title: A novel cholesteryl ester transfer protein promoter polymorphism (-971G/A) associated with plasma high-density lipoprotein cholesterol levels. Interaction with the TaqIB and -629C/A polymorphisms.
abstract: The plasma cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport (RCT) by mediating the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to atherogenic ApoB-containing lipoproteins, including VLDL, IDL and LDL. We describe a new polymorphism located at position -971 in the human CETP gene promoter, which corresponds to a G/A substitution at a potential AvaI restriction site. The relationship between the -971G/A polymorphism, plasma lipid parameters and plasma CETP concentration was evaluated in the Etude Cas-Témoins de l'Infarctus du Myocarde (control-myocardial infarction cases) cohort, and revealed that the -971G/A polymorphism (A allele frequency: 0.491) was significantly associated with both plasma high-density lipoprotein cholesterol (HDL-C) levels and CETP concentration (P=0.006 and 0.009, respectively). Subjects with genotype -971GG displayed both low HDL-C levels and high plasma CETP concentration, while genotype -971AA subjects displayed the inverse relationship. Evaluation of potential interactions between the -971G/A and the -629C/A or TaqIB polymorphisms demonstrated that the -971G/A polymorphism interacts significantly with the functional -629C/A site and the TaqIB polymorphism with respect to plasma HDL-C levels (P=0.0014 and 0.012, respectively), but does not affect plasma CETP concentration. These results clearly suggest that the interaction between the 971G/A polymorphism and either the -629C/A or the TaqIB polymorphism on plasma CETP concentration is different than that implicated in HDL-C levels. Transient transfection of HepG2 cells revealed that the -971G/A polymorphism did not modulate transcriptional activity of the human CETP gene promoter. The -971G/A promoter polymorphism therefore constitutes a non-functional marker. Furthermore, the observed effects of the -971G/A polymorphism on both plasma CETP concentration and HDL-C levels are due to functional variants in linkage disequilibrium with it. Our findings strongly suggest the existence of as yet unidentified functional polymorphisms in the CETP gene promoter that could explain the association between specific polymorphisms of the CETP gene and both plasma HDL-C and CETP concentrations.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Hôpital de la Pitié, Unité 321 Lipoprotéines et Athérogénèse, Pavillon Benjamin Delessert, 83 Boulevard de l'Hôpital 75651 Paris 13, France. wlegoff@infobiogen.fr
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.forename: Maryse
authors.initials: M
authors.lastname: Guerin
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Christiane
authors.initials: C
authors.lastname: Dachet
authors.forename: Gérald
authors.initials: G
authors.lastname: Luc
authors.forename: Dominique
authors.initials: D
authors.lastname: Arveiler
authors.forename: J-B
authors.initials: JB
authors.lastname: Ruidavets
authors.forename: Alun
authors.initials: A
authors.lastname: Evans
authors.forename: Frank
authors.initials: F
authors.lastname: Kee
authors.forename: Caroline
authors.initials: C
authors.lastname: Morrison
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.forename: Joëlle
authors.initials: J
authors.lastname: Thillet
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000517:prevention & control; D002352:Carrier Proteins / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006023:Glycoproteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011336:Probability; D011401:Promoter Regions, Genetic; D012042:Registries; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000032:analysis / Q000235:genetics*
chemical_list: C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; C059680:DNA modification methylase TaqI; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)