Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease

Abstract

Since the identification of cholesteryl ester transfer protein (CETP), its role in the modulation of HDL levels and cardiovascular disease has been debated. With the early detection of genetic variants followed by the finding of families deficient in CETP, genetic studies have played a large role in the attempts to understand the association of CETP with lipids and disease; however, results of these studies have often led to disparate conclusions. With the availability of a greater variety of genetic polymorphisms and larger studies in which disease has been examined, it is now possible to compare the breadth of CETP genetic studies and draw better conclusions. The most broadly studied polymorphism is TaqIB for which over 10,000 individuals have been genotyped and had HDL levels determined. When these studies are subjected to a meta-analysis, the B2B2 homozygotes are found to have higher HDL levels than B1B1 homozygotes (0.12 mmol/l, 95% CI ‫؍‬ 0.11-0.13, P Ͻ 0.0001). A similar analysis of the I405V polymorphism yields 0.05 mmol/l higher HDL levels in 405VV homozygotes than in 405II homozygotes (95% CI ‫؍‬ 0.03-0.07, P Ͻ 0.0001). The implications of these studies for cardiovascular disease will be addressed. -Boekholdt, S. M., and J. F. Thompson. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J. Lipid Res. 2003. 44: 1080-1093.

Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

“…In contrast, the present results are consistent with our recent meta-analysis, which showed that throughout a large number of studies in both healthy and diseased populations, CETP gene variants associated with decreased CETP activity also were associated with elevated HDL-C levels. 35 This observed correlation is also consistent with the fact that individuals with genetic CETP deficiency invariably present with high HDL-C levels 36 -38 and with the fact that pharmacological CETP inhibition raises HDL-C levels. 10 -12 …”

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

“…As the result, CETP protein mass in the medium and the transcripts from transfected cell had not significantly changed compared to those of wild-type cell (supplemental fig.1), and it suggests that c.658G>A mutation caused abnormal splicing but it does not have a missense effect. Subject 3 had also I405V polymorphism as the heterozygote, but it was reported that the effect of I405V as 405VV homozygote for plasma CETP protein level by meta-analysis was -0.19 μg/mL less [21]. I405V polymorphism would decrease CETP mass in subject 3 slightly, but c.658G>A…”

HDL cholesterol response to GH replacement is associated with common cholesteryl ester transfer protein gene variation (−629C>A) and modified by glucocorticoid treatment

“…Circulating CETP levels are highest in K629 CETP CC allele carriers (14,(16)(17)(18), whereas both GH and glucocorticoids are able to reduce serum CETP (7,8,20). The increase in HDL-C after GH replacement in glucocorticoid-treated hypopituitary patients homozygous for the K629 CETP CC allele may thus be explained in part by assuming that GH elicits a more pronounced decrease in circulating CETP levels in these patients.…”

“…Consequently, increased CETP activity results in a lower HDL-C (11)(12)(13). Common genetic variations have been identified in CETP (14,15), among which the K629 CETP COA promoter polymorphism (rs1800775) has been shown to regulate CETP transcriptional activity in vitro (16). The more frequent C allele is associated with higher circulating CETP mass and activity and a lower HDL-C (17,18).…”