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European Heart Journal Advance Access published online on October 28, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn465
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction

Jakub J. Regieli1,2, J. Wouter Jukema3,4,5,*, Diederick E. Grobbee1, John J.P. Kastelein6, Jan Albert Kuivenhoven6, Aeilko H. Zwinderman7, Yolanda van der Graaf1, Michiel L. Bots1 and Pieter A. Doevendans2

1 Juliuscenter for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
2 Department of Cardiology, UMCU, Utrecht, The Netherlands
3 Department of Cardiology and Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, C5-P PO Box 9600, 2300 RC Leiden, The Netherlands
4 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
5 Durrer Institute for Cardiogenetic Research, Amsterdam, The Netherlands
6 Department of (Experimental) Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
7 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands

Received 13 April 2008; revised 7 September 2008; accepted 29 September 2008.

* Corresponding author. Tel: +31 71 5266695, Fax: +31 71 5266885, E-mail: j.w.jukema{at}lumc.nl

See page 2708 for the editorial comment on this article (doi:10.1093/eurheartj/ehn450)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Aims: Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB-B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes.

Methods and results: We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB-B2 showed reduced CETP levels and higher HDL-cholesterol (P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 (P = 0.01) for atherosclerotic disease death, 1.53 (P = 0.03) for ischaemic heart disease death, and 1.30 (P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints.

Conclusion: In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.

Key Words: Cholesteryl ester transfer protein • Lipoprotein metabolism • Pharmacogenetics • Risk factors • Prognosis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Lowering plasma low-density lipoprotein (LDL)-cholesterol is the cornerstone of secondary prevention to reduce cardiovascular events. The formation of atherosclerotic plaques in the arterial wall is promoted by the accumulation of atherogenic LDL particles, as well as by their oxidization and subsequent interactions with cellular and molecular components of the inflammatory response.1 Several lines of evidence suggest that each of these atherogenic processes can be counteracted by high-density lipoprotein (HDL).2,3 Low plasma HDL cholesterol (HDL-C) is consistently related to excess cardiovascular risk,4 and raising HDL-C levels thus seems a promising strategy to further reduce cardiovascular risk. Cholesteryl ester transfer protein (CETP)5 is considered a promising target. The main action of CETP is to transfer cholesteryl esters from HDL to apolipoprotein-B-containing particles in exchange for triglycerides, thereby reducing the concentration of HDL-C. Furthermore, recent insight suggests that CETP also plays a role in macrophage cholesterol homeostasis,6 which is considered atheroprotective,7–9 especially in normolipidaemic states.10 The net effect of CETP activity in humans is still debated11 and conflicting results from studies in mice,12–14 human CETP deficiency,15,16 and CETP gene polymorphisms17–22 constitute a prominent part of that discussion. Interactions with concomitant statin therapy23 appear to lead to further complications since the efficacy of these drugs may vary due to patients' CETP genotype24,25 and CETP concentration.26 Moreover, the safety of pharmacological CETP inhibition on top of statin therapy was recently questioned in view of the results of the Investigation of Lipid Level Management to Understand its impact in Atherosclerotic Events (ILLUMINATE) trial.27 In this trial, in 15 067 symptomatic statin-treated coronary artery disease (CAD) patients randomized to the CETP inhibitor torcetrapib or placebo, a 58% increase in total mortality was observed in the torcetrapib arm, leading to early termination of the trial.

The Regression Growth Evaluation Statin Study (REGRESS)28 was a prospective placebo-controlled double-blinded angiographic trial evaluating the effects of 2-year pravastatin 40 mg therapy vs. placebo, on the evolution of established atherosclerotic lesions in male patients with proven CAD. In this study, a pharmacogenetic interaction24 between statin therapy and CETP genotype was observed: the frequent TaqIB-B1 allele (higher CETP level, lower HDL-C) was associated with a better response to statin-treatment compared with the rare TaqIB-B2 allele (lower CETP level, higher HDL-C). Since statins reduce CETP activity29 up to 30%,30 this led to our hypothesis that such CETP activity reduction by statins, in patients with intrinsically low CETP levels may have adverse effects. The unexpected outcome of ILLUMINATE prompted us to investigate CETP genotype and mortality in the REGRESS patients who had been using statins for 8 years after the initial 2-year angiographic study.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Participants and the 2-year follow-up angiographic study
The study participants were derived from the REGRESS angiographic trial cohort, which enrolled 884 male patients with symptomatic CAD between 1989 and 1993. The trial design and main findings have been reported.24,28 In brief, the primary objectives of this randomized, placebo-controlled double-blinded angiographic trial were to evaluate the effects of 24 months of 40 mg pravastatin vs. placebo therapy on the evolution of atherosclerotic lesions in male patients with proven CAD. Within the framework of the trial, clinical and angiographic follow-up was documented after the initial 2-year trial. The clinical outcomes assessed (by an independent clinical event committee) were fatal or non-fatal myocardial infarction (MI), death due to ischaemic heart disease (IHD), repeated coronary revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty), stroke, and death due to non-coronary causes. All participants gave written informed consent. The 2-year REGRESS results demonstrated a distinct positive effect of pravastatin treatment on both the risk of adverse cardiac events as well as on the angiographic progression of CAD.28 After termination and presentation of the study (along with the publication of the 4S31 clinical and the Multicentra Anti-Atheroma Study (MAAS)32 angiographic statin studies), all participants and treating physicians were informed of the major trial outcomes and were explicitly recommended to start (placebo group) or continue (pravastatin group) statin therapy. A survey at 5 years after completion of the trial provided data that 91% of patients were using statin therapy, according to national and international guidelines.

Morbidity and mortality 10-year follow-up study
In order to obtain 10-year follow-up data of the REGRESS participants, cause-specific mortality and hospitalization until 1 January 2001 were extracted from nation-wide registries. All diagnoses in these registers are coded according to the International Classification of Diseases, 9th and 10th Revisions (ICD9 and ICD10) for mortality, and ICD9 Clinical Modification (ICD9-CM) for morbidity. The research protocol was approved by the institutional review board and ethics committee of the coordinating center (UMC Utrecht).

Linkage process method
The study database, comprising all 884 REGRESS participants, was linked to the national inhabitant registers on the basis of birth date, sex, and postal address code.33 As is customary due to privacy legislation, patient names were omitted in the linkage process. On a per-patient basis, historical registers of the Dutch inhabitants were searched for this unique combination of characteristics, and once found, this automatically merged migration history over the follow-up time. The vital status of the participants was then obtained through linking municipal administration registries using a six-character postal code. Out of the 884 participants in the original trial, 861 (97%) could be uniquely traced using the above method. The 23 patients who could not be uniquely traced were right-censored at the end of the 24-month follow-up in the mortality analyses. Information on the occurrence of non-fatal MI was obtained through linkage with the register of hospital discharge diagnoses which uses the four-digit part of the postal code. The register files admissions of all general and university hospitals in the Netherlands. Out of the 884 participants, 740 (84%) could be uniquely traced. The 144 patients who could not be uniquely traced were right-censored at the end of the 24-month follow-up for morbidity analyses.

Outcome events
In the outcome events analyses, we considered the primary causes of mortality and the primary clinical diagnosis recorded during hospitalization. The composite endpoint ‘death due to IHD’ consisted of all primary causes of mortality within the ICD9 codes 410–414 and ICD10 codes I20–I25. ‘non-fatal MI or death due to IHD’, additionally comprised the clinical occurrence of ICD9CM codes 4100–4109. The composite endpoint ‘death due to atherosclerotic disease’ consisted of all primary causes of mortality within the ICD9 codes 410–414, 430–438, 440–448 and ICD10 codes I20–I25, I60–I69, I70–I79 and F01.

DNA analyses
Genomic DNA was extracted from blood collected at baseline according to standard procedures. Genotyping of available samples for the TaqIB variant (dbSNP number rs708272), the G-2708A (rs12149545), the C-629A(rs1800775), and the CCC+784A (no dbSNP rs number designated) polymorphisms was performed using restriction fragment length polymorphism methods as described earlier.24,34

Data analyses
Differences in baseline clinical characteristics between the TaqIB variant genotype groups were assessed by one-way analysis of variance and Pearson's {chi}2 test. The latter was also used to assess Hardy–Weinberg equilibrium. Since triglyceride concentrations had a skewed distribution, the statistical analyses were based on log-transformed data. However, the triglyceride concentrations in the table are given as means [±standard error (SE)]. The time-to-death due to IHD, time-to-death due to atherosclerotic disease, time to all-cause mortality, and time-to-non-fatal MI or death due to IHD, was calculated for survival analyses. The absolute risk in each TaqIB genotype group was estimated using the Kaplan–Meier method and temporal pattern displayed in survival curves. Next, a competing risks analysis was performed according to the method of Fine and Gray,35 in order to account for potential bias from competing events in the case of cause-specific mortality endpoints (death due to IHD, death due to atherosclerotic disease, non-fatal MI, or death due to IHD). The effect of genotype on outcome was analysed using proportional hazards (Cox' regression); the number of rare allele copies was entered as a linear covariate into the model. The proportional hazards assumption was assessed for all endpoints through testing the regression coefficient of the interaction between the covariate(s) and time, and verified visually by a log–log plot; in all instances the assumption was satisfied. Furthermore, in order to take into account the randomized nature of the first 2 years of the follow-up study, a model adjusting for randomization group was added.

Moreover, possible heterogeneity of these effects between the randomized treatment groups was explored by modelling interaction terms of genotype and randomization group.

All the abovementioned statistical analyses were carried out using SPSS for Windows, release 15.0 (SPSS Inc., Chicago, IL, USA).

With respect to the haplotypic context of the TaqIB variant, the linkage disequilibrium (LD) structure between this and three previously linked variants was calculated and visualized using the application Haploview,36 release 4.0. Variants linked with D'>0.8 were included in the following haplotype effects analysis. The application Thesias,37,38 release 3.1 was used for the following procedures: the prevalence of haplotypes was estimated according to the maximum likelihood method. The threshold for inclusion of haplotypes in further analyses was set to a prevalence of 5%. Time-to-death due to IHD, time-to-death due to atherosclerotic disease, and time to all-cause death, were used as outcome measures in a survival analysis based on proportional hazards. Throughout, a two-tailed P-value of 0.05 was interpreted as indicating a statistically significant difference. All statistical analyses were performed by two of the authors (J.J.R. and A.H.Z.). All authors had full access to the data and take responsibility for its integrity.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 
Distribution of TaqIB allele frequencies
Genotype data regarding the TaqIB variant were available from 812 REGRESS participants and comprised 292 (36%) B1B1, 392 (48%) B1B2, and 128 (16%) B2B2 subjects, respectively. These frequencies are similar to those reported in other Caucasian populations.19 Baseline characteristics according to genotypes are shown in Table 1 with means and SE between brackets for continuous variables, and frequencies with percentages between brackets for dichotomous variables. Mean age of the patients was around 56 years, with controlled blood pressures (RR around 135/82 mmHg) and preserved left ventricular ejection fraction (LVEF). At baseline, plasma CETP concentration (µg/µL) was 2.06 (SE 0.033) for B1B1, 1.93 (SE 0.028) for B1B2, and 1.70 (SE 0.066) for B2B2 patients and HDL-C (mmol/L) was 0.89 (SE 0.012) for B1B1, 0.92 (SE 0.011) for B1B2, and 1.02 (SE 0.023) for B2B2 patients (both P < 0.001). CETP concentration was 17% lower and HDL-C concentrations were 15% higher in B2B2 homozygotes relative to the B1B1 homozygotes (P < 0.001), consistent with literature.19 Otherwise, no significant differences were observed between the genotypes in baseline CAD risk factors including lipoprotein profile, angiographic, or lifestyle parameters as depicted in Table 1.


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  		Table 1 Baseline demographics and coronary artery disease characteristics according to the CETP genotype (TaqIB)

 
TaqIB, statin use, and 10 years outcome
Among the 812 patients included in the survival analysis, 127 patients died during follow-up: 60 patients died from atherosclerotic disease, and 49 deaths from IHD. The composite of non-fatal MI or death from IHD occurred in 94 subjects. Figure 1 displays the Kaplan–Meier curves for the outcome events. After 10 years of follow-up, carriers of the B2 allele had a considerably increased risk of all endpoints. For instance, the 10-year absolute risk of atherosclerotic death was 5% (SE 1%) in B1B1 patients, whereas it was 8% (SE 1%) in B1B2, and 15% (SE 4%) in B2B2 patients as displayed also in Table 2. The B2 allele thus conferred both a higher risk of mortality from all-causes; hazard ratio (HR) 1.30 (95% confidence interval (CI) 1.01–1.66, P = 0.04), of death from atherosclerotic disease; HR 1.59 (1.11–2.28), P = 0.01, and of non-fatal MI or fatal IHD; 1.37 (1.03–1.82), P = 0.03. The model adjusting for randomized treatment group changed none of these effects (Table 2). Models not accounting for competing events (not displayed) resulted in similar effect sizes and significance. Moreover, no heterogeneity was observed (data not displayed). From these data, it is clear that in all these male patients on statins, the TaqIB genotype has a significant and dose-dependent impact on hard clinical endpoints with the B2 allele predicting adverse outcomes.


Figure 1
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  		Figure 1 Survival curves for time-to-death from the four defined endpoints. Time in years is displayed horizontally and cumulative risk vertically.

 

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  		Table 2 Effect of CETP-TaqIB genotype on outcome

 
TaqIB, CETP haplotypes, and risk of coronary artery disease
The TaqIB variation is located in intron 1 and it has been shown that this variant is in fact a marker for a CETP promoter polymorphism (C-629A)34 and that other single nucleotide polymorphisms at the CETP gene locus allows to determine haplotypes (Figure 2). Using the available genotypes of G-2708A, C-629A, and CCC+784A, we estimated haplotypes frequencies (Figure 3). For the current analysis, four haplotypes meeting the prevalence threshold of 5% were entered into a haplotype effects analysis. The effects of the separate haplotypes on outcomes, relative to the most common haplotype are presented in Figure 3. Notably, one risk haplotype (A-C-B2-A) was identified to be associated with all endpoints. Compared with the effect of the TaqIB-B2 allele alone, this particular haplotypic context appeared to yield an even stronger effect on all clinical endpoints, P-values for IHD death: 0.003, for atherosclerotic death P = 0.003, and for all-cause mortality P = 0.004, respectively.


Figure 2
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  		Figure 2 Linkage disequilibrium (LD) at CETP locus regulatory region flanking the TaqIB variant in the REGRESS sample. Each square denotes LD between pairs of markers in region. Red indicates no or minimal evidence of historical recombination. Numbers in squares indicate 100x D', statistical measure of LD.

 

Figure 3
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  		Figure 3 Haplotype prevalence estimations and 95% confidence intervals (left) and effects on mortality endpoints (right).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Funding
 Acknowledgements
 References
 
The REGRESS 10-year follow-up study of statin-treated male CAD patients provides evidence that genetic variation associated with low CETP levels is associated with increased 10-year mortality. Specifically, the TaqIB-B2 genotype (low CETP level and high HDL-C), or rather the (ACB2A) haplotype can be considered a risk factor when statins are used. This is counterintuitive as the B2 allele has been shown to be cardioprotective in the original REGRESS placebo group (2 years) and in a recent meta-analysis.19 In the light of the meta-analysis on the effect of TaqIB variant (most widely studied worldwide), we revisited the current body of evidence in relation to the fraction of patients who received statin therapy in the different studies (Figure 4). In agreement with our initial analysis,24 we again find evidence for a pharmacogenetic interaction between the TaqIB and statin therapy: in the studies in which only 9% of the patients received statin therapy [Physicians' Health Study (PHS), Northwick Park Heart Study (NPHS), Etude Cas-Témoins de l'Infarctus du Myocarde (ECTIM), Oulu Project Elucidating Risk of Atherosclerosis (OPERA), Reykjavik and Arca studies], the B2 allele was indeed associated with better outcome (OR for CV outcome 0.77). In contrast, in the cohorts in which 50% of the patients received statins [REGRESS-2 year follow-up, West of Scotland Coronary Prevention Study (WOSCOPS), Cholesterol And Recurrent Events (CARE)], the OR for the B2 allele was 1.06 while in the current REGRESS 10 years study, we now show that the HR for the B2 allele is in fact 1.59. These insights also complement our initial report,24 which suggested worse angiographic outcome in B2 carriers when treated with statins, which in turn is in accordance with other reports describing detrimental effects of statins in the context of endogenous low CETP concentration.25,26


Figure 4
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  		Figure 4 Evidence for a pharmacogenetic interaction of statin therapy and CETP-TaqIB genotype. Fraction of patients using statins and the effect of CETP-TaqIB effect across different studies. The current findings in light of the previously described meta-analysis (data derived from the study of Boekholdt et al.).19 Studies with no to low (up to 9%) fraction of statin-treated patients (PHS, NHPS, ECTIM, OPERA, WOSCOPS, Reykjavik, and Arca studies) show association of the B2 allele (low CETP, high HDL) with a better outcome [risk ratio (RR) for coefficient of variation outcome 0.77]. In the 50% statin-treated cohort (REGRESS 2 year, WOSCOPS, CARE) this RR for the B2 allele was neutralized to 1.06 and in the 91% statin-treated cohort (REGRESS 10 year), the B2 allele now carried a RR of 1.60 (P = 0.01) for atherosclerotic death.

 
It is tempting to speculate that this insight may hold value with regard to the recently observed increased mortality rate, experienced with the CETP inhibitor torcetrapib on top of (high-dose) statin therapy in the ILLUMINATE study, apart from the fact that this compound may also have an off-target drug toxicity via an altered aldosterone mechanism.27 High-dose statin therapy is known to yield potent cholesteryl-ester transferase inhibition30 and this is further blocked by torcetrapib. Therefore, it could be understood that further suppression of CETP by statins may be related with negative outcomes in patients with already intrinsically lower CETP. Recent insight furthermore suggests that CETP also plays a role in macrophage cholesterol homeostasis,6 which is considered atheroprotective,7–9 especially, in normolipidaemic states.10 At present, a balanced level of CETP activity may be crucial in vascular physiology.

Limitations
Some aspects and possible limitations of our study merit consideration. First, the longitudinal REGRESS study constitutes a cohort of CAD patients with 10 years of follow-up. The follow-up data set was not complete for all patients: 3% and 16% of patients could not be uniquely identified in the mortality and hospital registries, respectively. However, as these patients were right-censored at lost-to-follow-up time, it seems unlikely that this would have affected the primary outcome of the current study. We elected to calculate survival times across genotypes, in contrast to the case–control design. Survival analysis enabled us to efficiently study all the available information, including that of censored participants. Another point is that after the initial 2 years, the patients and treating physicians were only advised to start (placebo group) or continue statin use (active group) during the follow-up period and the data are likely suffering from suboptimal compliance. However, we have no reason to assume that these factors would have differentially affected the three subgroups. A survey at 5 years after completion of this trial provided crucial insight that 91% of patients were indeed on statin therapy according to the guidelines. The original placebo group patients moreover used statins for 8 years and not 10 years as did the pravastatin group, but this fact will have if anything only diluted the primary outcome of the current study. Finally, the results in this study were obtained in a cohort of exclusively male patients with established CAD. Confirmation of the present result in males in other trials is needed and the effects in women may need special attention.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Funding
 Acknowledgements
 References
 
The results of this 10-year follow-up of a cohort of male patients with symptomatic CAD provide new and clear evidence for a pharmacogenetic interaction between the CETP genotypes, statin therapy, and clinical outcome. The results show that a CETP genotype (TaqIB2 allele—part of a distinct haplotype) associated with lower CETP level and higher HDL-C, adversely affects clinical outcome when a statin is used. These data provide a further basis for the hypothesis that reducing CETP activity by statins in patients with endogenously low CETP levels may have adverse effects.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
Acknowledgements
 References
 
The original REGRESS trial was sponsored by Bristol Myers Squibb, NY, USA. The current work was supported by grants from the Netherlands Organization for Health Research and Development (ZonMW): AGIKO grant 920-03-367 (J.R.) and programme grant project number 904- 65-095 (J.R., D.E.G., and Y.G.), and from the Interuniversity Cardiology Institute Netherlands (ICIN) project number 14 (J.W.J., A.H.Z.). Bekalis Foundation (P.D.). These funding sources had no involvement in the writing of this paper or its submission.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
References
 
J.W.J. and J.J.P.K. are established (clinical) investigators of the Netherlands Heart Foundation (e.g. grant 2001D032).

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 Acknowledgements
 References
 

  1. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, Lallone R, Fogelman AM. Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation (2002) 105:290–292.[Abstract/Free Full Text]
  2. Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov (2005) 4:193–205.[CrossRef][Web of Science][Medline]
  3. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res (2004) 95:764–772.[Abstract/Free Full Text]
  4. Boden WE, Pearson TA. Raising low levels of high-density lipoprotein cholesterol is an important target of therapy. Am J Cardiol (2000) 85:645–650. A10.[CrossRef][Web of Science][Medline]
  5. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, Maruhama Y, Mabuchi H, Tall AR. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med (1990) 323:1234–1238.[Abstract]
  6. Tanigawa H, Billheimer JT, Tohyama J, Zhang Y, Rothblat G, Rader DJ. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation (2007) 116:1267–1273.[Abstract/Free Full Text]
  7. de Grooth GJ, Klerkx AH, Stroes ES, Stalenhoef AF, Kastelein JJ, Kuivenhoven JA. A review of CETP and its relation to atherosclerosis. J Lipid Res (2004) 1967–1974.
  8. Fielding CJ, Havel RJ. Cholesteryl ester transfer protein: friend or foe? J Clin Invest (1996) 97:2687–2688.[Web of Science][Medline]
  9. Hirano K, Yamashita S, Kuga Y, Sakai N, Nozaki S, Kihara S, Arai T, Yanagi K, Takami S, Menju M. Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscler Thromb Vasc Biol (1995) 15:1849–1856.[Abstract/Free Full Text]
  10. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res (2004) 45:1594–1607.[Abstract/Free Full Text]
  11. de Grooth GJ, Smilde TJ, Van Wissen S, Klerkx AH, Zwinderman AH, Fruchart JC, Kastelein JJ, Stalenhoef AF, Kuivenhoven JA. The relationship between cholesteryl ester transfer protein levels and risk factor profile in patients with familial hypercholesterolemia. Atherosclerosis (2004) 173:261–267.[CrossRef][Web of Science][Medline]
  12. Foger B, Chase M, Amar MJ, Vaisman BL, Shamburek RD, Paigen B, Fruchart-Najib J, Paiz JA, Koch CA, Hoyt RF, Brewer HB Jr, Santamarina-Fojo S. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem (1999) 274:36912–36920.[Abstract/Free Full Text]
  13. Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature (1993) 364:73–75.[CrossRef][Web of Science][Medline]
  14. Westerterp M, van der Hoogt CC, de Haan W, Offerman EH, Dallinga-Thie GM, Jukema JW, Havekes LM, Rensen PC. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice. Arterioscler Thromb Vasc Biol (2006) 26:2552–2559.[Abstract/Free Full Text]
  15. Curb JD, Abbott RD, Rodriguez BL, Masaki K, Chen R, Sharp DS, Tall AR. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res (2004) 45:948–953.[Abstract/Free Full Text]
  16. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR. Increased coronary heart disease in Japanese–American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest (1996) 97:2917–2923.[Web of Science][Medline]
  17. Anderson JL, Carlquist JF. Genetic polymorphisms of hepatic lipase and cholesteryl ester transfer protein, intermediate phenotypes, and coronary risk: do they add up yet? J Am Coll Cardiol (2003) 41:1990–1993.[Free Full Text]
  18. Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, Meyer J, Cambien F, Tiret L. Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. J Am Coll Cardiol (2003) 41:1983–1989.[Abstract/Free Full Text]
  19. Boekholdt SM, Sacks FM, Jukema JW, Shepherd J, Freeman DJ, McMahon AD, Cambien F, Nicaud V, de Grooth GJ, Talmud PJ, Humphries SE, Miller GJ, Eiriksdottir G, Gudnason V, Kauma H, Kakko S, Savolainen MJ, Arca M, Montali A, Liu S, Lanz HJ, Zwinderman AH, Kuivenhoven JA, Kastelein JJ. 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. Circulation (2005) 111:278–287.[Abstract/Free Full Text]
  20. Carlquist JF, Muhlestein JB, Horne BD, Hart NI, Bair TL, Molhuizen HO, Anderson JL. The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease. Am Heart J (2003) 146:1007–1014.[CrossRef][Web of Science][Medline]
  21. Marschang P, Sandhofer A, Ritsch A, Fiser I, Kvas E, Patsch JR. Plasma cholesteryl ester transfer protein concentrations predict cardiovascular events in patients with coronary artery disease treated with pravastatin. J Intern Med (2006) 260:151–159.[CrossRef][Web of Science][Medline]
  22. McCaskie PA, Beilby JP, Chapman CM, Hung J, McQuillan BM, Thompson PL, Palmer LJ. Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease. Hum Genet (2007) 121:401–411.[CrossRef][Web of Science][Medline]
  23. Dullaart RP, Dallinga-Thie GM, Wolffenbuttel BH, van Tol A. CETP inhibition in cardiovascular risk management: a critical appraisal. Eur J Clin Invest (2007) 37:90–98.[CrossRef][Web of Science][Medline]
  24. 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) 338:86–93.[Abstract/Free Full Text]
  25. van Venrooij FV, Stolk RP, Banga JD, Sijmonsma TP, van Tol A, Erkelens DW, Dallinga-Thie GM. Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes. Diabetes Care (2003) 26:1216–1223.[Abstract/Free Full Text]
  26. Klerkx AH, de Grooth GJ, Zwinderman AH, Jukema JW, Kuivenhoven JA, Kastelein JJ. Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur J Clin Invest (2004) 34:21–28.[CrossRef][Web of Science][Medline]
  27. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med (2007) 357:2109–2122.[Abstract/Free Full Text]
  28. Jukema JW, Bruschke AV, van Boven AJ, Reiber JH, Bal ET, Zwinderman AH, Jansen H, Boerma GJ, van Rappard FM, Lie KI. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation (1995) 91:2528–2540.[Abstract/Free Full Text]
  29. Ahnadi CE, Berthezene F, Ponsin G. Simvastatin-induced decrease in the transfer of cholesterol esters from high density lipoproteins to very low and low density lipoproteins in normolipidemic subjects. Atherosclerosis (1993) 99:219–228.[CrossRef][Web of Science][Medline]
  30. Guerin M, Egger P, Soudant C, Le Goff W, van Tol A, Dupuis R, Chapman MJ. Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux. Atherosclerosis (2002) 163:287–296.[CrossRef][Web of Science][Medline]
  31. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet (1994) 344:1383–1389.[CrossRef][Web of Science][Medline]
  32. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet (1994) 344:633–638.[CrossRef][Web of Science][Medline]
  33. Herings RM, Bakker A, Stricker BH, Nap G. Pharmaco-morbidity linkage: a feasibility study comparing morbidity in two pharmacy based exposure cohorts. J Epidemiol Commun Health (1992) 136–140.
  34. Klerkx AH, Tanck MW, Kastelein JJ, Molhuizen HO, Jukema JW, Zwinderman AH, Kuivenhoven JA. 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. Hum Mol Genet (2003) 12:111–123.[Abstract/Free Full Text]
  35. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc (1999) 94:496–509.[CrossRef][Web of Science]
  36. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (2005) 21:263–265.[Abstract/Free Full Text]
  37. Tregouet DA, Ricard S, Nicaud V, Arnould I, Soubigou S, Rosier M, Duverger N, Poirier O, Mace S, Kee F, Morrison C, Denefle P, Tiret L, Evans A, Deleuze JF, Cambien F. In-depth haplotype analysis of ABCA1 gene polymorphisms in relation to plasma ApoA1 levels and myocardial infarction. Arterioscler Thromb Vasc Biol (2004) 24:775–781.[Abstract/Free Full Text]
  38. Tregouet DA, Garelle V. A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics (2007) 23:1038–1039.[Abstract/Free Full Text]

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R. A. Lange and M. L. Lindsey
HDL-cholesterol levels and cardiovascular risk: acCETPing the context
Eur. Heart J., November 2, 2008; 29(22): 2708 - 2709.
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