CETP Taq1 B:

DEFECT: A restriction polymorphism termed TaqI B in intron 1 of the CETP gene. The presence of the polymorphism is referred to as B1 and its absence is referred to as B2.

FREQUENCY: 30% of the general Caucasian population have the B1B1 genotype and 19% are B2B2.

MODE OF ACTION: CETP activity results in the net transfer of cholesteryl ester from HDL to other lipoproteins, and in the subsequent uptake of cholesterol by hepatocytes (liver cells).

ASSOCIATED RISK: The B1 variant of CETP is associated with both higher plasma CETP concentrations and lower HDL cholesterol concentrations. Very high levels of CETP depress plasma concentrations of HDL. HDL cholesterol concentration is inversely related to the risk of coronary artery disease (CAD). B2B2 carriers do not respond as well as B1B1 carriers to pravastatin treatment (cholesterol-lowering therapy).

METHOD OF DETECTION: Allele-specific PCR.

POSSIBLE CLINICAL UTILITY: Test should be done on people who are concerned about their cholesterol levels. The polymorphism can also identify CAD patients who will respond best to pravastatin treatment.

References:

1. Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, Lie KI, Kastelein JJ; The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 1998;Jan 8; 338 (2): 86-93

The researchers found a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis. The Taq1 variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis. In the placebo group, progression of coronary artery disease was most pronounced in B1B1 carriers, intermediate in B1B2 carriers, and least pronounced in B2B2 carriers. In the pravastatin group, B1B1 carriers fared better than those with the other two genotypes, and B1B1 carriers who took pravastatin had less progression of coronary artery disease than B1B1 carriers in the control group. Note: The results of this study are valid only for the progression of coronary disease, not for general clinical events. The benefits of reductase inhibitors (i.e. pravastatin) go beyond what is routinely measured. Reductase inhibitors have effects on cell proliferation, immune function, and macrophage metabolism that are independent of cholesterol lowering. They can improve endothelial function and decrease thrombogenesis. The polymorphism of CETP gene predicted only slowing of the angiographic progression of coronary disease.

2. Jose M. Ordovas, L. Adrienne Cupples, Dolores Corella, James D. Otvos, Doreen Osgood, Antonia Martinez, Carlos Lahoz, Oscar Coltell, Peter W.F. Wilson, Ernst J. Schaefer; Association of Cholesteryl Ester Transfer Protein-TaqIB Polymorphism With Variations in Lipoprotein Subclasses and Coronary Heart Disease Risk The Framingham Study. Arterioscler Thromb Vasc Biol. 2000;20:1323-1329.

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 (P,0.05) associated with decreased CETP activity. B1B1 carriers had lower HDL cholesterol levels compared with B1B2 and B2B2 carriers (P,0.001). After adjusting for age, body mass index, systolic blood pressure, diabetes, smoking, alcohol consumption, b-blocker use, total cholesterol, and HDL-C, the odds ratio for prevalent CHD associated with the B2 allele was 0.735 (P50.187) in men. 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.

3. Gudnason V, Kakko S, Nicaud V, Savolainen MJ, Kesaniemi YA, Tahvanainen E, Humphries S; Cholesteryl ester transfer protein gene effect on CETP activity and plasma high-density lipoprotein in European populations. The EARS Group. Eur J Clin Invest 1999 Feb;29(2):116-28

TaqIB and I405-->V polymorphisms represent two independent functional variations in the CETP gene that affect the activity of CETP and thus plasma levels of HDL. TaqI B2 and I405-->V polymorphisms were associated with lower activity of CETP (P < 0.001), 11.2% lower for the TaqI B2 and 7.0% lower for the I405-->V polymorphism. There was a statistically significant effect of the TaqIB polymorphism on both plasma HDL cholesterol and apoAI level (P < 0.001), with those homozygous for the B1 allele having lower levels of HDL.

4. Dullaart RP, Hoogenberg K, Riemens SC, Groener JE, van Tol A, Sluiter WJ, Stulp BK; 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. Diabetes 1997 Dec;46(12):2082-7

The TaqIB CETP gene polymorphism is a strong determinant of HDL cholesterol in type 1 diabetes. B2B2 carriers have higher HDL cholesterol levels than B1B1 homozygotes, even though CETP activity was similar for both genotypes. In response to a linoleic acid-enriched, low-cholesterol diet, plasma levels of VLDL and LDL decreased while HDL levels was unchanged in B1B1 homozygotes. In contrast, VLDL and LDL levels remained the same while HDL levels decreased in B1B2 heterozygotes. Thus, this diet is effective in decreasing VLDL and LDL levels in B1B2 heterozygotes.

5. Freeman DJ, Griffin BA, Holmes AP, Lindsay GM, Gaffney D, Packard CJ, Shepherd J; Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors. Associations between the TaqI B RFLP in the CETP gene and smoking and obesity. Arterioscler Thromb 1994 Mar;14(3):336-44

A raised HDL cholesterol level was found in B2B2 homozygotes compared with B1B1 homozygotes (P < 0.01), even though CETP activity was similar in both genotypes. The genetic variation appeared to be independent of metabolic factors that are known to regulate HDL levels. TaqI B polymorphism had an effect on HDL cholesterol and HDL2 that was independent of age, sex, body mass index, oral contraceptive use, exercise, alcohol consumption, and plasma triglycerides. In smokers, the presence of the B2B2 genotype did not result in increased HDL cholesterol or HDL2, whereas in obese subjects, the difference between B1B1 and B2B2 individuals was diminished.

6. Hannuksela ML, Liinamaa MJ, Kesaniemi YA, Savolainen MJ; Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers. Atherosclerosis 1994 Sep 30;110(1):35-44

CETP TaqI B polymorphism is related to plasma CETP activity and HDL cholesterol concentration, but the associations are affected by smoking and alcohol consumption. B1B1 controls who were non-smokers and did not consume alcoholic beverages had the highest plasma CETP activity and the lowest HDL cholesterol concentration. The lowest CETP activity and the highest HDL cholesterol were in B2B2 control subjects (non-smokers and did not consume alcoholic beverages, P = 0.03 for CETP activity and P = 0.05 for HDL cholesterol). Interestingly, the alcohol drinkers had 30% lower CETP activity (P < 0.001) and 48% higher HDL cholesterol (P < 0.001) than the controls. CETP activity was not affected by the TaqI B genotype in the alcohol drinkers.

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