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Human Molecular Genetics Advance Access published online on July 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi291
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 2, 2005
Revised July 12, 2005
Accepted July 20, 2005

Article

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

Eric Frisdal 1, Anke Hem Klerkx 2, Wilfried Le Goff 1, Michael WT Tanck 3, Jean-Pierre Lagarde 1, J Wouter Jukema 4, John JP Kastelein 2, M John Chapman 1, and Maryse Guerin 5*

1 Institut National de la Santé et de la Recherche Médicale (INSERM Unité 551, «Dyslipoproteinemia and Atherosclerosis»)
2 Department of Vascular Medicine, AMC, Amsterdam, The Netherlands
3 Department of Clinical Epidemiology and Biostatistics, AMC, Amsterdam, The Netherlands
4 Department of Cardiology, LUMC, Leiden, The Netherlands
5 INSERM Unité 551, «Dyslipoproteinemia and Atherosclerosis», Hôpital de la Pitié, Pavillon Benjamin Delessert, 83, boulevard de l'Hôpital, 75651 Paris Cedex 13, France

* To whom correspondence should be addressed.
Maryse Guerin, E-mail: mguerin{at}chups.jussieu.fr


  Abstract

Cholesteryl ester transfer protein (CETP) plays a key role in the determination of HDL levels via its action on intravascular HDL metabolism. The TaqIB polymorphism of the CETP gene is associated with both plasma CETP and HDL-C levels and with premature CAD. Such associations appear to result from linkage disequilibrium (LD) between TaqIB and other functional polymorphisms. To date only one functional promoter variant that 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 both plasma HDL-C and CETP levels (p = 0.0001 and p < .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 < .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.


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