Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment: Individual Patient Meta-Analysis of 13 677 Subjects

Background—Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. Methods and Results—A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. Conclusions—The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

[1]  P. Barter,et al.  Cholesteryl ester transfer protein, high density lipoprotein and arterial disease , 2001, Current opinion in lipidology.

[2]  E. Hawe,et al.  Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle‐aged men , 2002, Annals of human genetics.

[3]  K. Zerba,et al.  The cholesteryl ester transfer protein (CETP) TaqIB polymorphism in the cholesterol and recurrent events study: no interaction with the response to pravastatin therapy and no effects on cardiovascular outcome , 2004 .

[4]  A P Holmes,et al.  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. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[5]  R. Lawn,et al.  Multiple RFLPs at the human cholesteryl ester transfer protein (CETP) locus. , 1987, Nucleic acids research.

[6]  A. Montali,et al.  Lack of association of the common TaqIB polymorphism in the cholesteryl ester transfer protein gene with angiographically assessed coronary atherosclerosis , 2001, Clinical genetics.

[7]  D. Thelle,et al.  THE TROMSØHEART-STUDY HIGH-DENSITY LIPOPROTEIN AND CORONARY HEART-DISEASE: A PROSPECTIVE CASE-CONTROL STUDY , 1977, The Lancet.

[8]  David W. Hosmer,et al.  Best subsets logistic regression , 1989 .

[9]  N. Yoshiike,et al.  Association of Human Cholesteryl Ester Transfer Protein-TaqI Polymorphisms with Serum HDL Cholesterol Levels in a Normolipemic Japanese Rural Population , 2002, Journal of epidemiology.

[10]  P. Ridker,et al.  A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men. , 2002, Atherosclerosis.

[11]  A. Evans,et al.  A novel cholesteryl ester transfer protein promoter polymorphism (-971G/A) associated with plasma high-density lipoprotein cholesterol levels. Interaction with the TaqIB and -629C/A polymorphisms. , 2002, Atherosclerosis.

[12]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[13]  B. Horne,et al.  The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease. , 2003, American heart journal.

[14]  R. Peters,et al.  Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The Prospective EPIC (European Prospective Investigation into Cancer and nutrition)–Norfolk Population Study , 2004, Circulation.

[15]  D. Rader,et al.  Cholesteryl Ester Transfer Protein: A Novel Target for Raising HDL and Inhibiting Atherosclerosis , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[16]  V. Gudnason,et al.  Cholesteryl ester transfer protein gene effect on CETP activity and plasma high‐density lipoprotein in European populations , 1999, European journal of clinical investigation.

[17]  R. Lawn,et al.  DNA polymorphism at the locus for human cholesteryl ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels , 1989, Clinical genetics.

[18]  B. Nordestgaard,et al.  Common Cholesteryl Ester Transfer Protein Mutations, Decreased HDL Cholesterol, and Possible Decreased Risk of Ischemic Heart Disease: The Copenhagen City Heart Study , 2000, Circulation.

[19]  D. Erkelens,et al.  Elevated Cholesteryl Ester Transfer Protein Activity in IDDM Men Who Smoke: Possible Factor for Unfavorable Lipoprotein Profile , 1991, Diabetes Care.

[20]  Jammalamadaka.  Introduction to Linear Regression Analysis (3rd ed.) , 2003 .

[21]  A. Rantala,et al.  Variation at the cholesteryl ester transfer protein gene in relation to plasma high density lipoproteins cholesterol levels and carotid intima‐media thickness , 2001, European journal of clinical investigation.

[22]  J. Brian Gray,et al.  Introduction to Linear Regression Analysis , 2002, Technometrics.

[23]  N. Samani,et al.  A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study. , 2003, European heart journal.

[24]  L Tiret,et al.  Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene‐environment interaction , 2000, Genetic epidemiology.

[25]  A. van Tol,et al.  Proatherogenic Role of Elevated CE Transfer From HDL to VLDL1 and Dense LDL in Type 2 Diabetes: Impact of the Degree of Triglyceridemia , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[26]  D. Arveiler,et al.  Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. , 1995, The Journal of clinical investigation.

[27]  F. Cambien,et al.  New functional promoter polymorphism, CETP/-629, in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels: role of Sp1/Sp3 in transcriptional regulation. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[28]  D. Levy,et al.  Prediction of coronary heart disease using risk factor categories. , 1998, Circulation.

[29]  V. Gudnason,et al.  The -629C>A polymorphism in the CETP gene does not explain the association of TaqIB polymorphism with risk and age of myocardial infarction in Icelandic men. , 2001, Atherosclerosis.

[30]  J W Jukema,et al.  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. , 1998, The New England journal of medicine.

[31]  F. Cambien,et al.  Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. , 2003, Journal of the American College of Cardiology.

[32]  Thomas A Trikalinos,et al.  Genetic associations in large versus small studies: an empirical assessment , 2003, The Lancet.

[33]  C. Packard,et al.  The effect of smoking on post‐heparin lipoprotein and hepatic lipase, cholesteryl ester transfer protein and lecithin:cholesterol acyl transferase activities in human plasma , 1998, European journal of clinical investigation.

[34]  C. Bouchard,et al.  Contribution of the cholesteryl ester transfer protein gene TaqIB polymorphism to the reduced plasma HDL-cholesterol levels found in abdominal obese men with the features of the insulin resistance syndrome , 1999, International Journal of Obesity.

[35]  A. Rantala,et al.  Sex difference in the regulation of plasma high density lipoprotein cholesterol by genetic and environmental factors , 1996, Human Genetics.

[36]  C. Packard,et al.  Smoking and plasma lipoproteins in man: effects on low density lipoprotein cholesterol levels and high density lipoprotein subfraction distribution , 1993, European journal of clinical investigation.

[37]  P. Wilson,et al.  Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[38]  A. Zwinderman,et al.  Haplotype analysis of the CETP gene: not TaqIB, but the closely linked -629C-->A polymorphism and a novel promoter variant are independently associated with CETP concentration. , 2003, Human molecular genetics.

[39]  W. Kannel,et al.  Cigarette smoking and HDL cholesterol: the Framingham offspring study. , 1978, Atherosclerosis.

[40]  A. Tall.  Plasma lipid transfer proteins. , 1995, Annual Review of Biochemistry.

[41]  D. Corella,et al.  Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population. , 2000, Atherosclerosis.

[42]  David W. Hosmer,et al.  Applied Logistic Regression , 1991 .