal
authors.forename: Anke H E M
authors.initials: AH
authors.lastname: Klerkx
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.forename: Michael W T
authors.initials: MW
authors.lastname: Tanck
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lagarde
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.forename: Maryse
authors.initials: M
authors.lastname: Guerin
mesh_terms: D000368:Aged; D002352:Carrier Proteins / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D003324:Coronary Artery Disease / Q000235:genetics*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005838:Genotype; D006023:Glycoproteins / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008297:Male; D009426:Netherlands; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D017931:DNA Primers; D006023:Glycoproteins