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.

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 2629 in the CETP gene. Here we describe a C/T polymorphism located at position 21337 in the human CETP gene (C allele frequency: 0.684), which is significantly associated with plasma HDL-C and CETP levels (P 5 0.0001 and P < 0.0001, respectively). Transient transfection of a reporter gene construct containing the CETP promoter from 21707/ 1 28 in liver cells (HepG2) revealed that the 21337T allele was expressed to a significantly lower degree (234%, P < 0.0001) than the 21337C allele. In addition, we clearly demonstrated that the 2971G/A polymorphism is functional and that its functionality is intimately linked to the presence of the 21337 site. In vitro evaluation of potential interaction between 21337C/T and other functional variants of the CETP gene (2971G/A and 2629C/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.