Genetics
REGRESS Study identifies three interacting CETP promoter variants that jointly determine plasma CETP concentration (Hum Mol Genet 2005)
Original 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
Because the association of the well-studied CETP TaqIB polymorphism with HDL-C and CETP levels was thought to reflect linkage with other functional variants, researchers searched for and characterized a novel C/T polymorphism at position -1337 in the CETP gene (C allele frequency 0.684), finding it significantly associated with plasma HDL-C and CETP levels (P=0.0001 and P<0.0001, respectively) in the REGRESS Study. Reporter gene assays in HepG2 liver cells showed the -1337T allele was expressed 34% less than the -1337C allele (P<0.0001), and the researchers demonstrated that the previously identified -971G/A polymorphism is also functional, with its effect intimately linked to the -1337 site. In vitro evaluation of interactions among the three functional CETP promoter polymorphisms (-1337C/T, -971G/A, and -629C/A) showed they act together to determine overall CETP gene activity. The authors conclude these three interacting promoter polymorphisms jointly contribute significantly to variation in plasma CETP mass concentration.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.