Cholesteryl Ester Transfer Protein Gene Polymorphism Is a Determinant of HDL Cholesterol and of the Lipoprotein Response to a Lipid-Lowering Diet in Type 1 Diabetes

Abstract

The TaqIB cholesteryl ester transfer protein (CETP) gene polymorphism (B1B2) is a determinant of HDL cholesterol in nondiabetic populations. Remarkably, this gene effect appears to be modified by environmental factors. We evaluated the effect of this polymorphism on HDL cholesterol levels and on the lipoprotein response to a linoleic acid-enriched, low-cholesterol diet in patients with type 1 diabetes. In 44 consecutive type 1 diabetic patients (35 men), CETP polymorphism, apolipoprotein (apo) E genotype, serum lipoproteins, serum CETP activity (measured with an exogenous substrate assay, n = 30), clinical variables, and a diet history were documented. The 1-year response to diet was assessed in 14 type 1 diabetic patients, including 6 B1B1 and 6 B1B2 individuals. HDL cholesterol was higher in 10 B2B2 than in 14 B1B1 homozygotes (1.63 +/- 0.38 vs. 1.24 +/- 0.23 mmol/l, P < 0.01). HDL cholesterol, adjusted for triglycerides and smoking, was 0.19 mmol/l higher for each B2 allele present. CETP activity levels were not significantly different between CETP genotypes. Multiple regression analysis showed that VLDL + LDL cholesterol was associated with dietary polyunsaturated:saturated fatty acids ratio (P < 0.02) and total fat intake (P < 0.05) in the B1B1 homozygotes only and tended to be related to the presence of the apo E4 allele (P < 0.10). In response to diet, VLDL + LDL cholesterol fell (P < 0.05) and HDL cholesterol remained unchanged in 6 B1B1 homozygotes. In contrast, VLDL + LDL cholesterol was unaltered and HDL cholesterol decreased (P < 0.05) in 6 B1B2 heterozygotes (P < 0.05 for difference in change in VLDL + LDL/HDL cholesterol ratio). This difference in response was unrelated to the apo E genotype. Thus, the TaqIB CETP gene polymorphism is a strong determinant of HDL cholesterol in type 1 diabetes. This gene effect is unlikely to be explained by a major influence on the serum level of CETP activity, as an indirect measure of CETP mass. Our preliminary data suggest that this polymorphism may be a marker of the lipoprotein response to dietary intervention.

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.…”

“…3,4 The Taq1B polymorphism has also been shown to serve as a marker of lipoprotein response to dietary intervention. 5,6 Other studies have demonstrated a link between the CETP I405V gene polymorphism and HDL-C, but not with response to diet. 7,8 Several other single nucleotide polymorphisms (SNPs) in the CETP gene have been associated with interindividual variation in CETP plasma concentrations, HDL-C levels and risk of cardiovascular disease.…”

Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits

“…There are not sufficient numbers of these CETP-deficient subjects to definitively determine whether the complete absence of CETP is antiatherogenic. A number of clinical and experimental studies have established a clear inverse correlation between CETP activity and levels of HDL-C (19)(20)(21)(22)(23)(24). But as with the conflicting transgenic mouse data, the clinical data are split regarding whether reduced CETP activity is antiatherogenic (25)(26)(27)(28).…”

Genomics and Hypertension

“…A variant of CETP (presence of a TaqIB restriction site in the first intron, B1, absence called B2) has been described that results in a decreased plasma HDL, increased (VLDLϩLDL)/HDL ratio and increased rate of progression of atherosclerosis. Interestingly, the B1 genotype is associated with a better lipid profile after dietary intervention 34 and a dramatic response to prava- 35 Examples of pharmacogenomics can also be seen in hypertension. For example, in rat crosses, several loci have been shown to be linked to sodium sensitivity.…”