© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Association of Cholesteryl Ester Transfer Protein–TaqIB Polymorphism With Variations in Lipoprotein Subclasses and Coronary Heart Disease Risk
The Framingham Study
From the Lipid Metabolism Laboratory (J.M.O., D.C., D.O., A.M., C.L., O.C., E.J.S.), Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Mass; Boston University School of Public Health (L.A.C.), Boston, Mass; the Department of Biochemistry (J.D.O.), North Carolina State University, Raleigh, NC; and The Framingham Heart Study (P.W.F.W.), Boston University School of Medicine, Framingham, Mass.
Correspondence to Dr Jose M. Ordovas, Lipid Metabolism Laboratory, J.M. USDA HNRCA at Tufts University, 711 Washington St, Boston, MA 02111. E-mail ordovas{at}hnrc.tufts.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides and cholesteryl esters between lipoprotein particles, a key step in reverse cholesterol transport in humans. Variations at the CETP locus have been shown to be determinants of the levels and activity of CETP and high density lipoprotein (HDL) plasma concentration. The associations of the common CETP polymorphism, TaqIB in intron 1, with lipoprotein levels and particle size distribution, CETP activity, and coronary heart disease (CHD) risk were examined in a population-based sample of 1411 men and 1505 women from the Framingham Offspring Study. The B2 allele frequency was 0.444 in men and 0.433 in women, and its presence was significantly (P<0.05) associated with decreased CETP activity. B1B1 men had lower HDL cholesterol (HDL-C) levels (1.07 mmol/L) compared with B1B2 (1.14 mmol/L) and B2B2 (1.18 mmol/L) men (P<0.001). Likewise, B1B1 women had lower HDL-C levels (1.40 mmol/L) compared with B1B2 (1.46 mmol/L) and B2B2 (1.53 mmol/L) women (P<0.001). In men, the B2 allele was associated with increased particle size for HDL and low density lipoprotein. In women, a similar effect was demonstrated only for HDL particle size. The odds ratio for prevalent CHD associated with the B2 allele was 0.696 (P=0.035) in men. After adjusting for age, body mass index, systolic blood pressure, diabetes, smoking, alcohol consumption, ß-blocker use, total cholesterol, and HDL-C, this odds ratio was 0.735 (P=0.187), suggesting that the protective effect of the B2 allele was due in part to its association with HDL-C levels. No significant protective effects were observed in women. These data demonstrate that variation at the CETP gene locus is a significant determinant of HDL-C levels, CETP activity, and lipoprotein size in this population. Moreover, these effects appear to translate into a lower CHD risk among those men with the B2 allele.
Key Words: cholesteryl ester transfer protein • coronary heart disease • lipoproteins • gene polymorphisms
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides and cholesteryl esters between lipoprotein particles. In humans, CETP mRNA encodes a polypeptide of Mr 53 000, which is n-glycosylated at 4 sites, giving rise to the mature form of CETP of Mr 74 000.1 CETP is expressed primarily in liver, spleen, and adipose tissue, and lower levels have been detected in the small intestine, adrenal gland, heart, kidney, and skeletal muscle.1 2 The CETP gene encompasses 16 exons, and it has been localized on chromosome 16q21 adjacent to the lecithin-cholesterol acyltransferase gene. Several mutations at the CETP locus have been identified, resulting in the absence of detectable CETP mass and/or activity.3 These mutations are common in Japanese populations,4 5 6 7 although some have been recently reported in white subjects.8 9 CETP deficiency is associated with hyperalphalipoproteinemia, which is primarily due to an increase of cholesteryl ester–enriched large-sized HDL. Conversely, the triglyceride-rich lipoproteins and LDL are smaller, reflecting the role of CETP in neutral lipid exchange.3
Several common restriction fragment length polymorphisms (RFLPs) have been reported in the CETP gene locus.10 11 12 The most studied RFLP to date has been TaqIB, which has been shown to be a silent base change affecting the 277th nucleotide in the first intron of the gene.10 The B2 allele (absence of the TaqI restriction site) at this polymorphic site has been associated in normolipemic subjects with increased HDL cholesterol (HDL-C) levels and decreased CETP activity and levels,13 14 15 16 thus resembling a mild form of CETP deficiency. It has been suggested that this association may be population specific17 18 and highly influenced by environmental factors, such as alcohol consumption and tobacco smoking.15 19 20 Moreover, Kuivenhoven et al21 have shown an interaction between the TaqIB genotype and the progression of coronary heart disease (CHD) after therapy. These observations could be of significant relevance, because low plasma HDL levels are associated with an increase in the risk of coronary artery disease.22 23 Moreover, clinical evidence suggests that an increase of 1% in the plasma HDL-C levels is associated with a reduction in cardiovascular morbidity and mortality of 2% to 3%.24 Therefore, CETP could have a relevant role in atherogenesis through its effects on HDL metabolism.
The aim of the present study was to determine the frequency, phenotypic expression, and potential modulation of CHD risk in the general population by TaqIB RFLP in the first intron of the CETP gene. Specifically, we studied the interindividual variability in lipid levels, lipoprotein subclass profiles, and cardiovascular risk associated with this CETP polymorphism among Framingham Offspring Study participants.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The details of the design and methods of the Framingham Offspring Study have been presented elsewhere.25 Starting in 1971, a total of 5124 subjects were enrolled.26 Blood samples for DNA were collected between 1987 and 1991. Lipid phenotypes, DNA, and information on CHD risk factors were available for 1411 men and 1505 women who attended the fourth and fifth examination visits of the Framingham Offspring Study conducted between 1987 and 1995 and for whom lipid values were available in the absence of lipid-altering medication. Nearly all subjects were white. Data on smoking, blood pressure, height, weight, and diabetes were obtained for these subjects as previously described.26 27 CHD included the presence of myocardial infarction, angina pectoris, coronary insufficiency, and coronary death. All suspected CHD events were reviewed by a panel of 3 physicians to ascertain the presence of CHD. Subjects taking a lipid-lowering medication (n=100) were included for the analyses of CHD prevalence at examination 5 but excluded in all other analyses.
Plasma Lipid, Lipoprotein, Apolipoprotein, and CETP
Measurements
Twelve-hour fasting venous blood samples were collected in tubes
containing 0.1% EDTA. Plasma was separated from blood cells by
centrifugation and immediately used for the measurement
of lipids. Plasma total cholesterol, HDL-C, and
triglyceride levels were measured as previously
described.28 HDL-C was measured after precipitation of
apoB-containing lipoproteins with dextran-magnesium
sulfate.29 LDL cholesterol (LDL-C)
concentrations were estimated with the equation of Friedewald et
al.30 Coefficients of variation for total
cholesterol, HDL-C, and triglyceride
measurements were each <5%.31 Plasma levels of apoA-I
and apoB were measured by noncompetitive ELISA with the use of
affinity-purified polyclonal antibodies.32 33
Plasma lipoprotein concentrations and subclass distributions were determined by proton nuclear magnetic resonance (NMR) spectroscopy as previously described.34 35 Each profile displays the concentrations of 6 VLDL, 1 IDL, 3 LDL, and 5 HDL subclasses and the weighted-average particle sizes of VLDL, LDL, and HDL. The 10 lipoprotein subclass categories used were the following: large VLDL and remnants (80 to 220 nm), intermediate VLDL (35 to 80 nm), small VLDL (27 to 35 nm), large LDL (21.3 to 27.0 nm), intermediate LDL (19.8 to 21.2), small LDL (18.3 to 19.7 nm), large HDL (8.8 to 13.0 nm), intermediate HDL (7.8 to 8.8 nm), and small HDL (7.3 to 7.7 nm). Levels of VLDL subclasses are expressed in millimolar units of triglyceride, and those of LDL and HDL subclasses are expressed in millimolar units of cholesterol. LDL and HDL subclass distributions determined by gradient gel electrophoresis and NMR have been shown to be closely correlated.34 However, it should be noted that given the characteristics of this methodology, there could be some overlap between the IDL fraction and the small VLDL as well as the large LDL subfraction. Nevertheless, this should not have a major effect on the associations examined, given the low concentrations of IDL found in fasting plasma levels of normal subjects.
CETP activity was determined by using a CETP Activity Kit by Roar Biomedical, Inc. This kit includes donor (synthetic phospholipid and cholesteryl ester) and acceptor (VLDL) particles. The fluorescent neutral lipid is present in a self-quenched state when contained within the core of the donor. The CETP-mediated transfer is determined by the increase in fluorescence intensity as the fluorescent neutral lipid is removed from the self-quenched donor to the acceptor. Briefly, for each sample assayed, 10 µL of plasma was diluted (1:10) in 90 µL of sample buffer (10 mmol/L Tris, 150 mmol/L NaCl, and 2 mmol/L EDTA, pH 7.4). In a fluorescence-compatible microtiter plate (Dynex Laboratories), 20 µL of the plasma dilution was combined with 4 µL of donor and 4 µL of acceptor in a total volume of 200 µL and incubated for 3 hours at 37°C. The assay was read in a fluorescence spectrometer at excitation wavelength of 465 nm and emission wavelength of 535 nm. A standard curve was used, according to the manufacturer’s guidelines, to derive the relation between fluorescence intensity and mass transfer. Plasma controls were run in each plate to account for plate-to-plate variation. For standardization, the unquenched fluorescence intensity of the fluorescent cholesteryl ester contained within the donor particle core was determined by dispersing 5 µL of donor (fluorescent cholesteryl ester concentration 146 µg/mL, as reported by the manufacturer) in 2 mL of 100% isopropanol. Serial dilutions of the dispersion were made to generate a standard curve of fluorescence intensity (excitation 465 nm/emission 535 nm) versus mass of fluorescent cholesteryl ester. The fluorescence intensity transferred in the assay of plasma samples was applied to the standard curve to determine mass transfer. The intra-assay and interassay coefficients of variation were <3%.
DNA Analysis
Genomic DNA was isolated from peripheral blood
leukocytes by standard methods.36 CETP genotype
was performed as described by Fumeron et al.19 A fragment
of 535 bp in intron 1 of the CETP gene was amplified by polymerase
chain reaction (PCR) in a DNA Thermal Cycler (PTC-100, MJ Research,
Inc) with the use of oligonucleotide primers (forward
5'-CACTAGCCCAGAGAGA-GGAGTGCC-3', reverse
5'-CTGAGCCCAGCCGCACACTAAC-3'). Each amplification was performed by
using 100 ng of genomic DNA in a volume of 50 µL containing 40 pmol
of each oligonucleotide, 0.2 mmol/L dNTPs,
1.5 mmol/L MgCl2, 10 mmol/L Tris, pH
8.4, and 0.25 U of Taq polymerase. DNA templates were
denatured at 95°C for 3 minutes, and then each PCR reaction was
subjected to 30 cycles with a temperature cycle consisting of 95°C
for 30 seconds, 60°C for 30 seconds, 72°C for 45 seconds, and,
finally, an extension at 72°C for 5 minutes. The PCR products
were subjected to restriction enzyme analysis by digestion with
4 U of the restriction endonuclease TaqI for 16 µL of PCR
sample at 65°C for 2 hours in the buffer recommended by the
manufacturer (GIBCO-BRL), and the fragments were separated by
electrophoresis on an 1.5% agarose gel. After electrophoresis, the gel
was treated with ethidium bromide for 20 minutes, and DNA fragments
were visualized by UV illumination. The resulting fragments were 174
and 361 bp for the B1 allele and 535 bp for the uncut B2
allele. Restriction isotyping of the apoE genotype was
carried out as previously described.37
Statistical Analyses
To compare men and women who participated in the present
study, we used 
2 tests for categorical
measures and 2-sample t tests for continuous measures. We
estimated the allele frequency of the B2 allele and apoE
alleles with a chromosome-counting method and used a
2 test to compare the frequency in men and
women. To evaluate the relation between the CETP genotypes and
lipid levels, we used ANCOVA techniques, which accounted for the
familial relations among the members of the study (mostly siblings and
cousins). We used 2 approaches to accomplish these analyses.
First, we used a repeated-measures approach, which assumed an
exchangeable correlation structure among all members of a family (PROC
MIXED, SAS). Second, because this approach does not accurately
represent the true correlation structure within these
pedigrees, we used a measured-genotype
approach,38 as implemented in SOLAR, a variance
component analysis computer package for quantitative traits
measured in pedigrees of arbitrary size.39 The latter
approach fully accounts for the different types of relations within a
pedigree in performing an ANOVA on the defined genotypes. In
these analyses, we used several different models to adjust for
potential confounders. First, we obtained essentially crude results,
which accounted only for the family structure; second, we adjusted for
age, body mass index (BMI), smoking, alcohol consumption, ß-blockers,
and (in women) menopausal status and hormonal replacement therapy. In
our final analysis, we added apoE genotypes to the
model with E2/E2 and E2/E3 in one group, E3/E4 and E4/E4 in another
group, and E3/E3 as the reference group. Subjects with E2/E4
genotypes, of which there were very few, were excluded.
A sensitivity analysis was carried out to estimate the validity and precision of the regression coefficients for the CETP genotypic variables when additional independent terms were included into the model. Because similar results were obtained for both sexes, data from men and women were analyzed together to improve statistical power. Regression coefficients and 95% CIs for B1B2 and B2B2 compared with B1B1 genotypes were calculated by fitting several linear regression models with dummy variables for categorical and interaction terms as follows: model 1, CETP genotype (B1B1, B1B2, and B2B2); model 2, model 1+sex; model 3, model 2+BMI; model 4, model 3+tobacco smoking (nonsmoker and smoker); model 5, model 4+alcohol consumption (consumption and no consumption); and model 6, model 5+apoE genotypes (E2, E3, and E4). In all cases, the first category was taken as a reference. Regression diagnostics were used to check the assumptions and to assess the accuracy of computations.
Finally, using a 2 analysis, we
estimated the odds of prevalent CHD at examination 5 for those with the
B1B2 or B2B2 genotypes relative to those with the B1B1
genotype. CHD includes myocardial infarction, angina pectoris,
and coronary insufficiency. To adjust this estimated odds ratio
for covariates, we used logistic regression. We also applied
generalized estimating equations with a logit link to account for the
correlation among the observations and obtained essentially the same
results. Hence, we report the results assuming independent
observations.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subject Characteristics
To investigate the frequency and phenotypic association of the TaqIB-CETP polymorphism at the population level, we analyzed a total of 2876 subjects (1411 males and 1505 females) who participated in the Framingham Offspring Study and for whom lipid values were available in the absence of lipid-altering medication. Table 1
provides a summary of the
demographic, genotypic, and biochemical characteristics of the
participants according to sex. The mean age of men and women at
examination was 51.6 and 51.2 years, respectively. Although a similar
proportion of men and women were smokers (23.4% and 22.8%,
respectively), male subjects smoked more cigarettes per day (5.8±12.5)
than did the female subjects (4.7±10.3, P<0.016), and over
half of the female participants (54.2%) were postmenopausal. There was
no significant difference in the frequency of the B2 allele between
men and women, and the distribution of alleles was
consistent with Hardy-Weinberg equilibrium. Alcohol
consumption, BMI, plasma LDL-C, total apoB, triglyceride,
and glucose levels were significantly higher in men than in women, and
total HDL-C, HDL2-C, and
HDL3-C concentrations were significantly higher
in female participants. The apoE genotypic distribution was similar in
men and women (P=0.398).
|
Association of TaqIB Polymorphism With
Variations in Plasma Levels of Lipids, Lipoproteins, Apolipoproteins,
and CETP Activity
Table 2 shows that in men and women,
the 3 genotype groups were equivalent with respect to age and
BMI. Male homozygotes for the B1 allele had lower HDL-C levels
(1.07±0.27 mmol/L) than did B1B2 (1.14±0.28 mmol/L) and
B2B2 (1.18±0.34 mmol/L) male subjects (P<0.001).
Likewise, female homozygotes for the B1 allele had lower HDL-C
levels (1.40±0.38 mmol/L) than did B1B2 (1.46±0.39 mmol/L)
and B2B2 (1.53±0.40 mmol/L) female subjects
(P<0.001). Similar associations were noted for apoA-I
values. The higher HDL-C levels associated with the B2 allele were
due to increases in HDL2-C and
HDL3-C subfractions. A significant association
was noted between the TaqIB genotype and CETP
activity. Male and female carriers of the B2 allele had
significantly lower CETP activity than did those homozygotes for the B1
allele. In both sexes, there were no statistically significant
differences among the genotype groups in the plasma levels of
total cholesterol, LDL-C, and apoB. These results were
confirmed by the variance component approach and revealed that
TaqIB accounts for 
1% of the variability in HDL-C.
|
To test the consistency of the association between the
CETP-TaqIB genotype and HDL-C levels, a sensitivity
linear regression analysis was carried out as described in
Methods. The Figure shows regression coefficients and
95% CIs for B1B2 and B2B2 compared with B1B1 genotypes when
each indicated variable was included into the linear regression
models (models 1 to 6). First, the only variables included were
dummies for the TaqIB genotype (model 1). This
genetic factor accounted for 1% of the variability of HDL-C
(P<0.001). The initial regression coefficients for B1B2 and
B2B2 after controlling for the effect of sex (model 2) were 0.06 (95%
CI 0.03 to 0.09) mmol/L (P<0.001) and 0.14 (95% CI
0.09 to 0.18) mmol/L (P<0.001), respectively. When
other variables were progressively added to the core model (BMI,
tobacco smoking, alcohol consumption, and apoE genotypes), only
slight variation of the initially estimated values for the regression
coefficients were observed, revealing an independent association of
TaqIB polymorphism with HDL-C levels with a strong
consistency no matter additional environmental or genetic
factor was considered. The final model explained 35% of the
variability of HDL-C in the population, and the regression coefficients
for B1B2 and B2B2 were 0.07 (95% CI 0.03 to 0.10) mmol/L and 0.14
(95% CI 0.09 to 0.18) mmol/L, respectively
(P<0.001).
|
To understand better the metabolic basis of the association
of higher HDL-C levels with the B2 allele in men and women, we
measured lipoprotein subclass profiles by using automated NMR
spectroscopy and observed that this association was specifically due to
a significant increase in the large HDL subfraction (8.8 to 13.0 nm).
In males, the HDL-C concentrations in this HDL subfraction were
0.31±0.27, 0.37±0.29, and 0.45±0.37 mmol/L for B1B1, B1B2, and
B2B2 subjects, respectively (P<0.001). No changes were
observed for the small and intermediate-sized HDL subfractions. These
data were consistent with an increase in HDL size in male
carriers of the B2 allele, as demonstrated by NMR (8.83±0.37,
8.92±0.40, and 8.98±0.45 nm for B1B1, B1B2, and B2B2 subjects,
respectively; P<0.001) as well as by an increase in the
HDL-C/apoA-I values (see Table 2
). In addition to the
genotype associations seen with the HDL subfractions, we
observed a significant association between this polymorphism and
LDL subfractions in men. The B2 allele was associated with
increased levels of the large LDL subfraction (1.77±0.89 and
1.94±0.88 mmol/L for B1B2 and B2B2, respectively) compared with
B1B1 subjects (1.64±0.86 mmol/L). Conversely, B1B1 men had
increased levels of the small LDL fraction (0.86±0.65 mmol/L)
compared with B1B2 (0.79±0.60 mmol/L) and B2B2 (0.80±0.65
mmol/L) men (P=0.031). Therefore, the B2 allele was
associated with increased particle size for HDL and LDL after
adjustment for familial relations, age, BMI, smoking, alcohol intake,
use of ß-blockers, and apoE genotype. In women, a similar
effect was noted with the large HDL subfraction. The concentrations
were 0.76±0.43, 0.81±0.42, and 0.87±0.44 for B1B1, B1B2, and B2B2
female subjects, respectively (P<0.001). The associations
between the B2 allele and LDL subfractions observed in men were not
detected in women. Consequently, an association between HDL particle
size and genotype, similar to that shown for men, was
demonstrated for women after adjustment for the variables indicated
above as well as for menopausal status and estrogen therapy. However,
no genotype differences were observed for LDL size.
CETP-TaqIB Genotype and Risk of CHD
To examine the associations of the TaqIB
polymorphism with CHD risk, we also included subjects on
lipid-lowering medications; CHD was present in 163 men and 62
women. When we examined CHD prevalence in men at examination 5 versus
the absence (B1B1) or presence of the B2 allele (B1B2 or B2B2) by
2 analysis, we demonstrated a
significantly (P=0.035) lower frequency of carriers of the
B2 allele (58.7% versus 70.6%) among those subjects with positive
CHD. Likewise, the odds ratio for CHD associated with the presence of
the B2 allele was 0.696 (95% CI 0.50 to 0.98, P=0.035).
After adjusting for age, BMI, systolic blood pressure,
diabetes, smoking, and alcohol consumption, this odds ratio remained at
0.700 (95% CI 0.46 to 1.05), but the statistical significance dropped
to P=0.090. After additional adjustment for the previous
factors plus ß-blocker use, cholesterol-lowering drugs,
total cholesterol, and HDL-C, the odds ratio was 0.735
(95% CI 0.46 to 1.162, P=0.188). These odds ratios were
similar after excluding those subjects on lipid-lowering medications
(data not shown). In women, we did not find any significant association
between the presence of the B2 allele and CHD risk by
2 analysis (75.8% versus 67.9%,
P=NS) or by logistic analysis (data not shown).
However, there were too few CHD cases to draw definitive conclusions
about the association between TaqIB polymorphism and CHD
risk in women.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the present study, we found an association of CETP-TaqIB polymorphism with HDL-C levels and apoA-I in men and with HDL-C in women. No statistically significant differences in other lipid levels were observed across TaqIB genotypes after controlling for familial relations, age, BMI, smoking, alcohol intake, use of ß-blockers, apoE genotype, and (in women) menopausal status and estrogen therapy. Moreover, we found that the B2 allele was significantly associated with an
30% lower risk of CHD, which was no longer statistically
significant after adjustment for multiple CHD risk factors, including
HDL-C levels, indicating that a proportion of this effect may be due to
the increased HDL-C levels associated with the presence of the B2
allele. This association with HDL-C has been previously reported in
several other studies.13 16 18 19 20 21 40 41 Some of them
also found significant associations with LDL-C or
triglyceride levels.13 21 42 In agreement with
some previous studies,16 20 21 43 we have found a
significant association between the CETP-TaqI B
polymorphism and CETP activity, with the B1 allele being
associated with increased activity compared with the B2 allele.
However, a lack of significant association between CETP activity and
TaqIB polymorphism has also been reported by other
investigators.14 The mechanism by which
TaqIB polymorphism may affect CETP activity or HDL-C
levels is not known. It is unlikely that this polymorphism located
in an intron represents a functional mutation. Given the
reported associations of the B2 allele with increased CETP mass
and/or activity, the most plausible explanation is that this
polymorphism is in linkage disequilibrium with a still unknown
functional mutation in the regulatory region of the CETP gene. The role of CETP in atherogenesis is still under debate.43 44 CETP may play a proatherogenic role, in view of the fact that it mediates a redistribution of plasma cholesterol from lipoproteins, which is associated with a protection against atherosclerosis, into the proatherogenic apoB-containing lipoproteins. This concept is also supported by the fact that animal species that are resistant to diet-induced atherosclerosis have little CETP activity. However, CETP mediates 1 of the steps in reverse cholesterol transport, an antiatherogenic process. The results of the present study support the concept that increased HDL-C levels resulting from lower CETP activity appear to be associated with a lower risk of CHD in male subjects.
Human and transgenic mouse experiments have shown that environmental factors play an important role in the modulation of CETP gene expression.45 Various studies in human populations have analyzed the possible interaction between some environmental factors and the CETP-TaqIB polymorphism on plasma HDL-C levels. In this regard, Kondo et al13 showed that the association of the CETP gene with HDL-C levels was present only in nonsmokers. In another study carried out in Finland,20 male smokers with the B2 allele tended to have HDL-C levels 10% lower than those levels of male smokers with the B1 allele, but this effect was not observed in women; thus, the authors also concluded that allele effects differed according to sex. Fumeron et al19 did not find an interaction with tobacco smoking, but they found an important interaction with alcohol consumption in the Etude Cas-Temoins de l’Infarctus du Myocarde (ECTIM) study. In the present study, when gene-environmental terms were tested, no statistically significant interactions of the TaqIB genotypes with alcohol consumption or tobacco smoking were found. This was also true in terms of apoE-CETP interactions. These observations allow us to conclude that the effect of this polymorphism on plasma HDL-C in this cohort seems statistically independent and uniform across several levels of these environmental factors, as well as across the different apoE alleles. The study of these gene-gene and gene-environmental interactions can provide an important basis for refining the predictive value of traditional epidemiological risk factors and for targeting intervention and prevention activities for high-risk individuals.
In addition to the reported associations between classical risk factors and TaqIB polymorphism, our results show that this genetic variant is significantly associated with differences in the distribution of lipoprotein subclasses as determined by NMR. The B2 allele was significantly associated in men and women with higher levels of the large, more antiatherogenic HDL subfraction.46 47 48 This effect is consistent with the fact that the B2 allele is associated with lower CETP activity and results in an increase of cholesteryl ester–enriched large-sized HDL, such as those found in CETP-deficient subjects. The findings from the NMR data are also supported by the increase in the HDL-C/apoA-I ratio that we found associated with the presence of the TaqIB2 allele. In addition to this effect, which was observed in men and women, we found significant effects for LDL subfraction distribution in men only. The B2 allele was associated with a less atherogenic LDL particle size distribution, consisting of decreased levels of the more atherogenic small LDL subfraction and increased levels of the less atherogenic large LDL.46 49 50 These effects were not significant in women. Therefore, the protective effects associated with the B2 allele in men may not only be due to quantitative changes in lipid profiles but may also be due to qualitative changes in particle composition, which are manifested as differences in size distribution. It is interesting to highlight that the B2 allele was not protective in women despite its association with higher HDL-C levels and increased HDL size. The most plausible explanation for this lack of effect could be the small number of CHD events in this group of women. However, one could speculate that the sex differences observed for the association between the B2 allele and CHD risk could be due to the fact that in men the B2 allele was associated with less atherogenic HDL and LDL subclass distributions, whereas in women no effect was observed in the LDL subfraction. These observations point out the relevant role of LDL subclass distribution as a predictor of CHD risk.
In summary, the present study, which was carried out in a large
population-based white cohort, supports the hypothesis that the CETP
gene locus, as examined with TaqIB polymorphism, plays a
significant role in determining HDL-C variability in men and women and
apoA-I levels and LDL size in men and accounts for 1% of the
variability in HDL-C. These associations translate into a less
atherogenic lipid profile in both sexes and a lower CHD risk in men.
Further studies need to be carried out to demonstrate whether the lower
CHD risk associated with this polymorphism is also found in
women.
|
Acknowledgments |
|---|
This study was supported by grants HL-54776 and National Institutes of Health/National Heart, Lung, and Blood Institute contract NO1–38038 and contract 53-K06-5-10 from the US Department of Agriculture Research Service.
Received September 10, 1999; accepted December 29, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Drayna D, Jarnagin AS, McLean J, Henzel W, Kohr W, Fielding C, Lawn R. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature. 1987;327:632–634.[Medline] [Order article via Infotrieve]
2. Bruce C, Chouinard RA Jr, Tall AR. Plasma lipid transfer proteins, high density lipoproteins, and reverse cholesterol transport. Annu Rev Nutr. 1998;18:297–330.[Medline] [Order article via Infotrieve]
3. Yamashita S, Sakai N, Hirano K, Arai T, Ishigami M, Maruyama T, Matsuzawa Y. Molecular genetics of plasma cholesteryl ester transfer protein. Curr Opin Lipidol. 1997;8:101–110.[Medline] [Order article via Infotrieve]
4. 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]
5. Koizumi J, Inazu A, Yagi K, Koizumi I, Uno Y, Kajinami K, Miyamoto S, Moulin P, Tall AR, Mabuchi H. Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency. Atherosclerosis. 1991;90:189–196.[Medline] [Order article via Infotrieve]
6. Takegoshi T, Haba T, Kitoh C, Inazu A, Koizumi J, Mabuchi H, Takeda R. Compound heterozygote of cholesteryl-ester transfer protein deficiency in a patient with hyperalphalipoproteinemia. Atherosclerosis. 1992;96:83–85.[Medline] [Order article via Infotrieve]
7. Inazu A, Jiang X-C, Haraki T, Yagi K, Kamon N, Koizumi J, Mabuchi H, Takeda R, Takata K, Moriyama Y. Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol. J Clin Invest. 1994;94:1872–1882.
8. Hill SA, Nazir DJ, Jayaratne P, Bamford KS, McQueen MJ. Mutations in cholesteryl ester transfer protein and hepatic lipase in a North American population. Clin Biochem. 1997;30:413–418.[Medline] [Order article via Infotrieve]
9. Tamminen M, Kakko S, Kesäniemi YA, Savolainen MJ. A polymorphic site in the 3' untranslated region of the cholesteryl ester transfer protein (CETP) gene is associated with low CETP activity. Atherosclerosis. 1996;124:237–247.[Medline] [Order article via Infotrieve]
10.
Drayna D, Lawn R. Multiple RFLPs at the human
cholesteryl ester transfer protein (CETP) locus. Nucleic Acids
Res. 1987;15:4698.
11.
Freeman D, Shepherd J, Packard CJ, Humphries SE,
Gaffney D. An StuI RFLP at the human cholesteryl ester transfer protein
(CETP) locus. Nucleic Acids Res. 1989;17:2880.
12.
Zuliani G, Hobbs HH. EcoNI polymorphism in the
human cholesteryl ester transfer protein (CETP) gene. Nucleic
Acids Res. 1990;18:2834.
13. Kondo I, Berg K, Drayna DT, Lawn RM. DNA polymorphism at the locus for human cholesteryl ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels. Clin Genet. 1989;35:49–56.[Medline] [Order article via Infotrieve]
14.
Freeman DJ, Griffin BA, Holmes AP, Lindsay GM, Gaffney
D, Packard CJ, Shepherd J. Regulation of plasma HDL
cholesterol and subfraction distribution by genetic and
environmental factors: associations between the TaqI B RFLP
in the CETP gene and smoking and obesity. Arterioscler
Thromb. 1994;14:336–344.
15. Hannuksela ML, Liinamaa MJ, Kesäniemi YA, Savolainen MJ. Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers. Atherosclerosis. 1994;110:35–44.[Medline] [Order article via Infotrieve]
16.
Kuivenhoven JA, de Knijff P, Boer JMA, Smalheer HA,
Botma GJ, Seidell JC, Kastelein JJ, Pritchard PH.
Heterogeneity at the CETP gene locus: influence on
plasma CETP concentrations and HDL cholesterol levels.
Arterioscler Thromb Vasc Biol. 1997;17:560–568.
17. Tenkanen H, Koskinen P, Kontula K, Aalto-Setälä K, Mänttäri M, Manninen V, Runeberg SL, Taskinen MR, Ehnholm C. Polymorphisms of the gene encoding cholesterol ester transfer protein and serum lipoprotein levels in subjects with and without coronary heart disease. Hum Genet. 1991;87:574–578.[Medline] [Order article via Infotrieve]
18. Mitchell RJ, Earl L, Williams J, Bisucci T, Gasiamis H. Polymorphisms of the gene coding for the cholesteryl ester transfer protein and plasma lipid levels in Italian and Greek migrants to Australia. Hum Biol. 1994;66:13–25.[Medline] [Order article via Infotrieve]
19. Fumeron F, Betoulle D, Luc G, Behague I, Ricard B, Poirier O, Jemaa R, Evans A, Arveiler D, Marques-Vidal P. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest. 1995;96:1664–1671.
20. Kauma H, Savolainen MJ, Heikkilä R, Rantala AO, Lilja M, Reunanen A, Kesaniemi YA. Sex difference in the regulation of plasma high density lipoprotein cholesterol by genetic and environmental factors. Hum Genet. 1996;97:156–162.[Medline] [Order article via Infotrieve]
21.
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.
22. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease: The Framingham Study. Am J Med. 1977;62:707–714.[Medline] [Order article via Infotrieve]
23. Gordon DJ, Rifkind BM. High-density lipoprotein: the clinical implications of recent studies. N Engl J Med. 1989;321:1311–1316.[Medline] [Order article via Infotrieve]
24.
Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP,
Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P. Lipid
alterations and decline in the incidence of coronary heart
disease in the Helsinki Heart Study. JAMA. 1988;260:641–651.
25. Feinleib M, Kannel WB, Garrison RJ, McNamara PM, Castelli WP. The Framingham Offspring Study: design and preliminary data. Prev Med. 1975;4:518–525.[Medline] [Order article via Infotrieve]
26.
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.
27. Dawber TR, Meadors GF, Moore R. Epidemiological approaches to heart disease: The Framingham Study. Am J Public Health. 1951;41:279–286.
28. Cupples LA, Gagnon DR, Kannel WB. Long- and short-term risk of sudden coronary death. Circulation. 1992;85:111–118.
29.
Warnick GR, Benderson J, Albers JJ. Dextran
sulfate-Mg2+ precipitation procedure for
quantitation of high-density-lipoprotein cholesterol.
Clin Chem. 1982;28:1379–1388.
30. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
31. McNamara JR, Schaefer EJ. Automated enzymatic standardized lipid analyses for plasma and apolipoprotein fractions. Clin Chim Acta. 1987;166:1–9.[Medline] [Order article via Infotrieve]
32. Schaefer EJ, Ordovas JM. Metabolism of the apolipoproteins A-I, A-II, and A-IV. In: Segrest J, Albers J, ed. Methods in Enzymology, Plasma Lipoproteins, Part B: Characterization, Cell Biology and Metabolism. New York, NY: Academic Press; 1986:420–442.
33. Ordovas JM, Peterson JP, Santaniello P, Cohn J, Wilson PWF, Schaefer EJ. Enzyme linked immunosorbent assay for human apolipoprotein B. J Lipid Res. 1987;28:1216.[Abstract]
34.
Otvos JD, Jeyarajah EJ, Bennett DW, Krauss RM.
Development of a proton nuclear magnetic resonance spectroscopic method
for determining plasma lipoprotein concentrations and subspecies
distributions from a single, rapid measurement. Clin Chem. 1992;38:1632–1638.
35. Otvos JD. Measurement of lipoprotein subclass profile by nuclear magnetic resonance. In: Rifai N, Warnick GR, Dominiczak MH, ed. Handbook of Lipoprotein Testing. Washington, DC: AACC Press; 1997:497–508.
36.
Miller SA, Dykes DD, Polesky HF. A simple salting out
procedure for extracting DNA from human nucleated cells. Nucleic
Acids Res. 1989;16:1215.
37. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–548.[Abstract]
38. Boerwinkle E, Utermann G. Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Am J Hum Genet. 1988;42:104–112.[Medline] [Order article via Infotrieve]
39. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62:1198–1211.[Medline] [Order article via Infotrieve]
40.
Bernard S, Moulin P, Lagrost L, Picard S, Elchebly M,
Ponsin G, Chapuis F, Berthezene F. Association between plasma
HDL-cholesterol concentration and TaqIB CETP gene
polymorphism in non-insulin-dependent diabetes mellitus. J
Lipid Res. 1998;39:59–65.
41. Freeman D, Packard CJ, Shepherd J, Gaffney D. Polymorphisms in the gene coding for cholesteryl ester transfer protein are related to plasma high density lipoprotein cholesterol and transfer ester activity. Clin Sci. 1990;79:575–581.[Medline] [Order article via Infotrieve]
42. Gudnason V, Kakko S, Nicaud V, Savolainen MJ, Kesaniemi YA, Thavanainen E, Humphries S. Cholesteryl ester transfer protein gene effect on CETP activity and plasma high density lipoprotein in European populations. Eur J Clin Invest. 1999;29:116–128.[Medline] [Order article via Infotrieve]
43. Fielding CG, Havel RJ. Cholesteryl ester transfer protein: friend or foe? J Clin Invest. 1996;97:2687–2688.[Medline] [Order article via Infotrieve]
44. Stevenson CG. Cholesterol ester transfer protein: a molecule with three faces? Crit Rev Clin Lab Sci.. 1998;35:517–546.[Medline] [Order article via Infotrieve]
45. Jiang XC, Agellon LB, Walsh A, Breslow JL, Tall A. Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice: dependence on natural flanking sequences. J Clin Invest. 1992;90:1290–1295.
46. Brunzell JD, Hokanson JE. Low-density and high-density lipoprotein subspecies and risk for premature coronary artery disease. Am J Med. 1999;107:16S–18S.[Medline] [Order article via Infotrieve]
47. Tailleux A, Fruchart JC. HDL heterogeneity and atherosclerosis. Crit Rev Clin Lab Sci. 1996;33:163–201.[Medline] [Order article via Infotrieve]
48.
Roheim PS, Asztalos BF. Clinical significance of
lipoprotein size and risk for coronary
atherosclerosis. Clin Chem. 1995;41:147–152.
49.
Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG,
Sacks FM, Hennekens CH. A prospective study of
triglycerides, low-density lipoprotein particle diameter,
and risk of myocardial infarction. JAMA. 1996;276:882–888.
50.
Gardner CD, Fortmann SP, Krauss RM. Association of
small low-density lipoprotein particles with the incidence of
coronary artery disease in men and women. JAMA. 1996;276:875–881.
This article has been cited by other articles:
 |
|
 |
|
  K. Musunuru, M. Orho-Melander, M. P. Caulfield, S. Li, W. A. Salameh, R. E. Reitz, G. Berglund, B. Hedblad, G. Engstrom, P. T. Williams, et al. Ion Mobility Analysis of Lipoprotein Subfractions Identifies Three Independent Axes of Cardiovascular Risk Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1975 - 1980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Y. Tsai, N. Li, A. R. Sharrett, S. Shea, D. R. Jacobs Jr, R. Tracy, D. Arnett, V. Arends, and W. Post Associations of Genetic Variants in ATP-Binding Cassette A1 and Cholesteryl Ester Transfer Protein and Differences in Lipoprotein Subclasses in the Multi-Ethnic Study of Atherosclerosis Clin. Chem., March 1, 2009; 55(3): 481 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Lambrinoudaki, G. Kaparos, D. Papadimitriou, T. N Sergentanis, M. Creatsa, A. Alexandrou, E. Logothetis, G. Christodoulakos, and E Kouskouni Methylenetetrahydrofolate reductase C677T polymorphism is associated with central adiposity and increased androgenicity in healthy postmenopausal women Eur. J. Endocrinol., September 1, 2008; 159(3): 233 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Thompson, E. Di Angelantonio, N. Sarwar, S. Erqou, D. Saleheen, R. P. F. Dullaart, B. Keavney, Z. Ye, and J. Danesh Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk JAMA, June 18, 2008; 299(23): 2777 - 2788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Frikke-Schmidt, B. G. Nordestgaard, M. C. A. Stene, A. A. Sethi, A. T. Remaley, P. Schnohr, P. Grande, and A. Tybjaerg-Hansen Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease JAMA, June 4, 2008; 299(21): 2524 - 2532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Porchay-Balderelli, F. Pean, N. Bellili, R. Jaziri, M. Marre, F. Fumeron, and for the DIABHYCAR Study Group The CETP TaqIB Polymorphism Is Associated With the Risk of Sudden Death in Type 2 Diabetic Patients Diabetes Care, November 1, 2007; 30(11): 2863 - 2867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Mukamal, R. H. Mackey, L. H. Kuller, R. P. Tracy, R. A. Kronmal, M. A. Mittleman, and D. S. Siscovick Alcohol Consumption and Lipoprotein Subclasses in Older Adults J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2559 - 2566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Shah Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease Eur. Heart J., January 1, 2007; 28(1): 5 - 12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Borggreve, H. L. Hillege, B. H. R. Wolffenbuttel, P. E. de Jong, M. W. Zuurman, G. van der Steege, A. van Tol, R. P. F. Dullaart, and 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., September 1, 2006; 91(9): 3382 - 3388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Barter and J. J.P. Kastelein Targeting Cholesteryl Ester Transfer Protein for the Prevention and Management of Cardiovascular Disease J. Am. Coll. Cardiol., February 7, 2006; 47(3): 492 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Krauss Dietary and Genetic Probes of Atherogenic Dyslipidemia Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2265 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Frisdal, A. H.E.M. Klerkx, W. L. Goff, M. W.T. Tanck, J.-P. Lagarde, J. W. Jukema, J. J.P. Kastelein, M. J. Chapman, and M. Guerin Functional interaction between -629C/A, -971G/A and -1337C/T polymorphisms in the CETP gene is a major determinant of promoter activity and plasma CETP concentration in the REGRESS Study Hum. Mol. Genet., September 15, 2005; 14(18): 2607 - 2618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Shearman, S. Demissie, L. A. Cupples, I. Peter, C. H. Schmid, J. M. Ordovas, M. E. Mendelsohn, and D. E. Housman Tobacco smoking, estrogen receptor {alpha} gene variation and small low density lipoprotein level Hum. Mol. Genet., August 15, 2005; 14(16): 2405 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Deguchi, N. M. Pecheniuk, D. J. Elias, P. M. Averell, and J. H. Griffin High-Density Lipoprotein Deficiency and Dyslipoproteinemia Associated With Venous Thrombosis in Men Circulation, August 9, 2005; 112(6): 893 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Yang, C.-Q. Lai, L. Parnell, L. A. Cupples, X. Adiconis, Y. Zhu, P. W. F. Wilson, D. E. Housman, A. M. Shearman, R. B. D'Agostino, et al. Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study J. Lipid Res., July 1, 2005; 46(7): 1416 - 1425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Festa, K. Williams, A. J.G. Hanley, J. D. Otvos, D. C. Goff, L. E. Wagenknecht, and S. M. Haffner Nuclear Magnetic Resonance Lipoprotein Abnormalities in Prediabetic Subjects in the Insulin Resistance Atherosclerosis Study Circulation, June 28, 2005; 111(25): 3465 - 3472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Tai, D. Corella, S. Demissie, L. A. Cupples, O. Coltell, E. J. Schaefer, K. L. Tucker, and J. M. Ordovas Polyunsaturated Fatty Acids Interact with the PPARA-L162V Polymorphism to Affect Plasma Triglyceride and Apolipoprotein C-III Concentrations in the Framingham Heart Study J. Nutr., March 1, 2005; 135(3): 397 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.M. Boekholdt, F.M. Sacks, J.W. Jukema, J. Shepherd, D.J. Freeman, A.D. McMahon, F. Cambien, V. Nicaud, G.J. de Grooth, P.J. Talmud, et al. 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, January 25, 2005; 111(3): 278 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. de Grooth, A. H. E. M. Klerkx, E. S. G. Stroes, A. F. H. Stalenhoef, J. J. P. Kastelein, and J. A. Kuivenhoven A review of CETP and its relation to atherosclerosis J. Lipid Res., November 1, 2004; 45(11): 1967 - 1974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ballantyne and V. Nambi Apolipoprotein A-I and high-density lipoprotein: Is this the beginning of the era of noninvasive angioplasty? J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1436 - 1438. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Keavney, A. Palmer, S. Parish, S. Clark, L. Youngman, J. Danesh, C. McKenzie, M. Delepine, M. Lathrop, R. Peto, et al. Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk Int. J. Epidemiol., October 1, 2004; 33(5): 1002 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Wolfe and D. J. Rader Cholesteryl Ester Transfer Protein and Coronary Artery Disease: An Observation With Therapeutic Implications Circulation, September 14, 2004; 110(11): 1338 - 1340. [Full Text] [PDF]
|
|
|
|
 |
|
 G. R Thompson Is good cholesterol always good? BMJ, August 28, 2004; 329(7464): 471 - 472. [Full Text] [PDF]
|
|
|
|
|
|
Y. Bosse, L. Perusse, and M.-C. Vohl Genetics of LDL particle heterogeneity: from genetic epidemiology to DNA-based variations J. Lipid Res., June 1, 2004; 45(6): 1008 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J J McCarthy, A Parker, R Salem, D J Moliterno, Q Wang, E F Plow, S Rao, G Shen, W J Rogers, L K Newby, et al. Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes J. Med. Genet., May 1, 2004; 41(5): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Brousseau, E. J. Schaefer, M. L. Wolfe, L. T. Bloedon, A. G. Digenio, R. W. Clark, J. P. Mancuso, and D. J. Rader Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol N. Engl. J. Med., April 8, 2004; 350(15): 1505 - 1515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.C. Shoulders, E.L. Jones, and R.P. Naoumova Genetics of familial combined hyperlipidemia and risk of coronary heart disease Hum. Mol. Genet., April 1, 2004; 13(90001): R149 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. de Grooth, K. E. Zerba, S.-P. Huang, Z. Tsuchihashi, T. Kirchgessner, R. Belder, P. Vishnupad, B. Hu, A. H. E. M. Klerkx, A. H. Zwinderman, et al. The cholesteryl ester transfer protein (CETP) TaqIB polymorphism in the cholesterol and recurrent events study: no interaction with the response to pravastatin therapy and no effects on cardiovascular outcome: A prospective analysis of the CETP TaqIB polymorphism on cardiovascular outcome and interaction with cholesterol-lowering therapy J. Am. Coll. Cardiol., March 3, 2004; 43(5): 854 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J Freeman, N. J Samani, V. Wilson, A. D McMahon, P. S Braund, S. Cheng, M. J Caslake, C. J Packard, D. Gaffney, and on behalf of the West of Scotland Study Group A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study Eur. Heart J., October 2, 2003; 24(20): 1833 - 1842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Boekholdt and J. F. Thompson Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease J. Lipid Res., July 1, 2003; 44(6): 1080 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Blankenberg, H. J. Rupprecht, C. Bickel, X.-C. Jiang, O. Poirier, K. J. Lackner, J.u. Meyer, F. Cambien, L. Tiret, and AtheroGene Investigators 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., June 4, 2003; 41(11): 1983 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Anderson and J. F. Carlquist Genetic polymorphisms of hepatic lipase and cholesteryl ester transfer protein, intermediate phenotypes, and coronary risk: Do they add up yet? J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1990 - 1993. [Full Text] [PDF]
|
|
|
|
|
|
D. Osgood, D. Corella, S. Demissie, L. A. Cupples, P. W. F. Wilson, J. B. Meigs, E. J. Schaefer, O. Coltell, and J. M. Ordovas Genetic Variation at the Scavenger Receptor Class B Type I Gene Locus Determines Plasma Lipoprotein Concentrations and Particle Size and Interacts with Type 2 Diabetes: The Framingham Study J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2869 - 2879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Lottenberg, V. S. Nunes, E. R. Nakandakare, M. Neves, M. Bernik, L. Lagrost, J. E. dos Santos, and E. Quintao The Human Cholesteryl Ester Transfer Protein I405V Polymorphism Is Associated with Plasma Cholesterol Concentration and Its Reduction by Dietary Phytosterol Esters J. Nutr., June 1, 2003; 133(6): 1800 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Bosse, L. Perusse, J.-P. Despres, B. Lamarche, Y. C. Chagnon, T. Rice, D.C. Rao, C. Bouchard, and M.-C. Vohl Evidence for a Major Quantitative Trait Locus on Chromosome 17q21 Affecting Low-Density Lipoprotein Peak Particle Diameter Circulation, May 13, 2003; 107(18): 2361 - 2368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. V. van Venrooij, R. P. Stolk, J.-D. Banga, T. P. Sijmonsma, A. van Tol, D. W. Erkelens, and G. M. Dallinga-Thie Common Cholesteryl Ester Transfer Protein Gene Polymorphisms and the Effect of Atorvastatin Therapy in Type 2 Diabetes Diabetes Care, April 1, 2003; 26(4): 1216 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barter, H. B. Brewer Jr, M. J. Chapman, C. H. Hennekens, D. J. Rader, and A. R. Tall Cholesteryl Ester Transfer Protein: A Novel Target for Raising HDL and Inhibiting Atherosclerosis Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 160 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H.E.M. Klerkx, M. W.T. Tanck, J. J.P. Kastelein, H. O.F. Molhuizen, J. W. Jukema, A. H. Zwinderman, and J. A. Kuivenhoven 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., January 15, 2003; 12(2): 111 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Brousseau, J. J. O'Connor Jr, J. M. Ordovas, D. Collins, J. D. Otvos, T. Massov, J. R. McNamara, H. B. Rubins, S. J. Robins, and E. J. Schaefer 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, July 1, 2002; 22(7): 1148 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.S. Tai, S. Demissie, L.A. Cupples, D. Corella, P.W. Wilson, E.J. Schaefer, and J.M. Ordovas Association Between the PPARA L162V Polymorphism and Plasma Lipid Levels: The Framingham Offspring Study Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 805 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.C. Carr, A.F. Ayyobi, S.J. Murdoch, S.S. Deeb, and J.D. Brunzell Contribution of Hepatic Lipase, Lipoprotein Lipase, and Cholesteryl Ester Transfer Protein to LDL and HDL Heterogeneity in Healthy Women Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 667 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J Schaefer Lipoproteins, nutrition, and heart disease Am. J. Clinical Nutrition, February 1, 2002; 75(2): 191 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. von Eckardstein, J.-R. Nofer, and G. Assmann High Density Lipoproteins and Arteriosclerosis : Role of Cholesterol Efflux and Reverse Cholesterol Transport Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 13 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.C. Carr, A.F. Ayyobi, S.J. Murdoch, S.S. Deeb, and J.D. Brunzell Contribution of Hepatic Lipase, Lipoprotein Lipase, and Cholesteryl Ester Transfer Protein to LDL and HDL Heterogeneity in Healthy Women Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 667 - 673. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||