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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0182
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4198-4204
Copyright © 2005 by The Endocrine Society

The Effect of Cholesteryl Ester Transfer Protein –629C->A Promoter Polymorphism on High-Density Lipoprotein Cholesterol Is Dependent on Serum Triglycerides

Susanna E. Borggreve, Hans L. Hillege, Bruce H. R. Wolffenbuttel, Paul E. de Jong, Stephan J. L. Bakker, Gerrit van der Steege, Arie van Tol, Robin P. F. Dullaart on behalf of the PREVEND Study Group1

Departments of Endocrinology (S.E.B., B.H.R.W., A.v.T., R.P.F.D.), Cardiology (H.L.H.), Nephrology (P.E.d.J.), Clinical Pharmacology (S.J.L.B.), Internal Medicine (S.J.L.B.), and Genotyping Facility (G.v.d.S.), Medical Biology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; and Department of Cell Biology and Genetics (A.v.T.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: S. E. Borggreve, M.D., Department of Endocrinology, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: s.e.borggreve{at}int.umcg.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The –629C->A cholesteryl ester transfer protein (CETP) promoter polymorphism is a determinant of HDL cholesterol (HDL-C). The effect of the closely linked CETP TaqIB polymorphism on HDL-C has been suggested to be modified by obesity and hyperinsulinemia.

Objective: Because the CETP-mediated cholesteryl ester transfer out of HDL is stimulated by high triglycerides, we hypothesized that triglycerides modify the effect of the CETP –629C->A promoter polymorphism on HDL-C.

Design: In 7083 nondiabetic subjects of the PREVEND population, the –629C->A promoter polymorphism, HDL-C, serum triglycerides, waist circumference, and insulin resistance (HOMAir) were determined. Serum apolipoprotein A-I was available in 6948 subjects. The TaqIB polymorphism was also assessed.

Setting: The study is set in the general community.

Results: HDL-C and serum apolipoprotein A-I were on average 0.14 mmol/liter and 0.05 g/liter higher in –629AA (22.9%) compared to –629CC (26.8%) homozygotes (P < 0.001 for both). This genotype effect on HDL-C was on average 0.15 mmol/liter in the lowest triglyceride tertile but only 0.08 mmol/liter in the highest tertile (P < 0.01). Multiple regression analysis showed that HDL-C was determined by the CETP promoter variant (P < 0.001), gender (P < 0.001), triglycerides (P < 0.001), and interactions between triglycerides and genotype (P < 0.05), between triglycerides and gender (P < 0.05), and between genotype and gender (P < 0.05), independently from waist, HOMAir, alcohol use, age, and use of lipid-lowering drugs. The TaqIB polymorphism also interacted with triglycerides on HDL-C. The –629C->A promoter polymorphism did not interact with obesity and HOMAir on HDL-C.

Conclusions: The HDL-C-raising effect of the CETP –629A allele is diminished with higher triglycerides, which may be explained by a predominant effect of triglyceride-rich lipoproteins over circulating CETP itself on cholesteryl ester transfer out of HDL with rising triglycerides.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE CARDIOPROTECTIVE ROLE of high-density lipoproteins (HDL) is widely accepted (1, 2). The antiatherosclerotic effect of HDL is commonly ascribed to its role in reverse cholesterol transport, i.e. the process by which cholesterol is removed from peripheral cells and transported to the liver for metabolism and excretion in the bile (3, 4). Cholesteryl ester transfer protein (CETP) is important for HDL metabolism because this lipid transfer protein enables the transfer of cholesteryl ester from HDL toward triglyceride (TG)-rich lipoproteins and low-density lipoproteins (3), thereby contributing to low HDL cholesterol (HDL-C) (3, 5, 6, 7). Elevated plasma CETP levels may be associated with increased cardiovascular risk in subjects with high serum TG levels (8). On the other hand, this cholesteryl ester transfer process provides a potentially beneficial pathway for delivery of HDL-derived cholesteryl esters to the liver via apolipoprotein (apo) B-containing lipoproteins (6). Consequently, the role of this process in atherosclerosis development is still debated (9, 10).

Evidence is accumulating that common polymorphisms in the CETP gene influence HDL-C levels. The TaqIB polymorphism in intron 1 of the CETP gene has been most widely studied, and a recent meta-analysis showed a large difference in HDL-C between B1B1 and B2B2 homozygotes (11). This strong genetic effect is explained at least in part by an association of plasma CETP levels with this polymorphism (11, 12, 13, 14, 15), and it is of relevance that the TaqIB polymorphism is closely linked to the –629C->A promoter polymorphism in the CETP gene (15, 16). This promoter polymorphism modulates CETP gene transcriptional activity in vitro (16). Importantly, it has been documented that this variant rather than the TaqIB polymorphism is involved in regulating plasma CETP levels (17). Several studies, performed mostly in Caucasian subjects, have suggested that the effect of the TaqIB CETP polymorphism on HDL-C may be modified by gender (18, 19, 20) and environmental (19, 21) factors. For reasons that are not clear at present, obesity and hyperinsulinemia could also modulate the effect of this polymorphism on HDL-C, in such a way that this effect may be diminished in obese (13, 22) and hyperinsulinemic individuals (22). Because raised TG levels result in an enhanced transfer of cholesteryl esters out of HDL (7), the described modulations of the CETP gene effect on HDL-C by obesity and hyperinsulinemia could be explained by elevated serum TG. We therefore hypothesized that the effect of the –629C->A promoter polymorphism in the CETP gene on HDL-C is modified by the serum TG level, rather than by obesity or insulin resistance.

The aim of the present study was to investigate whether the influence of the CETP –629C->A promoter polymorphism on HDL-C is modulated by serum TG, independently from other clinical determinants of HDL-C. The relationships of HDL-C with the TaqIB CETP gene variants and of serum apo A-I, the major HDL-associated apolipoprotein, with these polymorphisms were also studied.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

Inhabitants of the city of Groningen participating in the PREVEND (prevention of renal and vascular end-stage disease) study were studied. Details of the protocol have been described elsewhere (23). In short, the PREVEND study investigates vascular and renal damage in the general population. The study was approved by the local medical ethics committee. All participants gave written informed consent.

The present study is focused on the effects of CETP gene polymorphisms in conjunction with clinical variables and serum TG on HDL-C and serum apo A-I. Therefore, participants who were not genotyped, subjects with missing values for HDL-C or TG, as well as subjects who were not examined after an overnight fast were excluded. Diabetic patients were also excluded, leaving 7083 subjects. A second database (n = 6948) was used to evaluate determinants of apo A-I, with similar exclusion criteria.

Study protocol

Information regarding the use of lipid-lowering drugs, smoking, alcohol consumption (categorized as <1 and ≥1 U/d) and hospital admission for myocardial infarction (MI) was obtained, using a checklist as described (23). Body mass index (BMI) was calculated as the ratio between weight and height squared (in kg/m2). Waist circumference was measured on bare skin between the 10th rib and the iliac crest. After 15 min rest, blood samples were taken.

Definitions

Diabetes mellitus was diagnosed if fasting plasma glucose level was at least 7.0 mmol/liter (24) or if the participant used blood glucose-lowering drugs. MI was documented if electrocardiogram detected MI by Minnesota code 1-1-1 to 1-2-8 and/or if the participant had a history of hospital admission for MI. In women, postmenopausal status was defined as absence of menstruation for more than a year or use of hormone replacement therapy for postmenopausal conditions. The homeostasis model assessment index for insulin resistance (HOMAir) was quantified as fasting insulin (mU/liter) x fasting glucose (mmol/liter)/22.5 (25).

Laboratory methods

Serum samples were stored at –20 C until analysis. Plasma glucose was measured shortly after blood sampling. Insulin levels were assessed using a microparticle enzyme immunoassay (AxSYM Insulin assay; Abbott Laboratories, Abbott Park, IL). Serum TG were measured enzymatically. Serum total cholesterol and plasma glucose were assessed using Kodak Ektachem dry chemistry (Eastman Kodak, Rochester, NY). HDL-C was measured with a homogeneous method (direct HDL, no. 7D67, AEROSET System; Abbott Laboratories). In this assay system, HDL and apo B-containing lipoproteins are complexed with one reagent, followed by solubilizing HDL particles by another reagent (26). Serum apo A-I was determined by nephelometry applying commercially available reagents for Dade Behring nephelometer systems (BN II; Dade Behring Marburg, Germany; apo A-I test kit, code no. OUED) (27, 28).

Genotyping

The –629C->A promoter single-nucleotide polymorphism was genotyped by two separate PCRs with allele-specific primers: 5'-FAM-GCCCCAGCTGTAGGTAAAGTA was used as forward primer in both reactions. Reversed primer 5'-GATATGCATAAAATAACTCTGGGT was used to amplify exclusively the A-allele, resulting in a 188-bp PCR product. Primer 5'-ttttGATATGCATAAAATAACTCTGGtG was used to amplify the C-allele. This latter primer has a four-5'-T-residue tail (lowercase) to generate a discriminating PCR product of 192 bp of the C-allele, and the second-to-last nucleotide (lowercase t) is a mismatch to improve specificity. After PCR cycling, using standard conditions, samples were combined and separated on a MegaBACE 1000 sequencer (Amersham Biosciences Benelux, Roosendaal, The Netherlands). Fragments were analyzed with Genetic Profiler 2.0 software (Amersham Biosciences Benelux).

The TaqIB was analyzed using TaqMan-MGB probes and primers, designed through the Assay-by-Design service of Applied Biosystems (Applied Biosystems, Applera Nederland, Nieuwerkerk aan de Ijssel, The Netherlands). For the TaqIB single-nucleotide polymorphism, the forward primer sequence was 5'-CCCCTAACCTGGCTCAGATC, the reversed primer sequence was 5'-GCCAGGTATAGGGATTTGTGTTTGT, and the TaqMan-MGB probes were FAM-CCCTAACTTGAACCC and VIC-CCCTAACTCGAACCC. Assays were carried out according to the manufacturer’s recommendations on an ABI 7900HT apparatus.

Statistical analysis

Stata SE 8, SPSS 12, and Excel were used for data analysis. Data are expressed as mean ± SD or median (interquartile range). Between-group differences of means were compared with ANOVA; medians were tested by K independent samples test. {chi}2 analysis was used to compare frequencies between groups. Best curve fit for TG, HOMAir, and waist was estimated by calculation using SPSS curve fit regression. These analyses showed that TG, HOMAir, and waist against HDL-C fitted best after natural logarithmic transformation.

Multiple linear regression analyses were used to evaluate determinants of HDL-C and serum apo A-I. In these analyses, the effects of the CETP promoter and the TaqIB CETP gene polymorphisms, TG, and clinical variables and of interactions of clinical variables and TG with the CETP gene polymorphisms were evaluated. In these models, CC and B1B1 homozygotes (i.e. the CETP gene polymorphisms associated with the lowest HDL-C and apo A-I levels) were used as reference group. In case of two variables being compared with one reference variable, a combined P value of both variables was calculated by Wald test in Stata 8. A two-sided P value < 0.05 was considered to be significant, except for interaction terms, for which P values < 0.10 were accepted.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
As shown in Table 1Go, with respect to the CETP promoter polymorphism, 26.8% of individuals were genotyped as –629CC, 50.3% as –629CA, and 22.9% as –629AA. The genotype distribution was in Hardy-Weinberg equilibrium (P > 0.9). The CETP –629C->A was in strong linkage disequilibrium with the TaqIB polymorphism (D' = 0.941; P < 0.001). There were no differences in gender distribution, age, BMI, and waist circumference among the CC, CA, and AA allele carriers (Table 1Go). In the whole group, 6.0% of the subjects had a history of MI, 6.1% used lipid-lowering drugs, 33.8% were smokers, and 59.5% consumed at least 1 U of alcohol per day, and 40.2% of the women were postmenopausal. The prevalences of previous MI, use of lipid-lowering drugs, postmenopausal status, alcohol intake, and current smoking as well as urinary albumin excretion were also not different among the three CETP promoter genotype groups (data not shown). HOMAir was slightly higher in AA genotype carriers (Table 1Go). HDL-C and serum apo A-I levels were on average 0.14 mmol/liter and 0.05 g/liter higher in AA genotype carriers compared with CC genotype carriers. Serum TG levels were slightly lower in AA genotype carriers.


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  		TABLE 1. Population characteristics according to CETP –629C->A promoter polymorphism (n = 7083)

 
Analysis of HDL-C, apo A-I, and TG, according to the TaqIB CETP polymorphism, showed that HDL-C was 1.27 ± 0.37, 1.34 ± 0.40, and 1.40 ± 0.41 mmol/liter and that apo A-I was 1.36 ± 0.28, 1.39 ± 0.29, and 1.41 ± 0.31 g/liter in B1B1, B1B2, and B2B2 carriers, respectively (P < 0.001 for both).

As shown in Table 2Go, HDL-C was independently determined by the CETP –629C->A promoter polymorphism, TG, and gender as well as by the interaction of CETP genotype with TG, after adjustment for age and the use of lipid-lowering drugs (model 1). Menopausal status did not affect these relationships (P = 0.30; data not shown). The negative ß-coefficients of this interaction term indicate that the HDL-C-raising effect of the A allele was diminished with higher levels of TG. When men and women were analyzed separately, similar trends concerning the CETP promoter polymorphism-TG interaction were found (data not shown). Moreover, when lipid-lowering drug users were excluded (n = 434), the interaction of the CETP promoter polymorphism with TG on HDL-C remained significant (Wald test P = 0.04). Model 2 shows that a significant interaction of this CETP gene polymorphism with gender on HDL-C was also present, in such a way that the HDL-raising effect of the A allele was greater in women, without a significant effect of menopausal status (P = 0.16). The positive interaction term of TG with male gender on HDL-C indicates that the inverse relation of HDL-C with the TG level is less steep in men than in women. In model 2, the interaction of the CETP –629C->A promoter polymorphism with TG remained significant. Finally, the interaction of the CETP promoter polymorphism with TG was still significant after additional adjustment for HOMAir, waist circumference, and the amount of alcohol consumption (model 3) and further adjustment for smoking (data not shown). In models that included the CETP promoter polymorphism, serum TG, gender, and alcohol use or smoking, we did not observe interaction between smoking or use of alcohol and the CETP –629C->A promoter polymorphism on HDL-C (Wald test for interaction P > 0.50 for both).


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  		TABLE 2. Effect of CETP –629C->A promoter polymorphism and other variables on HDL-C (n = 7083)

 
When the TaqIB CETP gene polymorphism was used as genetic determinant of HDL-C, similar findings were noted with respect to the interaction of TG with the TaqIB genotypes (Table 3Go).


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  		TABLE 3. Effect of CETP TaqIB polymorphism and other variables on HDL-C (n = 7083)

 
Table 4Go shows that apo A-I levels are determined by the CETP –629C->A promoter and TaqIB polymorphisms. However, the interaction of these CETP polymorphisms with TG did not independently affect serum apo A-I.


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  		TABLE 4. Effect of CETP –629C->A promoter and of TaqIB polymorphism and other variables on apo A-1 after adjustment for age and lipid-lowering drugs

 
Notably, models with each CETP polymorphism, waist, HOMAir, or insulin level and the interactions of these variables with CETP genotypes did not reveal significant interactions of waist, HOMAir, or serum insulin with CETP genotypes on HDL-C (data not shown; Wald test for interactions P > 0.30), except for an interaction between the TaqIB polymorphism and waist (Wald test P = 0.06).

Figure 1Go shows the unadjusted HDL-C levels according to CETP –629C->A promoter genotypes across tertiles of serum TG. In the tertile of lowest TG (TG < 0.94 mmol/liter), the mean difference of HDL-C between the –629CC and the AA genotype carriers was 0.15 mmol/liter, whereas in the highest TG tertile (TG > 1.43 mmol/liter), this difference was limited to 0.08 mmol/liter (P < 0.01).



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  		FIG. 1. Effect of CETP –629C->A promoter polymorphism on HDL cholesterol according to serum TG tertiles. Bars represent mean ± SE. {blacksquare}, –629CC homozygote; {permzspch024}, –629CA heterozygote; {permzspch022}, –629AA homozygote. P < 0.001 for the mean difference in HDL-C between CETP –629CC and –629AA homozygotes in lowest TG tertiles vs. highest TG tertile.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This population-based study demonstrates that the influence of the –629C->A CETP promoter polymorphism on HDL-C is diminished with rising serum TG. Moreover, such a CETP gene-TG interaction on HDL-C was also present for the TaqIB polymorphism, which is known to be in strong linkage disequilibrium with the –629C->A promoter variant (15, 16, 17, 29, 30, 31, 32, 33, 34). In contrast, neither central obesity, determined by waist circumference, nor insulin resistance, documented as HOMAir, modified the influence of the –629C->A promoter on HDL-C. The present data, therefore, indicate that the level of circulating TG-rich lipoproteins, as reflected by the TG concentration, is central in modulating these genetic effects on HDL-C.

The present report provides information from the largest single cohort so far concerning the magnitude of the effect of the –629C->A CETP promoter polymorphism on HDL-C, which was found to be 0.14 mmol/liter between AA and CC homozygotes. The crude difference in HDL-C between B2B2 and B1B1 homozygotes amounted to 0.13 mmol/liter, which closely corresponds to values of 0.11 to 0.12 mmol/liter, as retrieved by metaanalyses (11, 35). The associations between these polymorphisms and HDL-C were still present after adjustment for serum TG, obesity, alcohol use, and insulin resistance, as inferred from HOMAir. In these metaanalyses (11, 35), the effect the TaqIB CETP gene polymorphism on serum apo A-1 was not evaluated. Our study indicates that both CETP gene variants affect the serum apo A-I level as well, independently from serum TG. Significant differences in serum TG levels and the degree of insulin resistance were found between –629AA and CC homozygotes, with lower serum TG but diminished insulin sensitivity in AA allele carriers. We interpret these findings to be coincidental, because lower serum TG levels usually coincide with lower HOMAir values. Moreover, it cannot be easily explained how a direct or indirect effect of variation in the CETP gene could affect the serum TG level or the degree of insulin resistance.

Two relatively small studies with 220 (13) and 187 (22) participants have previously suggested that obesity and hyperinsulinemia may interact with the CETP TaqIB polymorphism on HDL-C. In Taiwanese Chinese, the effect of CETP TaqIB variation on HDL-C was diminished, i.e. not significant in obese and in hypertriglyceridemic subjects (36). A recently published meta-analysis reported that the serum TG level does not influence the effect of this CETP gene polymorphism on HDL-C (35). This discrepancy with the present report could be explained by heterogeneity between studies inherent to every meta-analysis, e.g. with respect to the median serum TG level in each study, the overrepresentation of elderly subjects with coronary artery disease in this metaanalysis, and the inclusion of subjects with diabetes in most studies. Moreover, in this meta-analysis, the influence of CETP gene variation on HDL-C in relation to TG was assessed by dichotomizing TG, which may have masked relatively small effects. We consider the currently revealed interactions of the –629C->A CETP promoter variant and the TaqIB polymorphism with serum TG on HDL-C to be robust, in particular because these interactions remained present after adjustment for central obesity and insulin resistance. This is of interest because obesity is associated with higher plasma CETP levels (37, 38). In our models, waist circumference rather than BMI was included, because the inverse relationship of HDL-C with waist circumference was stronger than with BMI, and BMI did not affect HDL-C independent from waist circumference. Of importance, previous studies suggest that the effect of the TaqIB CETP gene variant on HDL-C is modified by gender (19, 20), although such an interaction has not always been observed (13, 36). Our study shows that the effect of the CETP promoter polymorphism on HDL-C is stronger in women than in men, irrespective of menopausal status.

The CETP-mediated process of neutral lipid transfer results in a low content of cholesterol in HDL particles and a high cholesterol content in apo B-containing lipoproteins, with reciprocal changes in lipoprotein TG (5, 6, 7). Thus, enhanced transfer of cholesteryl esters out of HDL provides a metabolic intermediate between high serum TG levels and low HDL-C (39, 40, 41). The rate of cholesteryl ester transfer from HDL toward TG-rich lipoproteins is determined by the circulating amount of active CETP as well as by the composition and concentration of TG-rich lipoproteins, with large-sized TG-rich lipoproteins being the preferred cholesteryl ester acceptor lipoproteins (40, 42, 43, 44, 45). The –629C->A CETP promoter variant does not alter the molecular structure of this lipid transfer protein but affects its circulating mass and, hence, the amount of active CETP in serum (11, 13, 14, 16, 17, 20, 30). A likely explanation of our results is that when TG increase, the CETP promoter variant and, hence, CETP levels could become less important for the process of cholesteryl ester transfer compared with the concentration of TG-rich lipoproteins. The lack of a CETP gene-TG interaction with respect to serum apo A-I does not disregard this supposition but instead underscores that effects of the constellation of TG-rich lipoproteins on cholesteryl ester transfer out of HDL primarily affect the HDL-C content and only secondarily the concentration of its major apolipoprotein, apo A-I.

Both the serum CETP activity level (46) and the CETP concentration (15) are decreased by statin treatment, whereas small changes have been reported after fibrate therapy (7). Statins were the most widely used lipid-lowering drugs in our study population, estimated to account for more than 90% of lipid-lowering drug prescriptions, and it was decided to adjust HDL-C for the use of lipid-lowering drugs in all multivariate regression models. However, pharmacy-verified information regarding statin or fibrate treatment was not available for each participant, and we could not adjust separately for the use of each type of lipid-lowering drug. Of relevance, the interaction of the CETP promoter polymorphism with TG on HDL-C was also significant when subjects who used lipid-lowering drugs were excluded from the analyses. Complex alterations in the cholesteryl ester transfer process are present in the diabetic state (7). The specific activity of CETP, i.e. the level of active CETP divided by its concentration, is lower, indicating that CETP is less active in the diabetic state (47). On the other hand, the cholesteryl ester transfer process may be enhanced by in vitro glycation of HDL (48). Therefore, subjects with type 2 diabetes mellitus were excluded from the present study. A possible limitation of our analysis is that data concerning physical activity were not available because this item was considered not precise enough when documented by questionnaire.

What could be the practical consequences of the diminished effect of CETP gene variation on HDL-C with high serum TG? The Veterans Affairs HDL Intervention Trial has demonstrated that gemfibrozil treatment reduces the risk of cardiovascular diseases in subjects with low HDL-C (49) and that the extent of risk reduction is predicted by the HDL-C concentration attained during fibrate therapy (50). Further analysis of this study demonstrated that even after stratification according to the TaqIB CETP genotype, the HDL-C response was quite variable across the CETP genotype groups (51). From the present study, we surmise that more rigorous TG lowering is required to achieve the same increase in HDL-C in –629CC compared with –629AA genotype carriers. Nonetheless, the possible consequences of this CETP gene-serum TG interaction on HDL-C for cardiovascular risk are unknown at present.

In conclusion, the present study demonstrates that the effect of the –629C->A CETP promoter polymorphism on HDL-C was modified by the serum TG level. In the lowest TG tertile, this CETP gene effect amounts to 0.15 mmol/liter, whereas this effect is limited to 0.08 mmol/liter in the highest TG tertile. This CETP gene-TG interaction on HDL-C has consequences for the interpretation of genetic effects on the HDL phenotype and could be of help to predict the effect of TG-lowering treatment on raising HDL-C.


   Acknowledgments
 
The PREVEND Study Group consists of P. E. de Jong, G. J. Navis, R. T. Gansevoort, and A. H. Brantsma, Department of Nephrology; D. de Zeeuw, W. H. van Gilst, and J. W. Brinknan, Department of Clinical Pharmacology; R. O. B. Gans, S. J. L. Bakker., A. J. Smit, and A. M. van Roon, Department of Medicine; D. J. van Veldhuisen, H. L. Hillege, and C. A. Geluk, Department of Cardiology; B. H. R. Wolffenbuttel., R. P. F. Dullaart, and S. E. Borggreve, Department of Endocrinology; G. van der Steege, and M. W. Zuurman, Genotyping Facility, Medical Biology; V. Fidler and J. G. M. Burgerhof, Department of Epidemiology and Statistics; L. T. W. de Jong-van den Berg, M. J. Postma, and J. van den Berg, Department of Pharmaco-Epidemiology; J. H. J. Muntinga, Department of Medical Physiology, University Medical Center Groningen; and D. E. Grobbee, Department of Epidemiology, Julius Center, Utrecht, The Netherlands.

We thank Dade Behring (Marburg, Germany) for supplying equipment (Behring Nephelometer II) and analytes for the determination of apolipoproteins and other metabolites. We thank Abbott Laboratories for allowing for assessment of insulin levels by means of a microparticle enzyme immunoassay (AxSYM Insulin assay; Abbott Laboratories, Abbott Park, IL). We thank M. W. Zuurman, J. Conradie, and E. Oosterom for determining the CETP genotypes. We thank J. J. Duker and J. van der Wal-Haneveld (laboratory assistants) for their concise and elaborate work.


   Footnotes
 
S.E.B. is supported by The Netherlands Heart Foundation (Grant 2001.005).

1 For a list of PREVEND Study Group members, see Acknowledgments. Back

First Published Online April 19, 2005

Abbreviations: apo, Apolipoprotein; BMI, body mass index; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; HDL-C, HDL cholesterol; MI, myocardial infarction; TG, triglyceride.

Received January 27, 2005.

Accepted April 12, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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