Human Molecular Genetics, 2003, Vol. 12, No. 2 111-123
© 2003 Oxford University Press
Haplotype analysis of the CETP gene: not TaqIB, but the closely linked -629C
A polymorphism and a novel promoter variant are independently associated with CETP concentration
1Department of Vascular Medicine and 4Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands, 2Department of Medical Statistics and 3Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands and 5Unilever Research Vlaardingen, Unilever Health Institute, Vlaardingen, The Netherlands
Received September 2, 2002; Accepted October 29, 2002
The TaqIB polymorphism in intron 1 of the cholesteryl ester transfer protein (CETP) gene is associated with plasma CETP concentration, high-density lipoprotein cholesterol (HDL-C) and coronary artery disease (CAD). These associations are generally thought to arise from linkage disequilibrium between TaqIB and (an)other functional polymorphism(s). To identify putative functional sites, we investigated phenotypic associations of TaqIB and four tightly linked polymorphisms (novel -2708G
A and +784CCCA, and previously identified -971GA and -629CA) in 709 males with CAD (REGRESS). In addition to genotype analyses, a novel method to estimate haplotype effects was used to examine the individual and joint effects of these DNA variants on CETP concentration and HDL-C. All polymorphisms were associated with CETP concentration and HDL-C, except for -971 with HDL-C. Stepwise regression and haplotype analyses indicated that only -629 was independently associated with HDL-C. Similar analyses additionally indicated that -2708 and -629 were independently associated with CETP concentration, whereby the most frequent alleles acted in a cumulative manner. Nonetheless, detailed haplotype analysis revealed that a 3-polymorphism haplotype model consisting of -2708, -629 and -971 explained the variation in CETP concentration best. The involvement of -971 could be due to interaction effects that were observed between -971 and both -629 (P<0.001) and -2708 (P=0.047). In conclusion, the TaqIB polymorphism is not instrumental in determining CETP or HDL-C levels, but is a marker for the -629 promoter variant. Our analyses, furthermore, indicate that the -2708 and -971 polymorphisms are likely to play a role in determining CETP concentration.
* To whom correspondence should be addressed at: Department of Vascular Medicine, G1-114, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 205666118; Fax: +31 205669232; Email: a.klerkx{at}amc.uva.nl
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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