title: 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.
abstract: 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 +784CCC-->A, and previously identified -971G-->A and -629C-->A) 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.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. a.klerkx@amc.uva.nl
authors.forename: Anke H E M
authors.initials: AH
authors.lastname: Klerkx
authors.forename: Michael W T
authors.initials: MW
authors.lastname: Tanck
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Henri O F
authors.initials: HO
authors.lastname: Molhuizen
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D005786:Gene Expression Regulation; D006023:Glycoproteins; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / 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)