14 The Open Cardiovascular Medicine Journal, 2010, 4, 14-19
1874-1924/10 2010 Bentham Open
Cholesteryl Ester Transfer Protein Gene Polymorphisms and Longevity
Genovefa Kolovou1,*, Marianna Stamatelatou1, Katherine Anagnostopoulou1, Peggy Kostakou1,
Vana Kolovou1, Constantinos Mihas2, Ioannis Vasiliadis1, Olga Diakoumakou1,
Dimitri P Mikhailidis3 and Dennis V Cokkinos1
11st Cardiology Department, Onassis Cardiac Surgery Center Athens, Greece
2Internal Medicine Department, General Hospital of Kimi, Kimi, Greece
3Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free campus, University College London
Medical School, University College London (UCL), London, UK
Abstract: Purpose: High levels of high density lipoprotein (HDL) cholesterol are associated with a decreased risk of
coronary heart disease (CHD). Subjects with high levels of HDL cholesterol (>70 mg/dl; 1.79 mmol/l) as well as high
levels of low density lipoprotein (LDL) cholesterol, could represent a group with longevity syndrome (LS). Since HDL
particles are influenced by cholesteryl ester transfer protein (CETP) activity, it is worth studying the CETP polymor-
phism. The aim of the study was to detect whether 2 genetic variants of the CETP are associated with the LS.
Subjects and Methods: The study population consisted of 136 unrelated men and women with no personal and family
history of CHD; 69 met the criteria for LS and 67 did not meet these criteria and had “normal” HDL cholesterol (>40 and
<70 mg/dl; >1.03 and <1.79 mmol/l). All patients were genotyped for the TaqIB and I405V polymorphisms.
Results: The B2 allele frequency of TaqIB polymorphism was higher in the LS in comparison with the non-LS group
(p=0.03) whereas B1 allele frequency was higher in the non-LS group (p=0.03).
Conclusions: Gene polymorphisms could help decide whether individuals who have increased levels of both LDL choles-
terol and HDL cholesterol require treatment. Some of the prerequisites could include that subjects with LS should not only
have very high levels of HDL cholesterol but also favorable gene polymorphisms. However, further investigations with a
larger sample and including other gene polymorphisms, are needed.
Keywords: Coronary heart disease, high density lipoprotein-cholesterol, longevity syndrome, TaqIB and I405V polymor-
cholesterol concentrations are associated with a greater risk
of coronary heart disease (CHD) has been raised since the
1950s . More than 50 years on, following a number of
prospective studies [2-7], HDL cholesterol is now estab-
lished as an independent risk factor for CHD . However,
there may also be a positive association of HDL cholesterol
levels with increased CHD risk .
The hypothesis that low high density lipoprotein (HDL)
levels reduce CHD risk it is plausible that this characteristic
could also be associated with longer life expectancy .
This hypothesis is further supported by the fact that high
HDL cholesterol levels are often observed in healthy elderly
persons aged >85 years [10, 11]. The levels of HDL choles-
terol are influenced by various environmental and genetic
Based on clinical evidence that elevated HDL cholesterol
*Address correspondence to this author at the Onassis Cardiac Surgery
Center, 356 Sygrou Ave 176 74 Athens, Greece; Tel: +30 210 9493520;
Fax: +30 210 9493336; E-mail: firstname.lastname@example.org
factors. Family and twin studies have estimated that the heri-
tability of HDL cholesterol levels varies from 35 to 66% [10,
12, 13]. A degree of heritability has been also reported in
longevity. Siblings of centenarians have an 8- to 17-fold
higher probability of living past the age of 100 years,
accounting for only approximately 1 of 10000 individuals
in the general population . Several genes can affect
HDL metabolism; among these are those related to choles-
teryl ester transfer protein (CETP). A number of polymor-
phisms and rare variants in the human CETP gene have been
identified. Two of the common polymorphisms, TaqIB and
I405V, are associated with plasma HDL cholesterol levels
HDL cholesterol (>70 mg/dl), in at least 2 related members
of a family plus a history of longevity (any living or de-
ceased relative >90 years old) in the family are referred to as
longevity syndrome (LS). The occurrence of LS is very rare.
It is very likely that subjects with LS, besides high HDL cho-
lesterol levels, have additional protective metabolic traits.
Taking into account the National Cholesterol Education Pro-
In the current study, the prevalence of very high serum
CETP and Longevity The Open Cardiovascular Medicine Journal, 2010, Volume 4 15
gram Adult Treatment Panel III (NCEP ATP III) guidelines
for low-density lipoprotein (LDL) cholesterol levels [18, 19],
the dilemma arises whether subjects with “raised” levels of
LDL cholesterol but also with very high HDL concentration
are still candidates for hypolipidaemic treatment. Gene po-
lymorphisms could help decide whether individuals who
have increased levels of both LDL cholesterol and HDL cho-
lesterol require treatment. In line with previous work from
our group , we tested the hypothesis that subjects with
LS may carry the favorable variants of the CETP TaqIB
or/and I405V polymorphisms compared with subjects not
meeting the criteria for LS.
MATERIALS AND METHODOLOGY
women without history of CHD. They were recruited from
the Outpatient Lipid Clinic of our hospital (Athens, Greece)
or self-referred (hospital personnel). All subjects were re-
ferred for moderate hypercholesterolaemia. In order to ex-
clude underlying CHD the study population underwent a
physical and a stress testing examination. A detailed family
history was also obtained.
The study population consisted of 136 unrelated men and
lowing criteria for LS (LS group). The characterization of LS
was based on ALL of the following criteria: 1) plasma fast-
ing HDL cholesterol concentration >70 mg/dl (1.79 mmol/l),
2) at least 1 relative with plasma HDL cholesterol concentra-
tion >70 mg/dl (1.79 mmol/l), 3) at least 1 relative (deceased
or alive) over the age of 90 years old, and, 4) no personal or
family history of cardiovascular disease.
Sixty nine probands of long-lived subjects met the fol-
They had desirable HDL cholesterol (>40 mg/dl and <70
mg/dl; >1.03 and <1.79 mmol/l), according to the NCEP
ATP III guidelines [18, 19]. They did not have any relative
(deceased or alive) with plasma HDL cholesterol >70 mg/dl
(1.79 mmol/l) nor any relative (deceased or alive) over the
age of 90 years. This information was derived from the
analysis of 3 generations.
Sixty seven subjects served as controls (non-LS group).
mellitus and hypertension which are risk factors for CHD.
Additionally, they did not suffer from stroke, cancer, demen-
tia or other age-related diseases. They were referred to our
lipid clinic for their annual routine physical examination.
The majority of individuals (88%) from the LS group were
referred to us for increased LDL cholesterol levels according
to NCEP ATP III guidelines [18, 19]. The remained indi-
viduals were self-referred (hospital personnel) to the study
for their exceptional high HDL levels. Heavy drinking, he-
patic disease, renal disease, and hypothyroidism were among
the exclusion criteria. Hypertension was defined as systolic
arterial blood pressure >140 mmHg and/or diastolic blood
pressure >90 mmHg or as current treatment with antihyper-
tensive drugs. All subjects in both groups had a body mass
index (BMI) <30 kg/m2. Diabetes was defined according to
the diagnostic criteria of the World Health Organization or
Both LS and non-LS groups had no obesity, diabetes
as current treatment of diabetes . Only 15% of subjects
were smokers in each group. None of the subjects was taking
any medication. Triglycerides levels were < 150 mg/dl (1.68
mmol/l) in both groups and mean LDL-cholesterol levels
were < 130 mg/dl (3.3 mmol/l) in non-LS group. These lev-
els are normal according to the NCEP ATP III guidelines
[18, 19]. The mean value of LDL cholesterol in LS group
was above 160 mg/dl (4 mmol/l), which is raised according
to the NCEP ATP III guidelines [18, 19].
approved the protocol of this study. All patients signed an
informed consent form.
The Onassis Cardiac Surgery Center ethics committee
polymerase chain reaction and restriction fragment length
polymorphism as previously described [22-25].
CETP TaqIB and I405V genotyping was performed by
terol were measured using enzymatic colorimetric methods
on a Roche Integra Biochemical analyzer with commercially
available kits (Roche). The serum low density lipoprotein
(LDL) levels were calculated using the Friedewald formula
Plasma total cholesterol, triglycerides and HDL choles-
the Shapiro-Wilk statistic. None of the continuous variables
had a non-normal distribution.
Continuous variables are presented as mean ± standard
deviation, while qualitative variables are presented as abso-
lute and relative frequencies. Contingency tables were con-
structed to evaluate the association between genotypes, car-
riers and LS. The statistical evaluation for the categorical
variables was based on the calculation of the chi-square and
Fisher’s exact criteria. Comparison of mean values between
study groups was performed with the Student’s t-test. Esti-
mations of the multivariate association of the B2 allele with
LS were performed by the calculation of the odds ratio (OR)
and the corresponding confidence intervals through logistic
regression analysis, after adjusting for age and BMI.
The normality of continuous variables was tested using
considered significant. Data were analyzed using STATA™
(version 9.0, Stata Corporation, College Station, TX, USA).
All tests were two-sided and p-values of 0.05 were
Clinical and Laboratory Parameters
non-LS and LS groups are shown in Table 1. BMI was lower
in the LS compared with non-LS group. The mean age dif-
ference between the 2 groups was 6 years. Serum total LDL
and HDL cholesterol were higher while plasma triglyceride
concentration was lower in LS group compared with the
non-LS group. Moreover the LDL/HDL cholesterol ratio was
higher in the non-LS group and statistically significant in
comparison with LS group.
Clinical characteristics and laboratory parameters of the
16 The Open Cardiovascular Medicine Journal, 2010, Volume 4 Kolovou et al.
Distribution of CETP Genotypes
in the 2 groups. No significant differences were found con-
cerning the genotype frequency of TaqIB and I405V poly-
morphisms, between the 2 groups. However, the frequency
of B2B2 genotype in LS group was twofold higher in com-
parison with the same genotype frequency in the non-LS
group. The B2 allele frequency was significantly higher in
the LS compared with the non-LS group, while B1 allele
frequency was significantly higher in the non-LS compared
with the LS group. Concerning the I and V alleles, there was
a trend (p=0.053) with the latter being more frequent in the
LS group. There was no significant correlation between the
alleles of the TaqIB or I405V polymorphism and HDL levels
Table 2 shows the CETP genotype and allele frequencies
allele, compared with the non-LS, adjusting for age (Table
Those with LS had 69% more odds of having the B2
3). Although not significant, it should also be noted that the
same participants had 64% more odds of having the B2 allele
than the non-LS, adjusting for BMI (Table 3). When fully
adjusted for BMI and age, there was not any statistically
significant difference concerning the frequency of the Β2
allele between LS and non-LS. When adjusted for triglyc-
erides and age our result remained significant. When
adjusted for the other lipids the significance was lost.
B2 allele of the TaqIB polymorphism than healthy subjects.
The aim of the study was to evaluate whether subjects with
LS in the family who potentially will live longer than the
average life expectancy, have favourable CETP gene vari-
ants compared with healthy subjects. This genetic distinction
may be important in the management of patients.
Our subjects with LS were more frequently carriers of the
Table 1. Clinical Characteristics of the Non-LS and LS Group
Mean SD Mean SD
Age (years) 56 13 49 20 0.008
BMI (kg/m2) 26 4 23 3 <0.001
TC (mg/dl) 210 43 270 49 <0.001
TG (mg/dl) 93 34 81 36 0.043
HDL (mg/dl) 53 13 84 12 <0.001*
LDL (mg/dl) 128 27 168 45 <0.001
LDL/HDL ratio 2.6 0.8 2 0.6 <0.001
LS: longevity syndrome, BMI: body mass index, TC: total cholesterol, TG: triglycerides, HDL: high density lipoprotein cholesterol, LDL: low density lipoprotein cholesterol, SD:
* HDL was a criterion for the selection of patients.
To convert cholesterol from mg/dl to mmol/l divide by 38.67 and to convert triglycerides from mg/dl to mmol/l divide by 88.57.
Table 2. Distribution of CETP Genotype and Allele Frequencies in the 2 Groups
Genotype or Allele non-LS n (%) LS n (%)
TaqIB Β2Β2 13 (19) 26 (38)
Β1Β2 36 (54) 31 (45)
Β1Β1 17 (25) 12 (17)
Β1a 70 (53) 55 (40)
Β2a 62 (47) 83 (60)
I405V VV 1 (2) 5 (7)
IV 18 (42) 39 (56)
II 24 (56) 25 (36)
V 20 (23) 49 (35)
I 66 (77) 89 (64)
CETP: cholesteryl ester transfer protein, LS: longevity syndrome.
a p = 0.03
CETP and Longevity The Open Cardiovascular Medicine Journal, 2010, Volume 4 17
pending upon the lipid-metabolic setting . The HDL par-
ticle is influenced by CETP activity. CETP promotes the
exchange of cholesteryl esters for triglycerides between
HDL and triglyceride-rich lipoproteins  Furthermore, the
HDL particle is involved in reverse cholesterol transport
. The cholesterol from extrahepatic cells is incorporated
into the HDL particle and is transported to the liver .
Then, the excess cholesterol is removed via cholic acids to
the intestine . Low HDL levels (<40 mg/dl) are consid-
ered as an independent risk factor for CHD [2-7]. Ordovas et
al. suggested that increased HDL cholesterol levels resulting
from lower CETP activity appear to be associated with a
lower risk of CHD in male subjects .
CETP may have pro- or anti-atherogenic properties de-
lymorphisms can be associated with either increased CHD
risk or longevity [31-35]. Also, significant associations of
the B1B1 genotype with higher plasma CETP concentration
and/or CETP activity and lower HDL cholesterol were found
in several studies [30, 36, 37], but this is not consistently
observed [38, 39]. In our study, we did not measure CETP
activity, and we may only speculate that LS subjects had
lower CETP concentration and activity since they had nor-
mal BMI  and normal triglyceride levels .
There are controversial studies reporting that CETP po-
the association of CETP polymorphisms with the risk of car-
diovascular events . In this study, those homozygous for
the B2 allele had a 30% reduced risk of a cardiovascular
event (OR 0.70, CI (95) 0.51-0.96, p=0.03) compared with
B1 homozygotes. Furthermore, in a large population-based
cohort, 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 in-
creased levels of the less atherogenic large LDL [43-45]. In
the Framingham Offspring Study, the B2 allele was associ-
ated with a reduced risk of CHD in men , and this was
confirmed in the Veterans Affair HDL cholesterol Interven-
tion Trial (VA HIT) . In contrast, no association was
found between any of the TaqIB genotypes and CHD in sub-
jects with a history of myocardial infarction in the Coronary
and Recurrent Events Study  and in a cohort of healthy
middle-aged U.S. physicians . Brousseau et al.  re-
ported that in men with CHD and HDL deficiency (VA HIT
study), the frequency of the B2B2 genotype was reduced.
However, there are studies suggesting that B2 allele carriers
have higher HDL cholesterol levels than B1 allele carriers;
paradoxically they have an increased risk for CHD [49, 50,
22]. However, a meta-analysis of 7 studies (Physicians’
Health Study, Northwick Park Heart Study, Reykjavik, EC-
TIM, OPERA, EARS and the study of Arca et al), reported a
The West of Scotland Coronary Prevention Study tested
lower cardiovascular risk in B2 compared with B1 homozy-
CETP genotype with CHD risk is the influence on plasma
HDL. Kuivenhoven et al.  reported a strong association
between B1 allele and low HDL cholesterol levels, which is
in agreement with the results of others [36, 52, 53]. Moreo-
ver, our group reported a positive association between B1
genotype and postprandial lipemia . Bruce et al. re-
ported that the HDL cholesterol levels were higher in VV
than IV and II men . However, the increase in HDL cho-
lesterol was only significant in VV men with plasma triglyc-
eride > 165 mg/dl (1.85 mmol/l). In another study, the indi-
viduals homozygous for the V allele also had the highest
HDL cholesterol levels . Opposite to the beneficial in-
fluence of homozygosity of VV, Kakko et al., found that the
VV genotype seems to be most harmful for men with the
highest alcohol consumption . In our study, the lack of
an association between the TaqIB or I405V polymorphisms
and HDL cholesterol observed within groups does not
weaken the association between these polymorphisms and
the presence of the LS. This was expected since each group
was selected to have normal or very high HDL levels whose
range was narrow. Therefore, analysis with a larger number
of subjects is needed in order to assess such an association.
A possible mechanism that explains the association of
Eskimos, have high levels of HDL cholesterol (even with
conjointly elevated LDL) which is similar to our study popu-
lation . Additionally, subjects with familial hypobeta and
familial hyperalphalipoproteinaemia which are also associ-
ated with lower CHD rates, share a common characteristic,
a ratio of LDL:HDL of approximately 1:1. This ratio
of LDL:HDL is considerably lower than the usual 2.5:1
observed in the general population . In our LS group, the
ratio was 2:1 and in non-LS group 2.7:1 which is comparable
with other studies .
Populations with low CHD mortality rates, for example
(6 years) and the different BMI between the 2 groups. Al-
though significant, these factors can not influence the gene
distribution of our study population. The small number of
our sample and the differences in lipid levels are disadvan-
tages. When adjusted for triglycerides and age the statistical
significance of our results remained. When adjusted for the
other lipids there was not statistical significance concerning
the B2 allele between LS and non-LS groups. However hy-
per-HDL-cholesterolemia and longevity represent various
pathophysiological conditions and can not be represented
solely from the genetic constitution of an organism, nor
solely from the environmental factors. Additionally, our
sample although small, was not genetically heterogeneous,
The limitations in our study are the mean age difference
Table 3. Multiple Logistic Regression of LS on the B2 Allele, after Adjusting for BMI and Age
Dependent Variable Explanatory Variable Odds Ratio 95% Confidence Interval p
B2 allelea LS vs non-LS 1.643 (0.968-2.789) 0.07
B2 alleleb LS vs non-LS 1.687 (1.017-2.795) 0.04
LS: longevity syndrome, BMI: body mass index.
aAdjusted for BMI, b adjusted for age
18 The Open Cardiovascular Medicine Journal, 2010, Volume 4 Kolovou et al.
more specifically there was no population admixture, some-
thing that in past created inconsistencies to similar genetic
association studies. Considering the existence of a strong
familial component to extreme longevity, and the fact that
previous studies investigated longevity in families  or in
a preselected population, it was not possible to find a com-
pletely age-matched control group. For example, siblings
of centenarians have an 8- to 17-fold higher probability
of living past the age of 100 years, accounting for only
approximately 1 of 10000 individuals in the general popula-
and lower triglyceride levels compared with the non-LS
group. In the LS group, total and LDL cholesterol levels
were higher compared with non-LS individuals. Thus, the
dilemma arises whether or not LS subjects should/should not
receive hypolipidaemic treatment according to available
guidelines. Until more knowledge is available the manage-
ment of these individuals remains controversial. Some of the
prerequisites could include that subjects with LS should not
only have very high levels of HDL cholesterol but also fa-
vorable gene polymorphisms. However, further investiga-
tions with a larger sample and including other gene poly-
morphisms, are needed. Obviously, prospective studies in
patients with LS have their limitations.
In our study, LS subjects had higher B2 allele frequency
the TaqIB polymorphism than non-LS subjects. Gene poly-
morphisms could help decide whether individuals who have
increased levels of both LDL cholesterol and HDL choles-
terol require treatment.
Individuals with LS had a higher B2 allele frequency of
DECLARATION OF INTEREST
institution supported it financially. Some of the authors have
given talks, attended conferences and participated in trials
and advisory boards sponsored by various pharmaceutical
This study was conducted independently; no company or
BMI = Body mass index
CETP = Cholesteryl ester transfer protein
CHD = Coronary heart disease
HDL = High density lipoprotein
LDL = Low density lipoprotein
LS = Longevity syndrome
OR = Odds ratio
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Received: December 21, 2009
Revised: December 25, 2009 Accepted: December 28, 2009
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