The Role of a Common Variant of the Cholesteryl Ester Transfer Protein Gene in the Progression of Coronary Atherosclerosis
Jan Albert Kuivenhoven, Ph.D., J. Wouter Jukema, M.D., Aeilko H. Zwinderman, Ph.D., Peter de Knijff, Ph.D., Ruth McPherson, M.D., Ph.D., Albert V.G. Bruschke, M.D., Kong I. Lie, M.D., John J.P. Kastelein, M.D., for The Regression Growth Evaluation Statin Study Group
Background The high-density lipoprotein (HDL) cholesterol concentrationis inversely related to the risk of coronary artery disease.The cholesteryl ester transfer protein (CETP) has a centralrole in the metabolism of this lipoprotein and may thereforealter the susceptibility to atherosclerosis.
Methods The DNA of 807 men with angiographically documentedcoronary atherosclerosis was analyzed for the presence of apolymorphism in the gene coding for CETP. The presence of thisDNA variation was referred to as B1, and its absence as B2.All patients participated in a cholesterol-lowering trial designedto induce the regression of coronary atherosclerosis and wererandomly assigned to treatment with either pravastatin or placebofor two years.
Results The B1 variant of the CETP gene was associated withboth higher plasma CETP concentrations (mean [±SD], 2.29±0.62µg per milliliter for the B1B1 genotype vs. 1.76±0.51µg per milliliter for the B2B2 genotype) and lower HDLcholesterol concentrations (34±8 vs. 39±10 mgper deciliter). In addition, we observed a significant dose-dependentassociation between this marker and the progression of coronaryatherosclerosis in the placebo group (decrease in mean luminaldiameter: 0.14±0.21 mm for the B1B1 genotype, 0.10±0.20mm for the B1B2 genotype, and 0.05±0.22 mm for the B2B2genotype). This association was abolished by pravastatin. Pravastatintherapy slowed the progression of coronary atherosclerosis inB1B1 carriers but not in B2B2 carriers (representing 16 percentof the patients taking pravastatin).
Conclusions There is a significant relation between variationat the CETP gene locus and the progression of coronary atherosclerosisthat is independent of plasma HDL cholesterol levels and theactivities of lipolytic plasma enzymes. This common DNA variantappears to predict whether men with coronary artery diseasewill benefit from treatment with pravastatin to delay the progressionof coronary atherosclerosis.
Patients with clinically apparent coronary artery disease areat high risk for recurrent cardiovascular events. Efforts toprevent such events often involve cholesterol-lowering therapy,which has been demonstrated to reduce total mortality significantlyin men with coronary artery disease.1 Despite the potentialof cholesterol-lowering drugs to retard the progression of coronaryatherosclerosis2,3 and reduce the incidence of cardiovascularevents,1 these drugs did not prevent myocardial infarctionsin a substantial percentage of patients. Our understanding ofwhy not all patients benefit from such therapy is limited.4Both environmental and genetic factors are thought to contributeto this lack of response to cholesterol-lowering strategies.
The cholesteryl ester transfer protein (CETP), which has a keyrole in the metabolism of high-density lipoprotein (HDL), constitutessuch a factor. It mediates the exchange of lipids between lipoproteins,5,6resulting in the net transfer of cholesteryl ester from HDLto other lipoproteins and in the subsequent uptake of cholesterolby hepatocytes. This flux of cholesterol toward the liver isknown as reverse cholesterol transport. By increasing the cholesterylester content of low-density and very-low-density lipoproteins,CETP promotes the atherogenicity of these lipoproteins. In addition,high plasma concentrations of CETP are associated with reducedconcentrations of HDL cholesterol,7,8,9,10,11 a strong and independentrisk factor for atherosclerotic vascular disease.12,13 Thesedata and the results of other recent studies in both humans14,15and animals16,17 support the notion that CETP can contributeto atherogenesis. However, it should be emphasized that therelation between plasma concentrations of CETP and HDL cholesteroland atherosclerosis is complex. Several investigators have shownthat the role of CETP depends on the metabolic context and maybe affected by other plasma enzymes and proteins that are crucialin lipoprotein metabolism.18,19,20
Polymorphisms of the CETP gene have been studied to determinethe intricate association between CETP, HDL cholesterol, andcoronary artery disease. The majority of these studies haveconfirmed that variations in the CETP gene influence HDL cholesterolconcentrations in plasma.9,11,21,22,23
One specific polymorphism in the CETP gene, referred to as TaqIB,is associated with an effect on lipid-transfer activity9 andHDL cholesterol concentrations.9,21 We recently reported thatthis polymorphism is also associated with plasma CETP concentrationsin healthy men.11 To extend our knowledge of this CETP genevariant, we studied a large cohort of men with angiographicallydocumented coronary atherosclerosis who were randomly assignedto treatment with a 3-hydroxy-3-methylglutaryl–coenzymeA reductase inhibitor or placebo.2 The primary objective ofthis study was to examine the relation between this frequentvariant of the CETP gene and the progression of coronary atherosclerosis,as well as the influence of this variant on cholesterol-loweringtherapy.
Methods
Subjects with Coronary Artery Disease
We prospectively studied 807 men who were participating in theRegression Growth Evaluation Statin Study (REGRESS), which haspreviously been described in detail.2 In short, study participantswere required to have at least one coronary artery with stenosisof more than 50 percent as assessed by coronary angiography,a plasma total cholesterol concentration of 155 to 310 mg perdeciliter (4 to 8 mmol per liter), and a plasma triglycerideconcentration of less than 350 mg per deciliter (4 mmol perliter). Patients were subsequently randomly assigned to treatmentwith pravastatin sodium (Pravachol, Bristol-Myers Squibb, Princeton,N.J.) at a dose of 40 mg per day or placebo for a period oftwo years. Computer-assisted quantitative coronary angiographywas carried out at the start and the end of the study.2 Thefollowing two primary measures of outcome were used: the changein the average mean luminal diameter per patient (which we havepreviously referred to as the mean segment diameter2), reflectingdiffuse changes of atherosclerosis, and the change in the averageminimal luminal diameter per patient (which we have previouslyreferred to as the minimum obstruction diameter2), which reflectsfocal changes of atherosclerosis. A greater decrease in themean luminal diameter or the minimal luminal diameter reflectsmore progression of coronary atherosclerosis.
Both the REGRESS trial and the DNA substudy were approved byall seven institutional review boards of the participating centersand by the medical ethics committees of all centers.
DNA Analysis
Blood was collected at base line, and DNA was extracted accordingto standard procedures. The polymerase-chain-reaction–basedmethod of screening for the TaqIB polymorphism in intron 1 ofthe CETP gene was carried out as described previously.11
Biochemical Analyses
Plasma lipids and lipoproteins were measured with standard techniques.24Due to a lack of sufficient aliquots of plasma, CETP concentrationswere determined in 237 patients at base line and in only 68pravastatin-treated subjects at the end of the trial. Thesemeasurements were performed by solid-phase radioimmunoassaywith recombinant human protein (provided by Dr. A. Tall, ColumbiaUniversity, New York) as a standard and a CETP monoclonal antibody,TP2 (produced by Dr. R. Milne, University of Ottawa Heart Institute,Ottawa).10 In addition, the hepatic lipase and lipoprotein lipaseactivities were measured as reported previously.24
Statistical Analysis
Differences in base-line clinical characteristics and concentrationsof lipids, lipoproteins, lipolytic enzymes, and plasma CETPamong the TaqIB subgroups were measured. Since triglycerideconcentrations had a skewed distribution, the statistical analyseswere based on log-transformed data. However, the triglycerideconcentrations in the tables are given as means (±SD).The differences between the carriers of the three CETP genotypes(B1B1, B1B2, and B2B2) were tested by one-way analysis of varianceor Pearson's chi-square test. Changes in lipid concentrations,lipoprotein concentrations, and angiographic measurements duringthe trial were expressed as means (±SD), and the differenceswithin the two treatment groups were tested with one-way analysisof covariance, with base-line values as covariates.
The interaction between the three genotypes and treatment (placeboor pravastatin) was tested with the interaction test of two-waycovariance analysis. We tested whether the interaction betweengenotype and medication was independent of the base-line HDLcholesterol concentration, changes in the HDL concentrationduring the trial, base-line mean luminal diameter, base-lineminimal luminal diameter, hepatic lipase activity, and lipoproteinlipase activity by using these as covariates in a two-way analysisof covariance. This analysis was also carried out to test whetherthe significant differences in the decreases in either meanluminal diameter or minimal luminal diameter, as identifiedamong the TaqIB subgroups in the placebo group, were dependenton the above variables.
Differences in the rate of events between genotypes were analyzedwith Pearson chi-square tests within the treatment groups, andthe interaction between genotype and treatment was assessedwith logistic regression. Within each of the treatment groups,the assumption of Hardy–Weinberg equilibrium was testedby means of gene counting and chi-square analysis. Throughout,a two-tailed P value of 0.05 was interpreted as indicating astatistically significant difference. All statistical analyseswere carried out with SAS software (version 6.1, SAS Institute,Cary, N.C.) and adapted from the Egret manual.25
Results
Frequency of the CETP TaqIB Polymorphism
B1 and B2 were used to denote the presence and absence, respectively,of a restriction site for the enzyme TaqI in intron 1. In thetotal cohort, the B1 and B2 alleles were found at frequenciesof 0.594 and 0.406, respectively. These frequencies did notdiffer significantly between the two treatment groups (datanot shown). For the placebo group, the pravastatin group, andthe total cohort, the observed frequencies were in Hardy–Weinbergequilibrium.
Base-Line Characteristics of the Patients
When the patients were classified according to their TaqIB genotype,there were no statistically significant differences betweengroups at base line with respect to risk factors for coronaryartery disease or the severity or treatment of coronary atherosclerosis(Table 1). In each of the three groups, approximately 50 percentof the patients had been randomly assigned to cholesterol-loweringtherapy with pravastatin.
Table 1. Base-Line Demographic and Coronary Artery Disease Characteristics, According to the CETP TaqIB Genotype.
There was a clear association of the B1 allele with lower HDLcholesterol concentrations (Table 2). The observed differencesin plasma HDL cholesterol concentrations among the genotypeswere significant (P<0.001). There were no significant differencesamong the three genotypes in lipoprotein lipase or hepatic lipaseactivity (Table 2) or in other risk factors for coronary arterydisease, including concentrations of lipoprotein(a), fibrinogen,and serum glucose (data not shown).
Table 2. Base-Line Lipase Activity and Plasma Lipid, Lipoprotein, and CETP Concentrations, According to the CETP TaqIB Genotype.
Association between CETP Genotypes and CETP Concentrations in Plasma
At base line, the B1 allele was strongly associated with higherCETP concentrations in all patients (P<0.001) (Table 2).At the end of the trial, the patients assigned to pravastatinhad a 16 percent reduction in plasma CETP concentrations (from2.03±0.53 µg per milliliter at base line to 1.71±0.46µg per milliliter; P<0.001). There were too few patientsin the analysis to allow meaningful conclusions about differencesin reductions in the CETP concentration as a result of the useof pravastatin.
Changes in Lipid and Lipoprotein Concentrations during the Study
The TaqIB polymorphism had no effect on the changes in totalcholesterol, low-density lipoprotein cholesterol, triglyceride,and HDL cholesterol concentrations in the two study groups.Pravastatin reduced total cholesterol, low-density lipoproteincholesterol, and triglyceride and increased HDL cholesterolto a similar extent in all three subgroups of patients.
Angiographic Measurements
The angiographic measurements and clinical events (myocardialinfarction or death from cardiovascular causes) are shown accordingto the CETP genotype in the placebo and pravastatin groups inTable 3. A larger decrease in the mean luminal diameter or minimalluminal diameter indicates greater progression of atherosclerosis.
Table 3. Changes in Lipid and Lipoprotein Concentrations and Angiographic Outcomes during the Trial in the Placebo and Pravastatin Groups.
Placebo Group
In the placebo group there were statistically significant differencesamong the TaqIB subgroups in the decreases in both the meanluminal diameter (P<0.03) and the minimal luminal diameter(P< 0.05). There was an association between the B1 alleleand the degree of coronary atherosclerosis, with the most pronouncedprogression of atherosclerosis in the B1B1 carriers, an intermediatedegree of progression in the B1B2 carriers, and the least progressionin B2B2 carriers.
Pravastatin Group
In the pravastatin group, the differences in the decreases inthe mean luminal diameter (P = 0.36) and the minimal luminaldiameter (P = 0.38) among the genotype subgroups did not reachstatistical significance. However, the same dose-dependent effectnoted in the placebo group was evident, with B1B1, B1B2, andB2B2 carriers having the lowest, intermediate, and highest degreesof progression in diffuse atherosclerosis, respectively. Inaddition, we observed less focal atherosclerosis — asreflected by the smallest reduction in minimal luminal diameter— in the B1B1 carriers than in the carriers of the othertwo genotypes.
Comparison of Placebo and Pravastatin Groups
There was a significant interaction between pravastatin treatmentand decreases in the mean luminal diameter (P=0.01) (Figure 1)and the minimal luminal diameter (P=0.05). As shown in Figure 1,the association of the B1 allele with greater progressionof diffuse atherosclerosis (i.e., greater decreases in the meanluminal diameter), as observed in the placebo group, was influencedby the use of pravastatin. In fact, the B1 allele appeared tobe associated with less progression in the patients who werereceiving pravastatin.
Figure 1. Changes in Mean Luminal Diameter (and 95 Percent Confidence Intervals) According to the CETP TaqIB Genotype in Patients with Established Coronary Atherosclerosis Treated with Either Placebo or Pravastatin.
Higher values reflect increased diffuse progression of coronary atherosclerosis.
There was a dose-dependent relation between the B1 allele andthe efficacy of pravastatin in retarding the progression ofcoronary atherosclerosis. Carriers of two B1 alleles benefitedmost from treatment with pravastatin: they had significantlyless progression of coronary atherosclerosis, as evidenced bysmaller decreases in both the mean luminal diameter (P = 0.001)and the minimal luminal diameter (P = 0.002), than their B1B1counterparts in the placebo group. Furthermore, carriers ofonly one B1 allele (B1B2) who were receiving pravastatin hadsignificantly less focal atherosclerosis (P = 0.01) than theircounterparts in the placebo group. Finally, B2B2 homozygoteshad a nonsignificantly greater progression at the end of thestudy than their counterparts in the placebo group.
Both the association of the CETP TaqIB genotype with the decreasein either the mean luminal diameter or the minimal luminal diameterin the placebo group and the interaction between the genotypeand pravastatin treatment remained significant after adjustmentswere made for the mean luminal diameter (or minimal luminaldiameter) at base line, the base-line HDL cholesterol concentration,changes in HDL cholesterol concentrations, and activities ofboth hepatic lipase and lipoprotein lipase (data not shown).
Discussion
We investigated the relation between a common TaqIB polymorphismof the CETP gene and the progression of coronary atherosclerosisin a large cohort of men.2 The results indicate that this geneticmarker not only is associated with the progression of coronaryatherosclerosis in a dose-dependent manner but also can predictthe angiographic response to cholesterol-lowering therapy. Thisstudy complements previous reports in which we attempted todefine the genetic factors that affect the clinical presentationof the patients and their response to the study protocol.24,26,27Such studies are warranted since the majority of trials assessingthe progression of coronary atherosclerosis have focused primarilyon base-line concentrations of lipids and lipoproteins and environmentalfactors to predict outcome.1,3,28,29
Frequency of the TaqIB Polymorphism and Its Influence on Plasma CETP and HDL Cholesterol Concentrations
Screening of all study participants for the TaqIB polymorphismrevealed frequencies that were similar to those reported forother white populations,9,21,30 suggesting that our study populationis not genetically different from other cohorts. The respectivefrequencies of the B1B1, B1B2, and B2B2 genotypes were 35 percent,49 percent, and 16 percent, confirming that this marker is acommon genetic variation among white subjects. Moreover, weidentified a significant relation between the CETP genotypeand plasma concentrations of CETP at base line. Specifically,our results showed that the B1 allele was associated in a dose-dependentfashion with higher CETP concentrations, which is in agreementwith our previous findings in healthy men.11
Pravastatin reduced CETP concentrations by 16 percent in ourcohort, a finding that supports previous reports that the plasmaCETP concentration is influenced by 3-hydroxy-3-methylglutaryl–coenzymeA reductase inhibitors.31,32,33,34 By contrast, others did notfind such an effect, a fact that may be related to differencesin assay procedures or to the small number of subjects studied.35
In addition to the association of the TaqIB genotype with plasmaCETP concentrations, we also identified a significant relationbetween the B1 allele and low HDL cholesterol concentrations,which confirms earlier reports.9,21 Since plasma CETP concentrationsare closely related to CETP activity,10 and plasma CETP activityis inversely related to HDL cholesterol concentrations, it istempting to suggest that the TaqIB polymorphism is associatedwith HDL cholesterol concentrations through its relation withplasma CETP concentrations. However, it is more likely thatthis polymorphism constitutes a nonfunctional marker and thatthese relations can be explained by linkage disequilibrium betweenTaqIB and functional variants of the CETP gene or other closelylinked genes, such as that for lecithin–cholesterol acyltransferase.
TaqIB, Coronary Atherosclerosis, and the Response to Treatment with Pravastatin
Our study revealed a dose-dependent relation between the TaqIBgenotype and the progression of coronary atherosclerosis. Thisrelation was independent of HDL cholesterol concentrations,and it was not influenced by plasma lipase activities. The latterresults disagree with recent findings.36
In patients randomly assigned to placebo, angiographic measurementsdemonstrated that the B1 allele was associated with increasedprogression of coronary atherosclerosis. Subsequently, we identifieda dose-dependent interaction between the B1 allele and the abilityof pravastatin to inhibit the progression of coronary atherosclerosis.The association between the B1 allele and the progression ofcoronary atherosclerosis observed in the placebo group was notobserved in the pravastatin-treated patients. In contrast tothose in the placebo group, carriers of the B1B1, B1B2, andB2B2 genotypes in the pravastatin group had the lowest, intermediate,and highest degrees of progression of coronary atherosclerosis,respectively. In other words, the response to pravastatin withregard to coronary atherosclerosis was greatest for B1B1 carriers,whereas B2B2 carriers did not appear to benefit from this treatment.
Thus, our study has revealed a genetic predisposition to theresponse to cholesterol-lowering drugs. It should be noted thatalthough the CETP genotype was predictive of the outcome, HDLcholesterol concentrations were not.2 However, a direct comparisonbetween the CETP genotype and the CETP plasma concentrationremains to be carried out. The predictive value of this polymorphismin terms of the clinical outcome may, however, be limited, sincethe data not only were based on a post hoc analysis, but alsoare valid only with respect to the progression of coronary atherosclerosis.But, since anatomical changes are likely to predict future clinicalevents, as was shown by the collective results of several angiographictrials,37,38,39 the implications of our results are most likelyclinically significant. Specifically, our data suggest thatit may soon be possible to predict the magnitude of the clinicalbenefit of cholesterol-lowering strategies.
Putative Mechanism
The molecular mechanism that underlies the relation betweenthe CETP gene variant and the angiographic response to pravastatintreatment cannot be deduced from this study. However, it maybe related to plasma concentrations of CETP. Although pravastatinsignificantly reduced CETP concentrations, base-line CETP concentrationsdiffered among the genotype subgroups, and this may accountfor the effects observed. One could argue that high CETP concentrations,and therefore high levels of CETP activity,10 result in an enhancedtransfer of cholesteryl esters to atherogenic lipoproteins andhave negative effects on the structure and function of the HDLpool, which increases the risk of coronary artery disease. Thispossibility is in agreement with the observation that the pravastatin-inducedreduction in CETP concentrations was associated with beneficialangiographic effects in patients who had high CETP concentrations— that is, those who were homozygous for the B1 allele.In contrast, the reduction in CETP concentrations induced bypravastatin in patients with genetically determined low plasmaconcentrations of CETP — that is, those who were homozygousfor the B2 allele — was associated with a lack of retardationof the progression of coronary atherosclerosis. On the basisof these results and the finding of an increased risk of coronaryartery disease in subjects who are heterozygous for CETP deficiency,27we hypothesize that a critical concentration of CETP is requiredfor normal reverse cholesterol transport. In contrast, highplasma concentrations of CETP, as seen in placebo-treated B1B1patients, may promote atherosclerosis by increasing the cholesterolcomponent of atherogenic lipoproteins.
Conclusions
We found that, at least among Dutch men with established coronaryartery disease, the TaqIB polymorphism of the CETP gene is associatedwith the progression of coronary atherosclerosis. This relationwas dose-dependent and independent of HDL cholesterol concentrationsand plasma lipase activity. This marker also predicts the angiographicresponse to pravastatin and therefore appears to enable oneto identify those who will and those who will not benefit fromcholesterol-lowering therapy. The relevance of this findingis emphasized by the high frequency of this polymorphism: 16percent of our population had the B2B2 genotype. Therefore,we believe that this genetic variant of the CETP gene couldbecome an important factor in designing better treatment regimensand in improving the cost-effectiveness of treatment for coronaryartery disease.
Supported by Bristol-Myers Squibb.
We are indebted to P. Haydn Pritchard, Harry R. Büller,and Jan Wouter ten Cate for their critical and thorough reviewof the manuscript; to Paul Reymer and Björn Groenemeyerfor their technical support; and to Hans Jansen for determiningplasma lipase activity and providing us with the samples forCETP analysis.
Source Information
From the Departments of Vascular Medicine (J.A.K., J.J.P.K.) and Cardiology (K.I.L.), Academic Medical Center, Amsterdam, the Netherlands; the Departments of Cardiology (J.W.J., A.V.G.B.), Biostatistics (A.H.Z.), and Human Genetics (P. de K.), Leiden University, Leiden, the Netherlands; the Lipoproteins and Atherosclerosis Group, Ottawa Heart Institute, Ottawa, Ont., Canada (R.M.); and the Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands (A.V.G.B.).
Address reprint requests to Dr. Kastelein at the Academic Medical Center, Department of Vascular Medicine (Rm. G1-123), Meibergdreef 9, P.O. Box 22.700, 1105 AZ Amsterdam, the Netherlands.
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