(Circulation. 2000;101:1907.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
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
From the Department of Clinical Biochemistry (B.A.-L., A.T.-H.), Herlev University Hospital, University of Copenhagen, Herlev, Denmark; Department of Clinical Biochemistry (B.G.N.), Glostrup University Hospital, University of Copenhagen, Glostrup, Denmark; The Copenhagen City Heart Study (B.G.N., G.J., A.T.-H.), Bispebjerg University Hospital, University of Copenhagen, Copenhagen NV, Denmark; and Department of Medicine B (R.S.), Division of Cardiology, Rigshospitalet, National University Hospital, University of Copenhagen, Copenhagen, Denmark.
Correspondence to Anne Tybjærg-Hansen, MD, DMSc, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail at-h{at}rh.dk
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The level of HDL cholesterol is inversely related to the risk of ischemic heart disease.
Methods and Results—In 9168 women and men from a general population and 946 women and men with ischemic heart disease (all white), we tested the hypothesis that the Ile405Val mutation in the cholesteryl ester transfer protein gene (CETP) affects HDL cholesterol levels and the risk of ischemic heart disease. The relative frequencies of Ile/Ile, Ile/Val, and Val/Val carriers were 0.46, 0.43, and 0.11 for both women and men. Women with these 3 genotypes had mean HDL cholesterol levels of 1.68, 1.75, and 1.82 mmol/L, respectively (P<0.001, ANOVA), as well as a significant decrease in the ratio of total to HDL cholesterol (P=0.002, ANOVA). On multiple logistic regression analysis, women not treated with hormone replacement therapy who were heterozygous or homozygous for Val405 had a 1.4-fold (95% CI 1.0 to 1.9) to 2.1-fold (95% CI 1.3 to 3.4) increase in the risk of ischemic heart disease. No significant associations were found in men.
Conclusions—Increased HDL cholesterol levels caused by mutations in CETP are associated with an increased risk of ischemic heart disease in white women.
Key Words: transfer proteins • genetics • lipoproteins • heart diseases • apolipoproteins
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
There is a strong inverse relationship between plasma HDL cholesterol levels and the risk of ischemic heart disease risk (IHD).1 2 Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins.3 4 This stimulates reverse cholesterol transport (ie, the transport of cholesterol from peripheral cells to the liver for excretion).2 3 A genetic deficiency in CETP is associated with marked increases in HDL cholesterol levels in homozygotes and with moderate increases in heterozygotes.4 5 6 7 Although CETP deficiency might be an antiatherogenic state, due to HDL cholesterol elevation, the role of CETP in reverse cholesterol transport suggests the opposite.4 5
The common Ile405Val mutation in CETP is associated with a stepwise decrease in CETP activity in whites.8 We studied the effect of this mutation on lipid, lipoprotein, and apolipoprotein levels and on the risk of IHD in 5069 women and 4099 men from a general white population sample and in 946 patients with IHD.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
General Population Sample
We recruited 5069 women and 4099 men who participated in the Copenhagen City Heart Study from 1991 through 1994.9 10 11 12 13 14 15 16 Participants were stratified into 10-year age groups from 20 to
80
years and were drawn randomly from the Copenhagen Central Population
Register, with the aim of obtaining a representative
sample of the adult Danish general population. Participants were
screened for manifestations of IHD through a review of all hospital
admissions and diagnoses entered into the Danish National Hospital
Discharge Register: the diagnoses were based on the World Health
Organization International Classification of Diseases, eighth revision
(IHD codes 410 through 414).
Patients With IHD
From the general population sample, 500 subjects (177 women and
323 men) with IHD were identified. In addition, among 992 consecutive
Danish patients referred for coronary angiography from 1991
through 1993, 946 patients with IHD (247 women and 699 men) were
identified.9 12 13 14 16 The diagnosis was based on
characteristic symptoms of stable angina pectoris according to the
guidelines of the European Society of
Cardiology,17 including location,
character, and duration of pain and the relation of pain to exercise
plus at least 1 of the following: severe stenosis on
coronary angiography (70% stenosis of at least 1
coronary artery or 50% stenosis of the left main
coronary artery), a previous myocardial infarction, or a
positive exercise ECG test.
More than 99% of participants in this study were white and of Danish descent. The study was approved by Danish ethical committees 100.2039/91 and KA 93125.
DNA Analysis
The substitution of valine for isoleucine is caused by
an A
G mutation at codon 405 in exon 14 of the CETP gene
on chromosome 16. Exon 14 was amplified by PCR with primers located in
intron 13 (5'-AATGCTTGTCCAGGCCGTGCAGCAT-3') and in intron 14
(5'-CAGTTTCCCCTCCAGCC-CACACTTA-3'). The PCR product was digested
with FokI, followed by 2% agarose gel electrophoresis. This
resulted in bands of 35 and 85 bp for the A allele, a 120-bp band
for the G allele, and a common band of 55 bp.
Other Analyses
Colorimetric and turbidimetric assays were used
to measure plasma levels of total cholesterol, HDL
cholesterol, triglycerides, apoA-I, apoB (all
from Boehringer-Mannheim), and Lp(a) (DAKO). LDL
cholesterol levels were calculated as total
cholesterol-HDL
cholesterol-(triglycerides/2.2) (all in mmol/L).
Statistical Analysis
Statistical analyses were separately performed for each
sex with SPSS software.18 A P value on a
2-sided test of <0.05 for group comparisons and <0.10 for interaction
tests was considered statistically significant.
2 tests were used to compare genotype
frequencies in different groups. ANOVA or Kruskal-Wallis ANOVA (for
unequal variances) was used to evaluate the
heterogeneity of levels of lipids, lipoproteins, and
apolipoproteins across CETP genotypes. Student’s
t test or Mann-Whitney U test was used as a
post-hoc test for 2-genotype comparisons. We used Levene’s
test to examine the homogeneity of variance. The interaction between
CETP genotype and cholesterol, apoB, HDL
cholesterol, apoA-I, triglycerides, Lp(a), body
mass index, waist/hip ratio, glucose, wine consumption, 10-year age
groups, hypertension, diuretic use, diabetes mellitus, smoking,
physical activity, menopausal status (women), and hormone replacement
therapy (HRT; women) in the prediction of levels of lipids,
lipoproteins, and apolipoproteins was tested through the introduction,
1 at a time, for all possible 2-factor interaction terms in an ANCOVA
model that already included genotype and the covariate in
question. Evidence of interaction was further explored through division
of the interacting covariate into categorical groups, tertiles, or
quintiles, followed by tests of homogeneity of mean values across the 3
genotypes. In case of heterogeneity of variance
between groups when testing for interaction, the dependent variable
was weighted by the inverse variance.
Logistic regression analysis, with an allowance for age only, age and HDL cholesterol quintiles, or a group of known cardiovascular risk factors (age, cholesterol, body mass index, lipid-lowering medication, hypertension, diabetes mellitus, and smoking) plus HDL quintiles, was used to explore the impact of CETP genotype on the risk of IHD. Interaction between CETP genotype and the above-mentioned covariates was explored in logistic regression models that included CETP genotype, the risk factor in question, and an interaction term of these 2 factors; the likelihood ratio test between complete and reduced models was used to determine statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The basic characteristics of the subjects have been reported previously.9 11 12
CETP Genotype Frequencies
The relative CETP genotype frequencies in this
white Danish general population sample were 0.46 for Ile/Ile, 0.43 for
Ile/Val, and 0.11 for Val/Val. These frequencies did not differ
significantly from those predicted with the Hardy-Weinberg equilibrium
(P>0.70, 2) and did not differ
between women and men (P=1.00,
2).
Lipids, Lipoproteins, and Apolipoproteins as a Function of
CETP Genotype
In the general population sample, there was a stepwise increase in
HDL cholesterol levels, apoA-I, and HDL
cholesterol/apoA-I ratio from Ile/Ile to Ile/Val to Val/Val
in women (P<0.001, all ANOVA) but not in men (Table 1
). For HDL cholesterol, this
pattern was confirmed in the same individuals with the use of levels
measured 10 years earlier. With post-hoc tests, both Ile/Val and
Val/Val carriers had higher levels of HDL cholesterol,
apoA-I, and HDL cholesterol/apoA-I ratio than did female
Ile/Ile carriers. Plasma levels of triglycerides,
cholesterol, apoB, and Lp(a) were unaffected by Ile405Val
genotype.
|
Furthermore, the relative frequency of subjects heterozygous or
homozygous for Val405 increased significantly as a function of HDL
cholesterol level in quintiles in women
(P<0.001, 2) but not in men
(P=0.55, 2) (data not shown).
In women, the total cholesterol/HDL cholesterol
ratio was highest in noncarriers for Val405, intermediate for
heterozygous carriers of Val405, and lowest for homozygous carriers of
Val405 (P=0.002, ANOVA), whereas this ratio was unaffected
by genotype in men (P=0.56, ANOVA) (Table 1
).
Interaction With Other Cardiovascular Risk
Factors
In women, the interaction of CETP genotype with
HRT had an affect on HDL cholesterol levels
(P=0.08): the genotype affected HDL
cholesterol levels of premenopausal women
(P=0.005, ANOVA) and of postmenopausal women who were not
treated with HRT (P<0.001, ANOVA) but not of postmenopausal
women who were treated with HRT (P=0.80, ANOVA) (Figure 1). The use of HRT also reduced levels of
LDL cholesterol, apoB, and Lp(a) in postmenopausal women
(Table 2).
|
|
In men, there was an interaction between CETP
genotype and plasma triglycerides on HDL
cholesterol (P=0.09). As suggested in an earlier
study of Japanese men,19 the interaction was due to a
borderline significantly higher HDL cholesterol level in
homozygous VV men compared with IV and II men among those with
triglyceride levels of >1.86 mmol/L but not in those
with triglyceride levels of <1.86 mmol/L (Figure 1).
CETP Genotype and Risk of IHD
CETP genotype interacted with HRT on IHD risk
(P<0.05). In premenopausal women and postmenopausal women
without HRT, when age was allowed for, the odds ratio (OR) for the risk
of IHD for Ile/Val and Val/Val versus Ile/Ile was 1.21 (95% CI 0.90 to
1.62), and 1.65 (95% CI 1.06 to 2.58), respectively (Figure 2). This was even more pronounced when in
addition to age, the analyses allowed for HDL
cholesterol levels in quintiles (OR 1.36, 95% CI 1.00 to
1.83; OR 1.89, 95% CI 1.20 to 2.98) or for HDL cholesterol
in quintiles plus a group of known cardiovascular risk
factors (OR 1.38, 95% CI 1.01 to 1.90; OR 2.07, 95% CI 1.27 to 3.37).
In contrast, in postmenopausal women treated with HRT, there was no
effect of genotype on risk of IHD (Figure 2). In men,
there was no effect of genotype on risk of IHD (Figure 2).
|
The effects shown in Figure 2 are based on all subjects with IHD
versus all subjects without IHD (case-control design). However, in
other study designs that we have previously used, the results or trends
were similar (ie, showing an effect of genotype on risk of IHD
only in women): (1) patients with IHD versus the total general
population sample (case-referent design)9 12 13 14 or (2)
subjects in the general population sample with IHD versus those without
(cross-sectional design).9 11
In women, the association between carrying the valine allele and an
increased risk of IHD was most pronounced in the upper tertiles of LDL,
apoB, and Lp(a), whereas the middle and lower tertiles, which included
relatively fewer patients, showed similar, although not statistically
significant, trends (Figure 3). These
results were supported by a lack of interaction between
genotype and LDL cholesterol, apoB, or Lp(a) on
risk of IHD in women. In men, there was no association between
genotype and risk of IHD in tertiles of either LDL, apoB, or
Lp(a) (Figure 3), with the exception of an apparently increased
risk in heterozygote men in the middle tertile of apoB, suggesting a
chance effect.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We report that the common Ile405Val mutation in the CETP gene, despite being associated with increased levels of HDL cholesterol, is an independent risk factor for IHD in white women who are not treated with HRT. The evidence is based on genotyping of 10 114 women and men, of whom 1446 had IHD and the control subjects were from a general population sample.
Effect on HDL Cholesterol
Previous studies found that homozygosity for Val405 was associated
with increased HDL cholesterol levels in 234 Dutch
men,20 in 145 Icelandic men,21 and in 102
Japanese men with
hypertriglyceridemia.19 We
extended these findings in a large general population sample to
demonstrate that HDL cholesterol level increases in both
homozygotes and heterozygotes of Val405 in premenopausal women and in
postmenopausal women not treated with HRT, whereas in
hypertriglyceridemic men, only Val/Val
homozygosity is associated with increased HDL cholesterol.
In accordance with a previous study,21 we also observed an
apoA-I–raising effect of the Val405 allele in women.
Mechanistically, it seems plausible that the Ile405Val mutation in CETP will affect levels of HDL cholesterol and apoA-I, the major protein in HDL particles. Complete CETP deficiency as seen in the Japanese leads to massively elevated levels of HDL cholesterol and apoA-I,22 23 24 25 and previous studies have demonstrated that the Ile405Val mutation leads to reduced CETP mass19 20 and activity8 in plasma. After HDL particles accept cholesterol from nonliver cells, CETP facilitates the transfer of cholesteryl ester onto triglyceride-rich lipoproteins as part of the reverse cholesterol transport pathway, ultimately leading to cholesterol excretion by the liver.2 3 When CETP is dysfunctional, cholesterol accumulates in HDL, and the transfer of cholesterol from peripheral cells to the liver is blocked. In accordance with this, our data suggest the presence of both an increased number of HDL particles (elevated HDL cholesterol and apoA-I) and cholesterol enrichment of HDL particles (elevated HDL cholesterol/apoA-I ratio) for both heterozygous and homozygous female carriers of the Ile405Val mutation. Because apoA-I is found only in HDL and chylomicrons,26 the effects we observed on apoA-I most likely reflect changes in levels of apoA-I in HDL.
In women, the interaction between CETP genotype and HRT on HDL cholesterol seems biologically plausible. In accordance with previous studies,27 28 29 HRT raised HDL cholesterol levels in women in the Copenhagen City Heart Study, and therefore it is possible that the HRT effect on HDL cholesterol overrides that of CETP genotype. In men, an interaction between CETP genotype and plasma triglyceride levels on HDL cholesterol was previously observed.19 CETP exchanges cholesterol in HDL for triglycerides in triglyceride-rich lipoproteins, making it plausible that the effect of CETP genotype on HDL cholesterol is seen only in men with high triglyceride levels, a situation in which the rate-limiting factor in cholesteryl ester transfer is in fact CETP.19
Effect on IHD Risk
The most important novel observation in the present study is
the clear codominant pattern of increased risk of IHD from Ile/Ile to
Ile/Val to Val/Val in untreated white women. This is supported by
similar, but less clear and less significant, results of an earlier
study of hypertriglyceridemic men of
Japanese descent19 and of men of Japanese descent with the
Asp442Gly mutation in CETP.30
It is quite likely that a genetic deficiency of CETP caused by mutations like Ile405Val affects IHD risk. CETP is essential in the reverse cholesterol transport pathway, the main route by which the body can eliminate excess cholesterol.2 3 Dysfunctional CETP that causes reduced reverse cholesterol transport is reflected as an increase in HDL cholesterol levels, suggesting that cholesterol may also accumulate in the arterial intima, ultimately leading to increased risk of atherosclerosis and IHD.
The effect of the interaction between CETP genotype
and HRT on IHD risk may reflect the corresponding effect of the
interaction between CETP genotype and HRT on HDL
cholesterol levels. If HRT overrides the effect of
CETP genotype on HDL cholesterol, it is
equally possible that HRT may override the effect of CETP
genotype on IHD risk. This apparent
cardiovascular protective effect of estrogens in
postmenopausal women treated with HRT may also reflect the known
effects of HRT to reduce LDL cholesterol, apoB, and Lp(a)
concentrations, effects that were also found in the Copenhagen City
Heart Study (Table 2).
Sex-Specific Effects
Sex-specific effects of the CETP Ile405Val
polymorphism on plasma levels of HDL cholesterol and
risk of IHD are interesting but not easy to explain biologically. It is
well known, however, that men develop IHD at an earlier age than women
and that HDL cholesterol levels are lower in men than in
women. A priori, we stratified the data analyses by sex and
observed that the effects of the Ile405Val mutation on HDL
cholesterol, apoA-I, and IHD risk differed between women
and men. In accordance with this, CETP genotype and
sex interacted on HDL cholesterol (P=0.001) and
apoA-I (P<0.001) but not on IHD risk (P=0.35).
Because CETP levels appear to be higher in women than in
men31 and because CETP levels are raised in late
pregnancy in parallel with estrogen elevation,32 although
testosterone administration to both women and men does not appear to
affect CETP levels,33 34 it is not unlikely that the
effects of mutations in CETP will influence lipoprotein
metabolism and IHD risk differently in women and men.
Although the risk of IHD was increased only modestly at the level of the individual, the Ile405Val mutation may be important for the total risk of IHD in untreated women in the population at large. It can be calculated35 based on our data that 24% of female IHD risk can be attributed to this mutation in CETP, an attributable risk similar in magnitude to that of a conventional cardiovascular risk factor such as hypertension in our sample. This must be confirmed in other independent studies but nevertheless suggests that genetic variability in CETP may explain a large proportion of the genetic component of IHD risk in the population at large.
In conclusion, our data suggest that increased HDL cholesterol levels caused by mutations in CETP may be associated with an increased risk of IHD in white women and that the clinical use of the ratio of total to HDL cholesterol as a risk indicator may be misleading in persons with CETP mutations.
|
Acknowledgments |
|---|
This work was supported by Johann and Hanne Weimann’s Fund, The Danish Heart Foundation, The Danish Medical Research Council, The Danish Research Academy, Copenhagen County, and Chief Physician Johan Boserup and Lise Boserup’s Fund.
Received June 25, 1999; revision received October 28, 1999; accepted November 19, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. 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.
2. Barter PJ, Rye KA. High density lipoproteins and coronary heart disease. Atherosclerosis. 1996;121:1–12.[Medline] [Order article via Infotrieve]
3. Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Stanbury JB, Wyngaarden JB, Frederickson DS, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, NY: McGraw-Hill; 1995:2031–2052.
4. Bruce C, Chouinard RAJ, 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]
5. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34:1255–1274.[Medline] [Order article via Infotrieve]
6. Takahashi K, Jiang XC, Sakai N, Yamashita S, Hirano K, Bujo H, Yamazaki H, Kusunoki J, Miura T, Kussie P, Matsuzawa Y, Saito Y, Tall A. A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins. J Clin Invest. 1993;92:2060–2064.
7. 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]
8. Gudnason V, Kakko S, Nicaud V, Savolainen MJ, Kesaniemi YA, Tahvanainen E, Humphries SE. 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]
9.
Agerholm-Larsen B, Nordestgaard BG, Steffensen R,
Sørensen TI, Jensen, G, Tybjærg-Hansen A. ACE gene polymorphism:
ischemic heart disease and longevity in 10,150 individuals: a
case-referent and retrospective cohort study based on the Copenhagen
City Heart Study. Circulation. 1997;95:2358–2367.
10.
Agerholm-Larsen B, Tybjærg-Hansen A, Frikke-Schmidt R,
Grønholdt M-LM, Jensen G, Nordestgaard BG. ACE gene polymorphism
as a risk factor for ischemic cerebrovascular disease.
Ann Intern Med. 1997;127:346–355.
11.
Tybjærg-Hansen A, Agerholm-Larsen B, Humphries SE,
Abildgaard S, Schnohr P, Nordestgaard BG. A common mutation (G-455A)
in the beta-fibrinogen promoter is an independent predictor of plasma
fibrinogen, but not of ischemic heart disease: a study of 9,127
individuals based on the Copenhagen City Heart Study. J Clin
Invest. 1997;99:3034–3039.[Medline]
[Order article via Infotrieve]
12. Wittrup HH, Tybjærg-Hansen A, Abildgaard S, Steffensen R, Schnohr P, Nordestgaard BG. A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease. J Clin Invest. 1997;99:1606–1613.[Medline] [Order article via Infotrieve]
13.
Tybjærg-Hansen A, Steffensen R, Meinertz H, Schnohr P,
Nordestgaard BG. Association of mutations in the apolipoprotein B gene
with hypercholesterolemia and the risk of
ischemic heart disease. N Engl J Med. 1998;338:1577–1584.
14.
Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen
R, Jensen G, Tybjærg-Hansen A. Heterozygous lipoprotein lipase
deficiency: frequency in the general population, effect on plasma lipid
levels, and risk of ischemic heart disease.
Circulation. 1997;96:1737–1744.
15. Dahl M, Tybjærg-Hansen A, Lange P, Nordestgaard BG. DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet. 1998;351:1911–1913.[Medline] [Order article via Infotrieve]
16. Nordestgaard BG, Agerholm-Larsen B, Wittrup HH, Tybjærg-Hansen A. A prospective cardiovascular population study used in genetic epidemiology: the Copenhagen City Heart Study. Scand J Clin Lab Invest Suppl. 1996;226:65–71.[Medline] [Order article via Infotrieve]
17.
Recommendations of the Task Force of the European
Society of Cardiology. Management of stable angina
pectoris. Eur Heart J. 1997;18:394–413.
18. SPSS for Windows. Base System User’s Guide and Advanced Statistics, Release 70. Chicago, Ill: SPSS, Inc; 1996.
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.
20.
Kuivenhoven JA, de Knijff P, Boer JM, 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.
21. Gudnason V, Thormar K, Humphries SE. Interaction of the cholesteryl ester transfer protein I405V polymorphism with alcohol consumption in smoking and non-smoking healthy men, and the effect on plasma HDL cholesterol and apoAI concentration. Clin Genet. 1997;51:15–21.[Medline] [Order article via Infotrieve]
22. Yamashita S, Hui DY, Sprecher DL, Matsuzawa Y, Sakai N, Tarui S, Kaplan D, Wetterau JR, Harmony JA. Total deficiency of plasma cholesteryl ester transfer protein in subjects homozygous and heterozygous for the intron 14 splicing defect. Biochem Biophys Res Commun. 1990;170:1346–1351.[Medline] [Order article via Infotrieve]
23. Makita H, Tsuji M, Furuya Y, Tsuchihashi K, Akita H, Chiba H. A family with complete deficiency of plasma cholesteryl ester transfer protein activities. Intern Med. 1994;33:432–436.[Medline] [Order article via Infotrieve]
24. Matsunaga A, Araki K, Moriyama K, Handa K, Arakawa F, Nishi K, Sasaki J, Arakawa K. Detection of a point mutation in cholesteryl ester transfer protein gene by polymerase chain reaction-mediated site-directed mutagenesis. Biochim Biophys Acta. 1993;1166:131–134.[Medline] [Order article via Infotrieve]
25.
Hirano K, 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.
26. Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Stanbury JB, Wyngaarden JB, Frederickson DS, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, NY: McGraw-Hill; 1995:1841–1851.
27.
Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu
KK, Szklo M. Association of hormone-replacement therapy with various
cardiovascular risk factors in postmenopausal women:
the Atherosclerosis Risk in Communities Study
Investigators. N Engl J Med. 1993;328:1069–1075.
28.
Manolio TA, Furberg CD, Shemanski L, Psaty BM, O’Leary
DH, Tracy RP, Bush TL. Associations of postmenopausal estrogen use with
cardiovascular disease and its risk factors in older
women: the CHS Collaborative Research Group. Circulation. 1993;88:2163–2171.
29.
The Writing Group for the PEPI trial. Effects of
estrogen or estrogen/progestin regimens on heart disease risk factors
in postmenopausal women: the Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial. JAMA. 1995;273:199–208.
30. 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.[Medline] [Order article via Infotrieve]
31. Marcel YL, McPherson R, Hogue M, Czarnecka H, Zawadzki Z, Weech PK, Whitlock ME, Tall AR, Milne RW. Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects. J Clin Invest. 1990;85:10–17.
32. Silliman K, Tall AR, Kretchmer N, Forte TM. Unusual high-density lipoprotein subclass distribution during late pregnancy. Metab Clin Exp. 1993;42:1592–1599.
33. Tan KC, Shiu SW, Pang RW, Kung AW. Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins. Clin Endocrinol. 1998;48:187–194.[Medline] [Order article via Infotrieve]
34. Buckler HM, McElhone K, Durrington PN, Mackness MI, Ludlam CA, Wu FCW. The effects of low-dose testosterone treatment on lipid metabolism, clotting factors and ultrasonographic ovarian morphology in women. Clin Endocrinol. 1998;49:173–178.[Medline] [Order article via Infotrieve]
35. Khoury MJ, Beaty TH, Cohen BH. Fundamental epidemiologic concepts and approaches. In: Kelsey JL, Marmot MG, Stolley PD, Vessey MP, eds. Fundamentals of Genetic Epidemiology. New York, NY: Oxford University Press; 1993:77–79.
This article has been cited by other articles:
 |
|
 |
|
  R. S. Vasan, M. J. Pencina, S. J. Robins, J. P. Zachariah, G. Kaur, R. B. D'Agostino, and J. M. Ordovas Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community Circulation, December 15, 2009; 120(24): 2414 - 2420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah The Yin and Yang of Cholesteryl Ester Transfer Protein in Cardiovascular Disease Circulation, December 15, 2009; 120(24): 2408 - 2410. [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Johannsen, P. R. Kamstrup, R. V. Andersen, G. B. Jensen, H. Sillesen, A. Tybjaerg-Hansen, and B. G. Nordestgaard Hepatic Lipase, Genetically Elevated High-Density Lipoprotein, and Risk of Ischemic Cardiovascular Disease J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1264 - 1273. [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]
|
|
|
|
 |
|
 P. Sritara, P. Patoomanunt, M. Woodward, K. Narksawat, S. Tulyadachanon, W. Ratanachaiwong, C. Sritara, F. Barzi, S. Yamwong, and S. Tanomsup Associations Between Serum Lipids and Causes of Mortality in a Cohort of 3499 Urban Thais: The Electricity Generating Authority of Thailand (EGAT) Study Angiology, January 1, 2008; 58(6): 757 - 763. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Frikke-Schmidt, B. G. Nordestgaard, G. B. Jensen, R. Steffensen, and A. Tybjaerg-Hansen Genetic Variation in ABCA1 Predicts Ischemic Heart Disease in the General Population Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 180 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. G. Nordestgaard, M. Benn, P. Schnohr, and A. Tybjaerg-Hansen Nonfasting Triglycerides and Risk of Myocardial Infarction, Ischemic Heart Disease, and Death in Men and Women JAMA, July 18, 2007; 298(3): 299 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Morehouse, E. D. Sugarman, P.-A. Bourassa, T. M. Sand, F. Zimetti, F. Gao, G. H. Rothblat, and A. J. Milici Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits J. Lipid Res., June 1, 2007; 48(6): 1263 - 1272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Horne, N. J. Camp, J. L. Anderson, C. P. Mower, J. L. Clarke, M. J. Kolek, J. F. Carlquist, and for the Intermountain Heart Collaborative Study Gr Multiple Less Common Genetic Variants Explain the Association of the Cholesteryl Ester Transfer Protein Gene With Coronary Artery Disease J. Am. Coll. Cardiol., May 22, 2007; 49(20): 2053 - 2060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Nissen, J.-C. Tardif, S. J. Nicholls, J. H. Revkin, C. L. Shear, W. T. Duggan, W. Ruzyllo, W. B. Bachinsky, G. P. Lasala, E. M. Tuzcu, et al. Effect of Torcetrapib on the Progression of Coronary Atherosclerosis N. Engl. J. Med., March 29, 2007; 356(13): 1304 - 1316. [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]
|
|
|
|
 |
|
 D. B. Lloyd, M. E. Lira, L. S. Wood, L. K. Durham, T. B. Freeman, G. M. Preston, X. Qiu, E. Sugarman, P. Bonnette, A. Lanzetti, et al. Cholesteryl Ester Transfer Protein Variants Have Differential Stability but Uniform Inhibition by Torcetrapib J. Biol. Chem., April 15, 2005; 280(15): 14918 - 14922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Forrester, R. Makkar, and P.K. Shah Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition: An Update for Clinicians Circulation, April 12, 2005; 111(14): 1847 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G K Andrikopoulos, D J Richter, E W Needham, M N Zairis, E N Karabinos, E J Gialafos, P E Dilaveris, K E Paravolidakis, K G Kappos, E G Papasteriadis, et al. Association of the ile405val mutation in cholesteryl ester transfer protein gene with risk of acute myocardial infarction Heart, November 1, 2004; 90(11): 1336 - 1337. [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]
|
|
|
|
 |
|
 G. R Thompson Is good cholesterol always good? BMJ, August 28, 2004; 329(7464): 471 - 472. [Full Text] [PDF]
|
|
|
|
|
|
N. Barzilai, G. Atzmon, C. Schechter, R. Lipton, and A. R. Shuldiner Genetic Factors in Exceptional Longevity--Reply JAMA, February 25, 2004; 291(8): 942 - 943. [Full Text] [PDF]
|
|
|
|
|
|
G. K. Andrikopoulos and D. J. Richter Genetic Factors in Exceptional Longevity JAMA, February 25, 2004; 291(8): 941 - 942. [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. E. Bojesen, K. Juul, P. Schnohr, A. Tybjaerg-Hansen, and B.o. G. Nordestgaard Platelet glycoprotein IIb/IIIa PlA2/PlA2 homozygosity associated with risk of ischemic cardiovascular disease and myocardial infarction in young men: The Copenhagen City Heart Study J. Am. Coll. Cardiol., August 20, 2003; 42(4): 661 - 667. [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]
|
|
|
|
|
|
R. V. Andersen, H. H. Wittrup, A. Tybjaerg-Hansen, R. Steffensen, P. Schnohr, and B.o. G. Nordestgaard Hepatic lipase mutations,elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: The Copenhagen City Heart Study J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1972 - 1982. [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]
|
|
|
|
|
|
M. Dahl, A. Tybjaerg-Hansen, H. Sillesen, G. Jensen, R. Steffensen, and B. G. Nordestgaard Blood Pressure, Risk of Ischemic Cerebrovascular and Ischemic Heart Disease, and Longevity in {alpha}1-Antitrypsin Deficiency: The Copenhagen City Heart Study Circulation, February 11, 2003; 107(5): 747 - 752. [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]
|
|
|
|
|
|
M.C. Mahaney, L. Almasy, D.L. Rainwater, J.L. VandeBerg, S.A. Cole, J.E. Hixson, J. Blangero, and J.W. MacCluer A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 339 - 345. [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]
|
|
|
|
|
|
D. Baldassarre, M. Amato, L. Pustina, E. Tremoli, C. R. Sirtori, L. Calabresi, and G. Franceschini Increased Carotid Artery Intima-Media Thickness in Subjects With Primary Hypoalphalipoproteinemia Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 317 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Dugi, K. Brandauer, N. Schmidt, B. Nau, J. G. Schneider, S. Mentz, T. Keiper, J. R. Schaefer, C. Meissner, H. Kather, et al. Low Hepatic Lipase Activity Is a Novel Risk Factor for Coronary Artery Disease Circulation, December 18, 2001; 104(25): 3057 - 3062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gotto Jr Low High-Density Lipoprotein Cholesterol as a Risk Factor in Coronary Heart Disease : A Working Group Report Circulation, May 1, 2001; 103(17): 2213 - 2218. [Full Text] [PDF]
|
|
|
|
|
|
J. F. Bentzon, E. Skovenborg, C. Hansen, J. Moller, N. S.-C. de Gaulejac, J. Proch, and E. Falk Red Wine Does Not Reduce Mature Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, March 27, 2001; 103(12): 1681 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Sethi, B. G. Nordestgaard, B. Agerholm-Larsen, E. Frandsen, G. Jensen, and A. Tybjarg-Hansen Angiotensinogen Polymorphisms and Elevated Blood Pressure in the General Population : The Copenhagen City Heart Study Hypertension, March 1, 2001; 37(3): 875 - 881. [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]
|
|
|
|
|
|
B. Agerholm-Larsen, A. Tybjarg-Hansen, P. Schnohr, R. Steffensen, and B. G. Nordestgaard Common Cholesteryl Ester Transfer Protein Mutations, Decreased HDL Cholesterol, and Possible Decreased Risk of Ischemic Heart Disease : The Copenhagen City Heart Study Circulation, October 31, 2000; 102(18): 2197 - 2203. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||