Association of Cholesteryl Ester Transfer Protein– Taq IB Polymorphism With Variations in Lipoprotein Subclasses and Coronary Heart Disease Risk

Abstract

Abstract-Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides and cholesteryl esters between lipoprotein particles, a key step in reverse cholesterol transport in humans. Variations at the CETP locus have been shown to be determinants of the levels and activity of CETP and high density lipoprotein (HDL) plasma concentration. The associations of the common CETP polymorphism, TaqIB in intron 1, with lipoprotein levels and particle size distribution, CETP activity, and coronary heart disease (CHD) risk were examined in a population-based sample of 1411 men and 1505 women from the Framingham Offspring Study. The B2 allele frequency was 0.444 in men and 0.433 in women, and its presence was significantly (PϽ0.05) associated with decreased CETP activity. B1B1 men had lower HDL cholesterol (HDL-C) levels (1.07 mmol/L) compared with B1B2 (1.14 mmol/L) and B2B2 (1.18 mmol/L) men (PϽ0.001). Likewise, B1B1 women had lower HDL-C levels (1.40 mmol/L) compared with B1B2 (1.46 mmol/L) and B2B2 (1.53 mmol/L) women (PϽ0.001). In men, the B2 allele was associated with increased particle size for HDL and low density lipoprotein. In women, a similar effect was demonstrated only for HDL particle size. The odds ratio for prevalent CHD associated with the B2 allele was 0.696 (Pϭ0.035) in men. After adjusting for age, body mass index, systolic blood pressure, diabetes, smoking, alcohol consumption, ␤-blocker use, total cholesterol, and HDL-C, this odds ratio was 0.735 (Pϭ0.187), suggesting that the protective effect of the B2 allele was due in part to its association with HDL-C levels. No significant protective effects were observed in women. These data demonstrate that variation at the CETP gene locus is a significant determinant of HDL-C levels, CETP activity, and lipoprotein size in this population. Moreover, these effects appear to translate into a lower CHD risk among those men with the B2 allele. Key Words: cholesteryl ester transfer protein Ⅲ coronary heart disease Ⅲ lipoproteins Ⅲ gene polymorphisms C holesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides and cholesteryl esters between lipoprotein particles. In humans, CETP mRNA encodes a polypeptide of M r 53 000, which is n-glycosylated at 4 sites, giving rise to the mature form of CETP of M r 74 000. 1 CETP is expressed primarily in liver, spleen, and adipose tissue, and lower levels have been detected in the small intestine, adrenal gland, heart, kidney, and skeletal muscle. 1,2 The CETP gene encompasses 16 exons, and it has been localized on chromosome 16q21 adjacent to the lecithin-cholesterol acyltransferase gene. Several mutations at the CETP locus have been identified, resulting in the absence of detectable CETP mass and/or activity. 3 These mutations are common in Japanese populations, 4 -7 although some have been recently reported in white subjects. 8,9 CETP deficiency is associated with hyperalphalipoproteinemia, which is primarily due to an increase of cholesteryl ester-enriched large-sized HDL. Conversely, ...

TaqIB polymorphism in CETP gene: the influence on incidence of cardiovascular disease in statin-treated patients with familial hypercholesterolemia

“…Furthermore, we have investigated the associations of the different alleles with clinical characteristics and lipid profiles in these patients. The frequency of the TaqIB polymorphism in this population was similar to that found in other studies, 7,15 suggesting that our study population is not genetically different from others. Our data clearly show an association of the B1 allele of CETP-TaqIB polymorphism with HDL-cholesterol levels at baseline.…”

“…Furthermore, an odds ratio of 0.7 for CHD was found in male, but not in female, participants of the Framingham Offspring study. 7 In recently published studies, higher plasma CETP levels of FH patients were associated with a more atherogenic lipid profile. 18 -20 In one of these reports, the highest tertile of plasma CETP level was also associated with a higher increase of progression of atherosclerosis after 2 years of statin therapy.…”

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

“…Several previous studies have demonstrated such associations for HDL-C, specifically with SNP4 (TaqIB). [3][4][5]8,[35][36][37] In some reports, the association was seen only in subgroups, such as ex-and nonsmokers, 38 or in women, but not in men. 39 Alhough we could not replicate the association of an increased baseline HDL-C in the presence of the mutant B2 allele of SNP4, the strong stepwise decrease in CETP mass and activity associated with the number of B2 alleles of SNP4 clearly underlines such an expected effect on HDL-C. With respect to SNP 7 (A373P) and SNP8 (R451Q), the Copenhagen City Heart Study found a decrease in HDL-C and ApoA1 in carriers of the mutant allele, both in men and women.…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…Notably, other discrepant results were reported in distinct follow-up phases of the same study. In the Framingham Heart Study, both linear (43) and inverse (44) associations between plasma CETP activity and cardiovascular risk were reported. After a thorough search of the literature, we found incongruent results demonstrating both direct and inverse relationships as well as a lack of correlation between CETP levels or CETP genetic variants and atherosclerosis risk.…”