Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2759-2764
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2759-2764.)
© 1997 American Heart Association, Inc.
The Role of a Triplet Repeat Sequence of the Very Low Density Lipoprotein Receptor Gene in Plasma Lipid and Lipoprotein Level Variability in Humans
Nicole Helbecque;
Jean Dallongeville;
Valérie Codron;
Dominique Arveiler;
Jean-Bernard Ruidavets;
Alun Evans;
François Cambien;
Jean-Charles Fruchart;
;
Philippe Amouyel
From the Service d'Epidémiologie et de Santé
PubliqueINSERM CJF 95-05, Institut Pasteur de Lille (N.H., V.C., P.A.);
INSERM U 325, Institut Pasteur de Lille (J.D., J.-C.F.), Lille France;
Laboratoire d'Epidémiologie et de Santé Publique,
Strasbourg France (D.A.); Département d'Epidémiologie,
Faculté de Médecine, Toulouse (J.-B.R.) France; Department of
Epidemiology and Public Health, The Queen's University of Belfast,
Belfast, Northern Ireland (A.E.); INSERM SC7, Paris, France (F.C.)
Correspondence to Pr Philippe Amouyel, Service d'Epidémiologie et de Santé Publique et INSERM, CJF 95-05, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille Cedex, France.
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Abstract
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Abstract The biological role of the very low density
lipoprotein
receptor (VLDL-R) in humans is not yet elucidated. This
cellular
receptor binds apolipoprotein E (apoE)-containing
lipoparticles
and is mainly expressed in peripheral
tissues. The
VLDL-R gene
contains a polymorphic
triplet (CGG) repeat located 19 bp upstream
of the initiation codon. We
explored the allelic distribution
of this repeat in 1384 subjects of
European Caucasian origin,
609 of them surviving a myocardial
infarction. Six alleles corresponding
to 5, 6, 7, 8, 9, and 11
repeats were detected in this population.
The alleles 5, 8, and 9
were the most frequent, with frequencies
of 0.413, 0.275, and 0.292,
respectively. No association was
found between the
VLDL-R polymorphism and myocardial infarction.
In
controls without lipid lowering treatment, a statistically
significant
interaction between
VLDL-R genotype and apoE
phenotype
was found for plasma triglycerides
(
P<.04), suggesting a
gene-gene interaction. There was
also a main effect of the
VLDL-R polymorphism on
LpE:B and LpA-I. The
VLDL-R 9 allele was associated
with
lower levels of plasma LpE:B (
P<.05) and higher
concentrations
of plasma LpA-I (
P<.01) than the other
alleles. These results
suggest that
VLDL-R has a
modest influence on circulating lipoproteins
in humans.
Key Words: VLDL receptor triglyceride-rich lipoproteins polymorphism lipoprotein metabolism
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Introduction
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The
VLDL-receptor (VLDL-R)
1 belongs to the family of
protein
receptors that includes the LDL
receptor,
2 the LDL receptor-related
protein/

2-macroglobulin
receptor (LRP),
3 the
kidney glycoprotein 330,
4 a putative
G-protein-coupled
receptor in
Lymnaea
stagnalis,5 and the apoE receptor
2.
6 Among
these proteins, the VLDL-R is
structurally the most closely
related to the LDL receptor (LDL-R). Its
amino acid sequence
is highly uniform in a number of species. Compared
with the
LDL-R, the ligand-binding domain of the VLDL-R contains an
extra
cysteine-rich repeat that confers its specificity to the VLDL-R.
In
vitro, the VLDL-R binds only apoE-containing lipoproteins. In
addition,
the VLDL-R is essentially expressed in muscle and adipose
tissue,
but not in the liver, suggesting that VLDL-R may be primarily
involved
in triglyceride-rich lipoproteins (TRL)
metabolism in peripheral
tissues.
The human VLDL-R gene was cloned7 and
located on the short arm of chromosome 9. Its gene structure is similar
to that of the LDL-R gene. It differs by an additional exon
that encodes for a cysteine-rich repeat. The 5'-untranslated region
contains a polymorphic triplet (CGG) repeat
sequence.7 To date, four to nine triplet repeat
units have been described in random samples of
population,810,19 resulting in as many
alleles. Studies using the (CGG) triplet repeat as a genetic marker
did not show any significant association between the VLDL-R
polymorphism and dysbetalipoproteinemia, familial
hypertriglyceridemia, familial combined
lipemia, and type V
hyperlipidemia.7 However, these
studies were carried out in small samples without sufficient
statistical power to definitely exclude any association. Furthermore,
these disease-gene studies lacked the evidence of association with
intermediate phenotypes, such as plasma lipoprotein levels.
In the last decade, evidence has accumulated that apolipoproteins play
a critical role in lipoprotein metabolism. Apolipoprotein B
is the structural component of VLDL, IDL, and LDL. ApoC-III and apoE at
the surface of the B-containing lipoproteins modulate plasma enzyme
activities and receptor interactions. These particles are
triglyceride-rich lipoproteins (TRL) and bind to the LDL
receptor of cultured cells.11 Their affinity for
the LDL receptor depends on their relative contents in apoE and
apoC-III.12
Although the VLDL-R functional properties are characterized in vitro,
its physiological role in humans is not yet
established. VLDL-R is expressed in adipose tissue, whereas lipoprotein
clearance essentially takes place in the liver. Therefore, the question
of the implication of the VLDL-R in TRL metabolism is
important for the understanding of lipoprotein metabolism
in the peripheral tissues. The goal of our study was to
assess the association between VLDL-R gene polymorphism
and plasma lipoprotein levels. Particular attention was paid to
analyzing the particles that are enriched in apoE. These effects were
further analyzed to account for the interactions with apoE
phenotype, associated with functional differences in
lipoprotein clearance.
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Methods
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Subjects
The populations were selected in the course of a multicenter
retrospective
study of myocardial infarction, named ECTIM. This study
was
carried out between 1988 and 1991 in four European regions:
Belfast
(Northern Ireland), Toulouse (south of France), Strasbourg
(Northeast
of France), and Lille (north of France). Men between
the ages of 25 and
64 were eligible: their family had to have
been resident in the region
for at least two generations and
their four grandparents had to have
been born in Europe. During
the study period, all patients surviving
myocardial infarction
(MI) were eligible (n=609: 462 without lipid
lowering drugs,
147 with lipid lowering drugs). Blood samples were
obtained
between 3 and 9 months after MI.
Controls were obtained from electoral rolls in France and from lists of
general practitioners maintained by the Central Service
Agency in Belfast (775 men: 723 without lipid lowering drugs, 52 with
lipid lowering drugs). Stratification by age was used in the four study
populations to match the age distribution of the control samples to
that of cases in MI. Participants were examined at home or in clinics.
A questionnaire was completed (personal history, presence of disease,
drug intake); body weight and height were measured; 20 mL of blood was
drawn on disodium EDTA.
Statistical analysis was conducted on controls without lipid
lowering drugs. Two patientshaving plasma triglyceride
levels >12.5g/lwere excluded. This strategy equalized the
variances of the lipid and lipoprotein variables tested in this
work.
Lipid Analysis
A blood sample of 20 mL was drawn on EDTA
Na2 after the subjects had fasted for at least 10
hours, kept at 4°C, and centrifuged within 4 hours. After the
addition of conservative agents, the plasma was transported at 4°C to
the central laboratory in Lille, France, where all measurements were
performed within 5 days of venipuncture, as described
elsewhere.13 Human lipoprotein particles were
measured by a noncompetitive enzyme-linked immunosorbent assay
(sandwich ELISA) as described previously.14 The
bi-site ELISA assay allows for the determination of pairs of
apolipoproteins: C-III/B or E/B. The values are expressed as an amount
of apoB associated to either apoC-III or apoE. The intra- or
inter-assay coefficient variations (CV) were 8.7 and 11.1% for
LpC-III:B and 9.5 and 13.4% for LpE:B, respectively. Human
apoE15 and apoC-III16
levels were also measured by a noncompetitive enzyme-linked
immunosorbent assay (sandwich ELISA) as described previously. ApoA-I
and apoB were determined by immunonephelometry using the BNA system
(Behringwerke). Human LpA-I particles were measured by a differential
electroimmunoassay17 using commercially
available, ready-to-use plates from LpA-I hydragel kits (Sebia).
Genetic Analysis
Genomic DNA was prepared from white blood cells by
phenol-chloroform extraction. The (CGG)n repeat
genotype was detected for the 1384 subjects with PCR
amplification technique using previously described primer
pairs.7 PCR
amplifications18 were carried out using a Perkin
Elmer DNA Thermal Cycler model 4800 and Thermus aquaticus
polymerase (Gibco). After a first denaturing step at 95°C for 5
minutes, 30 cycles of amplification were performed as follows: in a
final volume of 50 µL, 200 ng of genomic DNA were mixed with 50
pmoles of each primer and 20 nmoles of each deoxynucleotide
triphosphate (Pharmacia) in the buffer recommended by the supplier
added with MgCl2 (1.5 mmol/L final).
Each cycle of the PCR reaction consisted of: 1 minute denaturation at
94°C, 1 minute annealing at 62°C followed by 1 minute elongation at
72°C. The amplified products were analyzed by
electrophoresis at 450V for 4 hours on 8%
acrylamide-bisacrylamide (19:1) gels stained by
ethidium bromide; pBR322/HaeIII DNA fragments (Appligene)
were used as molecular weight markers.
Statistical Analysis
The data were analyzed using the SAS statistical
software (release 6.10, SAS Institute Inc). Lipid and lipoprotein
levels were compared between genotypes by an analysis
of covariance. The tests were adjusted for age, sample origin,
BMI, tobacco, alcohol consumption and apoE phenotype.
Statistics were conducted on logarithmic variables for
triglycerides, VLDL-cholesterol, LpE:B and
LpC-III:B; results concerning these variables are expressed as
means at 95% confidence intervals.
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Results
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VLDL-R Allele Frequencies
The study was carried out on European men between the ages of
25
and 64, recruited in the framework of the ECTIM Study, a
case-control
study intended to identify candidate genes predisposing
to MI. The
allelic distribution of the
VLDL-R gene was assessed
in the
control group of this study (775 subjects; mean age 53.3±8.4
years).
The
VLDL-R gene locus was polymorphic with six different
alleles
corresponding to 5, 6, 7, 8, 9, and 11 (CGG) repeats,
represented
by 15 genotypes. The distribution of
the genotypes was in Hardy-Weinberg
equilibrium (Table 1

). The
VLDL-R 5/5, 5/8, and
5/9 genotypes
were the most frequent with each having an
average frequency
of 20%. The 8/9 genotype was the second most
frequent at 17.4%.
Each 8/8 and 9/9 genotype
represented an average frequency of
8%. The 5/6, 5/7,
5/11, 6/8, 6/9, 7/8, 7/9, 8/11, and 9/11 genotypes
shared the
remaining 4% of the genotypic frequencies.
Table 2
shows the corresponding
allele frequencies. Allele 5 was the most frequent allele
accounting for 41.3% of the whole sample. Alleles 8 and 9
represented each 27.5% and 29.2% of the sample
respectively. The frequency of the other
alleles6,7,11 was below 2% for each. The
allelic distribution of the VLDL-R polymorphism in the
ECTIM controls was significantly different from that of control
subjects of Japanese8,19 and
American10 (recruited in North Carolina) origin
(Table 2
). The VLDL-R 5 allele frequency was low in the
North Carolina10 and the
Japanese8,19 samples. In addition, the 9 repeat
allele (VLDL-R 9) was rare in the Japanese populations.
In contrast, there was no difference of allelic distribution between
the ECTIM sample and another American sample9
(recruited in Iowa and Massachusetts).
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Table 2. Distribution of VLDL-R Allele
Frequencies in the Control Group of the ECTIM Study and Different
Control Populations of Americans and
Japanese
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VLDL-R Interaction With ApoE
The association between VLDL-R genotypes and
the plasma lipid, lipoprotein and lipoparticle levels was assessed in
the control group of the ECTIM Study (n=723), excluding individuals
that were treated with lipid lowering drugs to avoid treatment bias.
Similarly, MI cases were excluded from this analysis to avoid
the possible confounding effects of cardiovascular
treatments (diet and drugs) on plasma lipid, lipoprotein, and
lipoparticle levels. To ensure enough subjects per group for the
statistical analyses, the calculations were restricted to
VLDL-R genotypes with a frequency greater than 5%.
The values were adjusted for age, body mass index (BMI), alcohol
consumption, cigarette smoking, and blood sample origin. Results are
presented in Table 3
.
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Table 3. Comparison of Plasma Lipid Levels Among
VLDL-R Genotypes in the Control Group of the ECTIM Study
(Subjects Without Any Lipid Lowering
Treatment)
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A number of studies have demonstrated that the apoE phenotype
is an important source of plasma lipid, lipoprotein, and lipoparticle
level variability. Therefore, the data were analyzed including
apoE phenotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4) in the
model. Results are summarized in Table 3
. At the 0.05 level of
significance, an interaction between VLDL-R genotype
and apoE phenotype was found only for plasma
triglycerides (P<.04), suggesting that
there may be gene-gene interactions. In order to ensure a sufficient
number of subjects per group, the post hoc analysis of this
interaction was performed for the most frequent VLDL-R
genotypes (5/5, 5/8, 5/9) and apoE phenotypes (apoE
3/2, 3/3 and 3/4). Results are presented in Fig 1
. This analysis showed no
difference in the mean value of triglycerides between
VLDL-R genotypes in the apoE 3/3 phenotype
subset. In contrast, in the apoE 3/2 group, the mean level of
triglycerides was lower in subjects bearing the
VLDL-R 8 or 9 allele than in those with the
VLDL-R 5 allele. Finally, in the apoE 3/4
phenotype group the mean level of triglycerides was
higher in individuals carrying the VLDL-R 8 or 9 allele
than in individuals homozygotes for the VLDL-R 5 allele.
A similar pattern was observed for LpC-III:B, although not reaching the
level of statistical significance.

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Figure 1. Plasma triglyceride levels according to
apoE phenotypes and VLDL-R genotypes. *
Statistically significantly different from 5/5 (P
<.05).
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VLDL-R Principal Effect
There was evidence in this sample for a significant
VLDL-R genotype effect on LpE:B (P<.04)
and LpA-I (P<.04) levels. Individuals bearing at least one
VLDL-R 9 allele had lower levels of LpE:B than those
without this allele (XX: 0.38 [0.11 to 1.29]; 9X or 99: 0.35
[0.11 to 1.14] g/l; P<.05). Similarly, LpA-I
levels were significantly higher in subjects carrying at least one
VLDL-R 9 allele (XX: 0.47±0.13; 9X or 99: 0.49±0.14
g/l; P<.01).
VLDL-R and Hyperlipidemia, Myocardial Infarction,
and Body Fat
The relationship between the VLDL-R polymorphism
and plasma lipid and lipoprotein levels suggests that VLDL-R
may be a candidate gene for dyslipidemia and/or for
cardiovascular disease risk. Table 4
compares the allelic distribution of
VLDL-R (CGG) repeat in the control group between subjects
that were treated with lipid lowering drugs and those without such
treatment. The frequencies of VLDL-R 9 and VLDL-R
5 alleles were lower and higher, respectively, in treated patients
than in nontreated subjects, but the difference in VLDL-R
polymorphism distribution between treated and untreated controls
was not statistically significant (P=.054). Table 5
shows the allele distribution in
the ECTIM Study of cases with MI versus controls. There is no
statistically significant difference in the allele distribution
between cases and controls. Finally, since the VLDL-R gene
is expressed in adipose tissue, we tested the hypothesis that its
genetic variability was associated with differences in fat deposition
in peripheral tissues. Body fat was assessed using body
mass index. There was no statistically significant difference in body
mass index among VLDL-R genotypes either in the
control group or in the whole ECTIM sample (data not shown).
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Table 4. Distribution of VLDL-R Allele
Frequencies in Controls That Were Treated or Nontreated With Lipid
Lowering Drugs in the ECTIM Study
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Discussion
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The VLDL-R belongs to the family of lipoprotein receptors and
shares
many structural domains with the LDL
receptor.
20 The physiological
properties
of the
VLDL-R in humans are unknown. Since VLDL-R
binds the
apoE-containing lipoproteins, VLDL, IDL, and
ß-VLDL,
21,22 it is a candidate gene for study
of its influence on the variability
of these lipoprotein levels in
humans. Indeed,
VLDL-R gene polymorphism
explains
partially plasma triglycerides and variability in LpE:B
and
LpA-I levels, suggesting that VLDL-R may be implicated in
triglyceride
metabolism in humans. In the
present sample, this association
is less marked than that of the
apoE phenotype. In addition,
no statistically significant
association was found between the
VLDL-R polymorphism
and myocardial infarction.
The results of the present study demonstrated the predominance of
the 5, 8 and 9 (CGG) repeats at the genetic locus of VLDL-R in a sample
of Europeans. The least frequent alleles have 4, 6, 7, 10 and 11
(CGG) repeats and are found in less than 3% of the study participants.
The relative frequencies of VLDL-R alleles are
remarkably different in Japanese and Europeans. These differences may
be the consequence of the random genetic drift of a mutant allele
that is neutral with respect to reproduction or may also result
from a balance between selective forces. The probability that
VLDL-R allele frequencies differences between Japanese
and Caucasian Europeans result from a genetic drift or a new mutation
is plausible.23 Such differences have been found
in the blood group or in genes implicated in lipoprotein
metabolism.24
On the basis of tissue expression,25 it has been
proposed that the VLDL-R may have a central role in fat deposition in
peripheral tissues.26 However, recent
studies in mice deficient in LDL-R have shown that adenovirus-mediated
gene transfer of the VLDL-R gene was accompanied by a
lowering in the plasma apoE and apoB
concentrations.27,28 The plasma lipoprotein
fraction most affected by VLDL-R gene transfer was IDL, the
clearance of which was clearly accelerated after treatment. These
experiments demonstrated that apoE-enriched lipoproteins are important
ligands for VLDL-R in vivo in rodents. One limitation, however, to the
extension of these observations to the human metabolism is
that adenovirus-mediated VLDL-R gene transfer leads to the
preferential expression of VLDL-R in the liver, an organ
where the processing of apoE-rich lipoproteins may differ substantially
from that of peripheral tissues. We addressed the question
of a potential implication of the VLDL-R in lipoprotein
metabolism in humans by assessing the possible association
between VLDL-R genetic polymorphism and circulating
lipoprotein levels. Considering that apoE is the main ligand of VLDL-R
and that apoE phenotype modulates lipoprotein binding to
lipoprotein receptors, it was necessary to account for potential
interactions between VLDL-R genotypes and apoE
phenotypes. Accordingly, VLDL-R gene
polymorphism was associated with plasma triglycerides
level variability, suggesting that VLDL-R and apoE may interact to
regulate TRL metabolism in humans.
In the present sample, the VLDL-R genotype was
associated with plasma LpA-I level variability. Lipoparticles
containing ApoA-I belong to plasma high density lipoproteins (HDL),
which are heterogeneous in terms of size, lipid
composition, and apolipoprotein content. LpA-I (particles containing
apoA-I as the sole apolipoprotein) and LpA-I:A-II (particles containing
apoA-II in addition to apoA-I) are two major HDL subclasses. The
relationship between VLDL-R polymorphism and LpA-I
plasma levels may appear unexpected since HDLs do not bind in vitro to
the VLDL-R.29 This discrepancy is only apparent,
since the plasma metabolism of VLDL and HDL are closely
linked.30,31 Changes in circulating VLDL are
usually associated with reciprocal changes in HDL, LpA-I, and
LpA-I:A-II levels.32 Therefore, the association
between VLDL-R gene polymorphism and LpA-I levels is
very likely indirect, depending on an alteration of VLDL or apoE-rich
lipoprotein metabolism.
The decrease in VLDL-R 9 allele frequency in subjects
receiving lipid lowering drugs is consistent with the variation
of plasma triglycerides and of LpE:B and LpA-I levels
observed in controls. This suggests that the occurrence of
dyslipidemia is related in part to the influence of the
VLDL-R on lipid metabolism. However, this hypothesis needs
to be confirmed in appropriate studies. Moreover, no association
between VLDL-R genotype and MI was detected in the
present study, suggesting that the VLDL-R
polymorphism is not a genetic marker for MI.
The VLDL-R gene polymorphism used in this study concerns
a (CGG) triplet repeat, a sequence that is highly polymorphic in
the normal population and is thought to be unstable. Expansions of
triplet repeat sequences have been linked to heritable genetic diseases
in humans.33 Different conformations have been
proposed for the (CGG) repeat: antiparallel double helix of base
triads;34 aggregates of
G-quadruplexes;35 tetrahelical
structures,36 or intramolecular
hairpins.37,38 These nonB structures can
interfere with the VLDL-R gene transcription. Although this
hypothesis seems very attractive in explaining the association between
VLDL-R polymorphism and TRL level, it cannot be excluded
that VLDL-R polymorphism acts only as a genetic marker
in linkage disequilibrium with a mutation on the coding sequence of the
protein.
In conclusion, the results of the present study demonstrated a
modest association between VLDL-R gene polymorphism and
plasma triglycerides, LpE:B and LpA-I levels. This finding
suggests that VLDL-R may be physiologically
implicated in TRL metabolism in humans, although the impact
of this polymorphism appears less potent than that of apoE
phenotype.
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Acknowledgments
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The ECTIM Study was supported by grants from the Squibb and
Parke-Davis
Laboratories, the Mutuelle Générale de
l'Education
Nationale, the British Heart Foundation, the Institut
National
de la Santé et de la Recherche Médicale, and the
Institut
Pasteur de Lille.
Received February 14, 1997;
accepted July 22, 1997.
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