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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Circulation. Author manuscript; available in PMC 2010 December 15.
Published in final edited form as:
PMCID: PMC2818786

Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community



Plasma high-density lipoprotein cholesterol (HDL-C) concentration is inversely related to the risk of cardiovascular disease (CVD). Inhibiting cholesteryl ester transfer protein (CETP) activity raises HDL-C and may be cardioprotective, but an initial clinical trial with a CETP inhibitor was prematurely stopped due to increased CVD in treated patients, raising concerns about this approach. Data relating circulating CETP concentrations to CVD incidence in the community are conflicting.

Methods and Results

Plasma CETP activity was measured in 1978 Framingham Study participants (mean age 51 years, 54% women) who attended a routine examination in 1987–90 and were free of CVD. On follow-up (mean 15.1 years), 320 participants experienced a first CVD event (fatal or non-fatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure). In multivariable analyses adjusting for standard risk factors including HDL-C, plasma CETP activity was inversely related to the incidence of CVD events (hazards ratio [HR] for activity ≥median 0.72, 95% CI 0.57–0.90, p=0.004 [compared to <median]; HR per SD increment, 0.86, 95% CI 0.76–0.97, p=0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years, and was maintained in analyses of incident ‘hard’ CVD events (myocardial infarction, stroke or heart failure).


In our prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk.

Keywords: CETP, reverse cholesterol transport, CVD, HDL-C


In prospective epidemiological studies, lower blood levels of high-density lipoprotein cholesterol (HDL-C) are associated with a greater risk of coronary heart disease (CHD),1 a relationship that is graded, continuous and independent of the effect of low-density lipoprotein cholesterol (LDL-C). 1,2 Therefore, raising HDL-C has emerged as a key strategy for reducing the residual CHD risk in individuals optimally treated for elevated LDL-C.3

Attempts to raise HDL-C have recently centered on inhibiting cholesteryl ester transfer protein (CETP),4 a plasma glycoprotein that mediates the transfer of cholesteryl esters from HDL to apoprotein B (apoB)-containing lipoproteins in exchange for triglycerides. As a result of CETP action, HDL-C is decreased (impairing reverse cholesterol transport) and the cholesterol content of very low-density lipoprotein (VLDL) and LDL is increased, which could result in a pro-atherogenic profile especially when hepatic uptake of apo-B containing lipoproteins is impaired.5 Thus, it would seem intuitive that inhibiting CETP and maintaining higher levels of HDL-C would translate into a lower CHD risk.4,6,7 However, patients randomized to torcetrapib, the first CETP-inhibitor to be evaluated in a large clinical trial (ILLUMINATE), experienced a higher rate of cardiovascular (CVD) events.8 Suggested possible causes for the untoward outcome associated with torcetrapib treatment include ‘off-target’ blood pressure raising effects, induction of dysfunctional HDL by this agent, and/or a potential direct atherogenic effect of CETP inhibition.911 Studies also failed to demonstrate a reduction in progression of atherosclerosis in the carotid and coronary arteries with torcetrapib treatment despite impressive increases in HDL-C levels.1214

Some genetic investigations have also raised questions about the desirability of inhibiting CETP. Although a recent meta-analysis noted a weak inverse association of common CETP gene variants (associated with lower CETP levels) with CVD risk,15 an updated meta-analysis separated community-based investigations from studies of high risk samples, and noted a direct association of CETP variants associated with lower CETP levels (and higher HDL-C) with CVD risk in the population-based samples.16 Some other studies focusing on partial genetic deficiency states have noted a paradoxical increased CVD risk in the setting of lower CETP activity.1721

Also, other investigations relating circulating CETP levels to CVD incidence in the community have yielded conflicting results. Thus, two recent reports indicated that lower blood CETP concentrations were associated with a greater risk of CVD in patients with prior coronary artery disease,22 and in men with low triglyceride levels.23 In contrast, a case-control investigation from the EPIC-NORFOLK Study reported a positive association between plasma CETP levels and CVD that was confined to individuals with high triglyceride levels.24 These investigations were limited by the modest number of CVD events in some reports,22,23 and by the case-control design in others.23,24 Accordingly, we related plasma CETP activity to the incidence of CVD prospectively in the community-based Framingham Heart Study.


Study sample

The design of the Framingham Offspring Study has been published elsewhere.25 Participants in this cohort are seen at the Heart Study clinic approximately every four years. At each examination cycle, participants undergo laboratory testing for CVD risk factors, anthropometry, and a standardized medical history and physical examination targeted at detection of CVD. A random subsample of participants (~50% of attendees) at the fourth examination cycle (1987–1990) underwent measurement of plasma CETP activity; a subsample was chosen for cost-containment combined with optimal use of nonrenewable plasma resources. Thus, of 4019 attendees at this examination, we excluded 2041 individuals for the following reasons hierarchically: prevalent CVD (n=343), missing values for covariates (n=15), loss to follow-up (n=16), plasma CETP activity not assayed (n=1623), and outlier CETP values (n=44; defined as values outside 1.5 times the interquartile range from the first or third quartile).26 After exclusions, 1978 participants remained eligible for the present investigation.

Participants who were excluded because they did not have plasma CETP activity measured did not differ from those with available CETP measurements in terms of their CVD risk factor profile (with the exception of a marginally lower prevalence of diabetes; see Appendix Table 1). Study participants provided written informed consent, and the study protocol was approved by the Institutional Review Board at the Boston University Medical Center.

Plasma CETP Activity Assay

CETP activity was determined using previously frozen (−80°C) EDTA plasma obtained from participants after an overnight fast. This measurement was performed using a CETP Activity Assay Kit (Roar Biomedical, Inc, New York, NY), as detailed previously.27 The method utilizes as a donor a synthetic phospholipid emulsion in which fluorescent cholesteryl ester [CE]) is solubilized and, as an accepter, native VLDL particles.28 In this assay the donor particle CE has been shown to be the preferred substrate for CETP in whole plasma and, indeed, does not compete with endogenous plasma HDL-CE as a substrate for CETP (unlike some radioisotopic assay methods that are affected by endogenous HDL-C concentrations).29 The reaction is linear (from 0.2 to 0.8 µl of normal human plasma) over 3 hours of incubation at 37°C,28,30 with CETP-mediated transfer of CE determined by an increase in fluorescence in acceptor VLDL particles (see Appendix 2 for further assay details). All measurements were made in duplicate and the intra-assay and interassay coefficients of variation were both <3%, as reported previously.27 Circulating lipids (total cholesterol, HDL-C and triglycerides) were measured using standardized methods.

Definitions of CVD events

All Framingham Heart Study participants are under continuous surveillance for the incidence of CVD events. A team consisting of 3 physicians reviews all relevant medical information, hospitalization records and physician office visits to adjudicate CVD events using standardized criteria.31 A separate group consisting of neurologists reviews and adjudicates all suspected cerebrovascular events. A diagnosis of CVD includes fatal or non-fatal coronary heart disease (CHD; recognized and unrecognized myocardial infarction [MI], stable or unstable angina, and CHD death), cerebrovascular disease (stroke, transient ischemic attack), peripheral vascular disease (intermittent claudication), and heart failure. In our primary analyses, we focused on incidence of a first CVD event as defined above, consistent with numerous prior Framingham reports.31 In secondary analyses, we related plasma CETP activity to the incidence of a first ‘hard’ CVD event, a composite endpoint that included fatal and non-fatal MI, unstable angina, stroke, or CHF; this combination of events was chosen to correspond roughly to the primary outcome in the ILLUMINATE trial.8

Statistical analyses

Given the near normal distribution of plasma CETP activity, we used untransformed values. We evaluated the correlation of plasma CETP activity with HDL-C using Pearson correlation coefficients. Because CETP activity distributions were quite similar in men and women, and we did not observe effect modification by sex upon formal testing, all analyses were performed for pooled sexes to maximize statistical power. We modeled plasma CETP activity as a binary variable (dichotomized at the median) in primary analyses. A median cut point is reasonable from a physiological perspective because pharmacological inhibitors reduce plasma CETP activity by about 35–65% in a dose-dependent manner,3234 and partial genetic CETP deficiency (associated with increased CVD risk1721) typically is associated with ~40–70% of normal activity.3537 We also performed additional analyses modeling plasma CETP activity as a continuous variable.

We compared the cumulative incidence of CVD for groups with plasma CETP activity at or above versus below the median value (131 nmol/L/hr). After confirming that the assumption of proportionality of hazards was met, we used Cox proportional hazards regression to relate plasma CETP activity to incidence of a first CVD event on follow-up. Four sets of models were constructed hierarchically: a. adjusting for age and sex; b. additionally adjusting for baseline levels of standard CVD risk factors other than HDL-C, i.e., systolic blood pressure, hypertension treatment, total cholesterol, smoking and diabetes; c. adjusting for baseline standard risk factors noted above and for HDL-C; d. adjusting for standard risk factors including HDL-C in time-dependent analyses with updating of risk factors every four years (including adjustments for the use of lipid-lowering treatment on follow-up). To gain insights into potential nonlinearity of associations between plasma CETP activity and incidence of CVD, we examined generalized additive Cox models using penalized splines. These analyses also facilitate assessment of the dose-response relation between plasma CETP activity and CVD incidence. We also performed sensitivity analyses: evaluating tertiles of CETP activity (instead of the median cutpoint), and; analyzing the entire sample with plasma CETP activity assay without the exclusion of outliers.

Recent reports have underscored the context-specific associations of altered CETP activity, depending on sex, the level of HDL-C, triglycerides or absolute CVD risk.16,17,19,23 Therefore, we tested for effect modification by age, sex, high triglyceride ( ≥250 mg/dl), low HDL-C (<40 [men] or <50 mg/dl [women]), high HDL-C (≥60 mg/dl), high LDL-C (≥130 mg/dl), apolipoprotein B levels (dichotomized at median), and a high Framingham risk score (10-year risk of CHD ≥20%) by incorporating corresponding interaction terms in models with the binary plasma CETP activity variable. In secondary analyses, we related plasma CETP activity to incidence of a first ‘hard’ CVD event on follow-up.

A p-value <0.05 was used to indicate statistical significance. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.


The baseline characteristics of our sample overall and according to CETP activity are shown in Table 1. Participants with plasma CETP activity below the median were slightly older, more likely to be men, and had slightly lower mean LDL-C but higher mean TG levels compared to those with activity at or above the median. Although the two groups had similar HDL-C, overall CETP activity was inversely related to HDL-C in the sample (r= −0.07, p=0.001); this modest correlation is consistent with that observed in relatively normolipemic individuals.38

Table 1
Baseline characteristics by Plasma CETP activity below versus at or above the median

On follow-up (mean 15.1 years, maximum 19.6 years), 320 participants (124 women) experienced a first CVD event, including 222 individuals with a first hard CVD event. Table 2 and Figure 1 suggest that individuals with plasma CETP activity below the median experienced higher CVD incidence relative to those with activity at or above the median.

Figure 1
Kaplan Meier curves showing survival free from cardiovascular disease (CVD) over the follow-up period in individuals above vs. below the median plasma CETP activity
Table 2
Event rates in individuals below vs. at or above the median of Plasma CETP activity

The results of analyses relating plasma CETP activity to CVD incidence are shown in Table 3. Plasma CETP activity at or above the median was associated with a 25–28% lower risk of CVD consistently across the various models. In models incorporating both HDL-C and CETP activity, HDL-C was associated inversely with CVD incidence (hazards rate [HR] per mg/dl increment of 0.98, 95% CI 0.97–0.99; HR per SD: 0.71, 95% CI 0.62–0.82, p<0.0001).

Table 3
Association of Plasma CETP activity with incidence of CVD: results of multivariable Cox regression.

When modeled as a continuous variable, a SD increment in plasma CETP activity was associated with a 12–14% lower risk of CVD. Regression splines confirmed the linearity of the inverse association of CETP activity and CVD incidence (Figure 2). In sensitivity analyses analyzing tertiles instead of a median cutpoint, the inverse relation of CETP activity and incident CVD was maintained (HR per tertile increment 0.87, 95% CI 0.76–1.00, lowest tertile as referent; HR for second tertile 0.86, 95% CI 0.66–1.12, HR for highest tertile 0.77, 95% CI 0.58–1.00). In other sensitivity analyses evaluating the entire sample with plasma CETP activity without excluding outlier values, the results of our primary analyses remained robust.

Figure 2
Multivariable-adjusted relations of plasma CETP activity (continuous variable) to the incidence of CVD on follow-up. Figure shows estimated multivariable hazard ratios for CVD (Y axis) in relation to plasma CETP activity (X axis) as a function of penalized ...

Figure 3 displays the association of plasma CETP activity with incidence of ‘hard’ CVD events (complementing analyses of ‘all CVD’ shown in Table 3). Plasma CETP activity at or above the median was associated with a 27–30% lower risk of CVD, consistent with the primary analyses. We did not observe any effect modification by age, sex, high triglyceride, low or high HDL-C, high LDL-C or apolipoprotein B levels, or a high Framingham risk score (p values for all interactions exceeded 0.05).

Figure 3
Association of plasma CETP activity with incidence of first ‘hard’ CVD events (complementing results for all CVD incidence shown in Table 3). Covariates for various models are as listed in footnote to Table 3. The vertical bars represent ...


The discovery of CETP and the elucidation of its diverse roles in lipid physiology have fuelled a contentious debate on its pro- and anti-atherosclerotic roles.4,3942 Genetic epidemiological studies also have not resolved the issue.15,18,43,44 Genetic investigations focusing on partial CETP deficiency states have yielded conflicting results,20,21,45,46 sometimes from the same study cohort.20,45 Experimental approaches are also challenged by the lack of CETP in some species, diverse cholesterol transport mechanisms, and a different time frame for development of atherosclerosis in susceptible animals compared to humans.43 The controversy surrounding CETP inhibition as a strategy for raising HDL-C and lowering CVD risk has further intensified,9,11,4750 in light of recent disappointing clinical trial data associated with one of several newly-synthesized inhibitors of CETP.8,1214,50 Given this background, we evaluated prospectively the relations of plasma CETP activity to CVD incidence in a community setting.

Principal Findings

Our principal finding was an inverse relation of plasma CETP activity and CVD incidence. While our findings are observational, the possibility that the observed relationship is a causal one is strengthened by its biological plausibility (see below), the demonstration of a linear dose-response (regression splines), the presence of a temporal relationship (plasma CETP activity was assessed before CVD events), and the consistency of the association in multiple analyses (incorporating covariates sequentially, including time-dependent models; modeling plasma CETP activity as a binary and as a continuous variable; and evaluation of all CVD and hard CVD events). The strength of the association (a 25–28% lower risk with plasma CETP activity values above the median [which corresponds to a hazard of 1.35–1.40 for plasma CETP activity values below the median, relative to those above]) is of a magnitude similar to that reported for partial CETP deficiency in some reports.17,18,20 We did not find evidence of effect modification by age, sex, HDL-C, LDL-C or triglyceride levels and the global CVD risk (as estimated by the Framingham risk score), in contrast to other reports that noted inverse associations of CETP levels (or of related genotypes) and CVD risk in select subgroups.16,17,19,23

Data on the relations of CETP mass and CVD are conflicting,2224 as noted earlier, in part related to modest numbers of CVD events and varying study designs. We used a plasma CETP activity assay that was already available in our study cohort at an earlier examination27 (as opposed to CETP mass assays used by several investigators2224), which facilitated a long-term prospective time-to-event analysis (20 years of follow-up) in this large community-based sample. It is noteworthy that circulating CETP mass and activity have been reported to be highly correlated (r of 0.85 or more) in several reports.5153

We observed a very modest inverse relation of plasma CETP activity with HDL-C in our sample. This may be in part because HDL-C concentrations are determined by several enzymatic processes in addition to CETP (such as lecithin:cholesterol acyltransferase, hepatic lipase and phospholipid transfer protein)54,55 or it may arise because we measured CETP activity using a fabricated substrate that does not interact with the natural substrate in this reaction (i.e., plasma HDL-CE). Of note, the relations of CETP activity and HDL-C have been inconsistent in the literature with some investigations reporting no correlation54,56 whereas others have noted modest inverse correlations of a magnitude consistent with our findings.38

The failure of the CETP inhibitor, torcetrapib, has drawn attention to the complex and potential beneficial effects of CETP on reverse cholesterol transport at several levels. Irrespective of the toxicity issues of torcetrapib, in clinical trials this agent did produce a substantial increase in HDL-C (as predominantly cholesteryl esters) but did not appear to reduce atherosclerosis in either carotid50 or coronary vessels.14 Studies by Schwartz et al.57 have shown with multi-compartmental analysis in humans that very little cholesteryl ester is transported directly from HDL to the liver but, instead, is predominantly delivered to the liver from apoB-containing lipoproteins. This is in contrast to the fate of HDL-unesterified cholesterol which is readily taken up by the liver and secreted in bile or utilized as the primary precursor for bile acid synthesis.58 In summary, these kinds of results would support raising levels of HDL-C, but not blocking a natural egress pathway of HDL-cholesteryl esters to apoB-containing lipoprotein for delivery to the liver. Given the development of agents in the same class that seem to lack the off-target effects of torcetrapib, it is important to conduct additional studies to confirm our findings.

Strengths and Limitations

The moderate-sized community-based sample of middle-aged men and women, prospective design, and the assessment of CVD outcomes blinded to plasma CETP activity levels strengthen our study. Several limitations must be acknowledged. First, assessment of plasma CETP activity in vitro is challenging.59 We used a standardized assay and any measurement error is likely random, biasing us towards the null hypothesis of no association of CETP activity with CVD incidence. The ex vivo assessment of CETP activity may not reflect in vivo activity. Further, the activity assay used estimates rates of mass transfer of cholesteryl esters from donor particles (phospholipids) to acceptor particles (VLDL), and therefore reflects only one aspect of CETP activity. CETP is involved in lipid transfer reactions involving several different lipid particles.43,59,60 Second, we had single-occasion measurements of CETP activity, which would result in an underestimation of the strength of the association (regression dilution bias).61 Third, given the observational study design, our results cannot be extrapolated directly to the potential effects of pharmacological inhibition of CETP activity using available agents. Last, our sample was middle-aged, with an intermediate pre-test probability of CVD, and exclusively white, which would limit the generalizability of our results to age groups or ethnicities not studied.


In our prospective investigation of a moderate-sized community-based sample, lower plasma CETP activity was associated with greater risk of CVD. These observations, if confirmed, call into question the strategy of pharmacological inhibition of CETP to lower CVD risk.

Clinical Summary

Inhibiting cholesteryl ester transfer protein (CETP) activity raises HDL-C levels and may be cardioprotective. However, an initial clinical trial with a CETP inhibitor was prematurely stopped due to increased CVD events in treated patients. Data relating circulating CETP mass to CVD incidence in the community are also conflicting. So, we related routinely assayed plasma CETP activity to the incidence of CVD events on follow-up (average 15 years) in the offspring cohort of the Framingham Study. In multivariable analyses adjusting for standard CVD risk factors, plasma CETP activity was inversely related to the incidence of CVD events, a finding that remained robust in time-dependent models updating CVD risk factors every 4 years on follow-up, and was maintained in analyses of incident ‘hard’ CVD events. These observational data based on prospective follow-up of a large community-based sample require confirmation. If confirmed, our findings would call into question the use of CETP inhibition as a strategy for lowering CVD risk.

Supplementary Material




This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), HL-54776, 2 K24 HL04334 (Dr. Vasan), and contract 53-K06-5-10 from the US Department of Agriculture Research Service.


Disclosures: none.

Reference List

1. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. The Lancet. 370:1829–1839. [PubMed]
2. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15. [PubMed]
3. Hausenloy DJ, Yellon DM. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels. Postgrad Med J. 2008;84:590–598. [PubMed]
4. Ansell B, Hobbs FD. The potential for CETP inhibition to reduce cardiovascular disease risk. Curr Med Res Opin. 2006;22:2467–2478. [PubMed]
5. Rye KA, Clay MA, Barter PJ. Remodelling of high density lipoproteins by plasma factors. Atherosclerosis. 1999;145:227–238. [PubMed]
6. Shah PK. Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease. Eur Heart J. 2007;28:5–12. [PubMed]
7. Tall AR. CETP Inhibitors to Increase HDL Cholesterol Levels. N Engl J Med. 2007;356:1364–1366. [PubMed]
8. 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. [PubMed]
9. Bloch MJ, Basile J. Cholesterol ester transfer protein inhibition with torcetrapib leads to an increase in cardiovascular events: an effect that is unlikely to be the result of increases in blood pressure alone. J Clin Hypertens (Greenwich) 2008;10:160–163. [PubMed]
10. Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, Hershey JC, Keller WJ, Ma X, McPherson HE, Messina E, Peterson LB, Sharif-Rodriguez W, Siegl PK, Sinclair PJ, Sparrow CP, Stevenson AS, Sun SY, Tsai C, Vargas H, Walker M, III, West SH, White V, Woltmann RF. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154:1465–1473. [PMC free article] [PubMed]
11. Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol. 2007;27:257–260. [PubMed]
12. Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007;370:153–160. [PubMed]
13. Kastelein JJP, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML. The RADI. Effect of Torcetrapib on Carotid Atherosclerosis in Familial Hypercholesterolemia. N Engl J Med. 2007;356:1620–1630. [PubMed]
14. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM. The I, I. Effect of Torcetrapib on the Progression of Coronary Atherosclerosis. N Engl J Med. 2007;356:1304–1316. [PubMed]
15. Thompson A, Di AE, Sarwar N, Erqou S, Saleheen D, Dullaart RP, Keavney B, Ye Z, Danesh J. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA. 2008;299:2777–2788. [PubMed]
16. Dullaart RP, Sluiter WJ. Common variation in the CETP gene and the implications for cardiovascular disease and its treatment: an updated analysis. Pharmacogenomics. 2008;9:747–763. [PubMed]
17. Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Jensen G, Tybjarg-Hansen A. Elevated HDL Cholesterol Is a Risk Factor for Ischemic Heart Disease in White Women When Caused by a Common Mutation in the Cholesteryl Ester Transfer Protein Gene. Circulation. 2000;101:1907–1912. [PubMed]
18. Borggreve SE, Hillege HL, Wolffenbuttel BHR, de Jong PE, Zuurman MW, van der Steege G, van Tol A, Dullaart RPF. on behalf of the PREVEND Study Group. An Increased Coronary Risk Is Paradoxically Associated with Common Cholesteryl Ester Transfer Protein Gene Variations That Relate to Higher High-Density Lipoprotein Cholesterol: A Population-Based Study. J Clin Endocrinol Metab. 2006;91:3382–3388. [PubMed]
19. Bruce C, Sharp DS, Tall AR. Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia. J Lipid Res. 1998;39:1071–1078. [PubMed]
20. 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. [PMC free article] [PubMed]
21. Hirano Ki, Yamashita S, Nakajima N, Arai T, Maruyama T, Yoshida Y, Ishigami M, Sakai N, Kameda-Takemura K, Matsuzawa Y. Genetic Cholesteryl Ester Transfer Protein Deficiency Is Extremely Frequent in the Omagari Area of Japan: Marked Hyperalphalipoproteinemia Caused by CETP Gene Mutation Is Not Associated With Longevity. Arterioscler Thromb Vasc Biol. 1997;17:1053–1059. [PubMed]
22. 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. [PubMed]
23. Borggreve SE, Hillege HL, linga-Thie GM, de Jong PE, Wolffenbuttel BHR, Grobbee DE, van Tol A, Dullaart RPF. on behalf of the PREVEND Study Group. High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. Eur Heart J. 2007 ehm062. [PubMed]
24. Boekholdt SM, Kuivenhoven JA, Wareham NJ, Peters RJG, Jukema JW, Luben R, Bingham SA, Day NE, Kastelein JJP, Khaw KT. 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. Circulation. 2004;110:1418–1423. [PubMed]
25. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol. 1979;110:281–290. [PubMed]
26. Tukey JW. Exploratory data analysis. Reading, MA: Addison-Wesley; 1977. pp. 43–44.
27. Ordovas JM, Cupples LA, Corella D, Otvos JD, Osgood D, Martinez A, Lahoz C, Coltell O, Wilson PW, Schaefer EJ. 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. [PubMed]
28. Roar CETP Activity Assay Kit. 2009. 3-20-2009.
29. Grandjean PW, Alhassan S. Essential laboratory methods for blood lipid and lipoprotein analysis. In: Moffatt RJ, Stamford BA, editors. Lipid Metabolism and Health. Boca Raton, FL: CRC Press; 2006. pp. 117–146.
30. Tan KC, Shiu SW, Janus ED, Lam KS. LDL subfractions in acromegaly: relation to growth hormone and insulin-like growth factor-I. Atherosclerosis. 1997;129:59–65. [PubMed]
31. Kannel WB, Wolf PA, Garrison RJ, editors. Section 34: Some risk factors related to the annual incidence of cardiovascular disease and death in pooled repeated biennial measurements. Framingham Heart Study, 30 year follow-up. Bethesda, MD: US Department of Health and Human Services; 1987.
32. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ. Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol. N Engl J Med. 2004;350:1505–1515. [PubMed]
33. Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ. Raising High-Density Lipoprotein in Humans Through Inhibition of Cholesteryl Ester Transfer Protein: An Initial Multidose Study of Torcetrapib. Arterioscler Thromb Vasc Biol. 2004;24:490–497. [PubMed]
34. de Grooth GJ, Kuivenhoven JA, Stalenhoef AFH, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJP. Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans: A Randomized Phase II Dose-Response Study. Circulation. 2002;105:2159–2165. [PubMed]
35. Chiba H, Akita H, Tsuchihashi K, Hui SP, Takahashi Y, Fuda H, Suzuki H, Shibuya H, Tsuji M, Kobayashi K. Quantitative and compositional changes in high density lipoprotein subclasses in patients with various genotypes of cholesteryl ester transfer protein deficiency. J Lipid Res. 1997;38:1204–1216. [PubMed]
36. 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. [PubMed]
37. Yamashita S, Hui DY, Wetterau JR, Sprecher DL, Harmony JA, Sakai N, Matsuzawa Y, Tarui S. Characterization of plasma lipoproteins in patients heterozygous for human plasma cholesteryl ester transfer protein (CETP) deficiency: plasma CETP regulates high-density lipoprotein concentration and composition. Metabolism. 1991;40:756–763. [PubMed]
38. Tato F, Vega GL, Tall AR, Grundy SM. Relation Between Cholesterol Ester Transfer Protein Activities and Lipoprotein Cholesterol in Patients With Hypercholesterolemia and Combined Hyperlipidemia. Arterioscler Thromb Vasc Biol. 1995;15:112–120. [PubMed]
39. Barter PJ, Brewer HB, Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl Ester Transfer Protein: A Novel Target for Raising HDL and Inhibiting Atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:160–167. [PubMed]
40. Fielding CJ, Havel RJ. Cholesteryl ester transfer protein: friend or foe? J Clin Invest. 1996;97:2687–2688. [PMC free article] [PubMed]
41. 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. [PubMed]
42. Rensen PCN, Havekes LM. Cholesteryl Ester Transfer Protein Inhibition: Effect on Reverse Cholesterol Transport? Arterioscler Thromb Vasc Biol. 2006;26:681–684. [PubMed]
43. Boekholdt SM, Thompson JF. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res. 2003;44:1080–1093. [PubMed]
44. Brousseau ME, O'Connor JJ, Jr, Ordovas JM, Collins D, Otvos JD, Massov T, McNamara JR, Rubins HB, Robins SJ, Schaefer EJ. Cholesteryl Ester Transfer Protein TaqI B2B2 Genotype Is Associated With Higher HDL Cholesterol Levels and Lower Risk of Coronary Heart Disease End Points in Men With HDL Deficiency: Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol. 2002;22:1148–1154. [PubMed]
45. 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. [PubMed]
46. Moriyama Y, Okamura T, Inazu A, Doi M, Iso H, Mouri Y, Ishikawa Y, Suzuki H, Iida M, Koizumi J, Mabuchi H, Komachi Y. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med. 1998;27:659–667. [PubMed]
47. Doggrell SA. The failure of torcetrapib: is there a case for independent preclinical and clinical testing? - author's reply. Expert Opin Pharmacother. 2008;9:2563–2564. [PubMed]
48. Joy TR, Hegele RA. The failure of torcetrapib: what have we learned? Br J Pharmacol. 2008;154:1379–1381. [PMC free article] [PubMed]
49. Shear CL. The failure of torcetrapib: is there a case for independent preclinical and clinical testing?--correspondence. Expert Opin Pharmacother. 2008;9:2561–2562. [PubMed]
50. Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW, Grobbee DE, Visseren FL, Stalenhoef AF, Stroes ES, Kastelein JJP. Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity: A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials. Circulation. 2008;118:2515–2522. [PubMed]
51. McPherson R, Mann CJ, Tall AR, Hogue M, Martin L, Milne RW, Marcel YL. Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables. Arterioscler Thromb. 1991;11:797–804. [PubMed]
52. Ikewaki K, Mabuchi H, Teramoto T, Yamada N, Oikawa S, Sasaki J, Takata K, Saito Y. Association of cholesteryl ester transfer protein activity and TaqIB polymorphism with lipoprotein variations in Japanese subjects. Metabolism. 2003;52:1564–1570. [PubMed]
53. van Venrooij FV, Stolk RP, Banga JD, Sijmonsma TP, van TA, 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. [PubMed]
54. Kinoshita M, Teramoto T, Shimazu N, Kaneko K, Ohta M, Koike T, Hosogaya S, Ozaki Y, Kume S, Yamanaka M. CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy Japanese. Atherosclerosis. 1996;120:75–82. [PubMed]
55. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 2006;116:3090–3100. [PMC free article] [PubMed]
56. Smaoui M, Hammami S, Attia N, Chaaba R, Abid N, Kilani N, Kchaou H, Mahjoub S, Abid M, Hammami M. Modulation of plasma cholesteryl ester transfer protein activity by unsaturated fatty acids in Tunisian type 2 diabetic women. Nutr Metab Cardiovasc Dis. 2006;16:44–53. [PubMed]
57. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res. 2004;45:1594–1607. [PubMed]
58. Halloran LG, Schwartz CC, Vlahcevic ZR, Nisman RM, Swell L. Evidence for high-density lipoprotein-free cholesterol as the primary precursor for bile-acid synthesis in man. Surgery. 1978;84:1–7. [PubMed]
59. Lagrost L. Regulation of cholesteryl ester transfer protein (CETP) activity: review of in vitro and in vivo studies. Biochim Biophys Acta. 1994;1215:209–236. [PubMed]
60. de Grooth GJ, Klerkx AHEM, Stroes ESG, Stalenhoef AFH, Kastelein JJP, Kuivenhoven JA. A review of CETP and its relation to atherosclerosis. J Lipid Res. 2004;45:1967–1974. [PubMed]
61. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, Peto R. Underestimation of Risk Associations Due to Regression Dilution in Long-term Follow-up of Prospective Studies. American Journal of Epidemiology. 1999;150:341–353. [PubMed]