Genetics
Haplotype analysis reveals that the famous CETP TaqIB polymorphism is not actually a driver of CETP or HDL cholesterol levels (J Mol Med 2003)
Original title: Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism
Although the CETP TaqIB B2 allele has been widely linked to lower plasma CETP and higher HDL-cholesterol and studied extensively as a possible antiatherogenic marker, its molecular mechanism has remained unclear. This study investigated ten novel and three previously reported polymorphisms within 3.3 kb of the CETP gene promoter in 357 elderly Japanese men, all in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the short allele of a (GAAA)n repeat, and TaqIB2 were each significantly associated with both lower CETP and higher HDL-cholesterol, whereas -971G/A and -629A/C were associated only with CETP concentrations. Twelve-polymorphism haplotype analysis identified eight main haplotypes, with one specific haplotype showing the lowest CETP (2.0 microg/mL) and highest HDL-cholesterol (55.1 mg/dL). Detailed sub-haplotype analysis indicated the -2505C/A polymorphism and the (GAAA)n repeat best explain CETP and HDL-cholesterol variation, whereas -629A/C and TaqIB, despite being the most frequently studied, were not themselves instrumental in determining either trait.
Original abstract
Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the (GAAA)n repeat ("S" denotes (GAAA)n=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, (GAAA)n, -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the (GAAA)n repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the (GAAA)n repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 20 August 2026. Methods.