Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:714-720
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:714-720.)
© 1995 American Heart Association, Inc.
The Lipoprotein Lipase HindIII Polymorphism Modulates Plasma Triglyceride Levels in Visceral Obesity
Marie-Claude Vohl;
Benoît Lamarche;
Sital Moorjani;
Denis Prud'homme;
André Nadeau;
Claude Bouchard;
Paul-J. Lupien;
Jean-Pierre Després
From the Lipid Research Center, CHUL Research Center (M.-C.V., B.L.,
S.M., P.-J.L., J.-P.D.), the Physical Activity Sciences Laboratory (D.P.,
C.B.), and the Diabetes Research Unit, CHUL Research Center (A.N.), Laval
University, Ste-Foy, Québec.
Correspondence to Dr Jean-Pierre Després, Lipid Research Center CHUL, 2705 Laurier Blvd, Québec, GIV 4G2, Canada.
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Abstract
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Abstract The aim of this study was to investigate the
potential
interaction between the lipoprotein lipase (LPL)
HindIII polymorphism
and visceral adipose tissue (AT)
accumulation in the modulation
of triglyceride levels in visceral
obesity. The LPL-
HindIII
genotype was determined by
polymerase chain reaction in 52 men.
Twenty-three subjects were
heterozygous (+/-) and 28 were homozygous
(+/+) for the presence of
the restriction site. One subject
who was homozygous for the - allele
was excluded from analysis.
Body mass index (BMI), fasting insulin
level, and visceral AT
area as measured by computed tomography were
positively correlated
with triglyceride levels only in subjects
homozygous for the
+ allele. Furthermore, whereas these variables were
negatively
correlated with plasma HDL
2 cholesterol
concentrations in the
+/+ group, these associations were not found in
+/- heterozygotes,
with the exception of BMI. To further investigate
the interaction
of the LPL-
HindIII polymorphism with
visceral obesity and hyperinsulinemia,
the two genotype groups
were further subdivided on the basis
of BMI (low versus high), fasting
insulin level (low versus
high), and visceral AT area (low versus
high), and their lipoprotein
profiles were compared. Elevated levels of
abdominal visceral
AT were significantly associated with increased
triglyceride
concentrations in +/+ homozygous men, suggesting that
visceral
obesity may lead to hypertriglyceridemia in the presence of
the
+/+ genotype. In the +/- group, variation in the amount of
visceral
AT was not associated with differences in triglyceride
concentration.
However, hypertriglyceridemia and an increased
cholesterol-toHDL
cholesterol ratio were observed in the
hyperinsulinemic state
irrespective of LPL-
HindIII
genotype status. Finally, similar
positive correlations were
observed between visceral AT accumulation
and plasma insulin level in
the homozygous (+/+) and heterozygous
(+/-) groups, suggesting that
the hyperinsulinemicinsulin-resistant
state that is frequently
associated with visceral obesity is
independent of
LPL-
HindIII genotype. These results suggest that
the
HindIII polymorphism may modulate the magnitude of the
dyslipidemic
state associated with visceral obesity.
Key Words: lipoprotein lipase visceral obesity insulin hypertriglyceridemia candidate genes
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Introduction
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Abdominal obesity is an important risk
factor for cardiovascular
disease and has been associated with several
metabolic complications,
such as hypertension, dyslipidemia, insulin
resistance, and
noninsulin-dependent diabetes
mellitus.
1 2 3 4 5 6 7 8 Studies that have assessed the distribution
of body fat by
computed tomography (CT) have concluded that the amount
of fat
located in the abdominal cavity, the so-called intra-abdominal
or
visceral fat, is the most critical correlate of metabolic
disturbances
associated with abdominal obesity.
9 10 11
However, severe metabolic
complications are not observed in all
viscerally obese subjects,
thereby suggesting that genetic
predisposition may be a key
factor in the susceptibility of viscerally
obese individuals
to metabolic disorders.
12 We have
previously proposed that
genetic variation at several loci that affect
lipoprotein metabolism
may alter the relation between visceral obesity
and plasma lipoprotein
levels.
4 12 13 In this regard, we
have shown that the magnitude
of hypertriglyceridemia associated with
visceral obesity and
hyperinsulinemia is influenced by three common
alleles at the
apo E gene locus.
14 15 We have also
reported that variation
at the apo B gene locus, as examined by
EcoRI polymorphism,
modulates the relation of visceral
obesity to plasma apo B and
LDLapo B levels.
16 These two
examples provide evidence
that the impact of visceral obesity on the
plasma lipoprotein-lipid
profile is partly dependent on the variation
at two loci for
apo B and apo E genes, both of which are involved in
lipid transport
as well as lipoprotein catabolism via specific
cell-surface
receptors.
Lipoprotein lipase (LPL) is an important enzyme for hydrolysis of
triglyceride-rich lipoproteins, and its activity is positively
correlated with the plasma HDL cholesterol level. An LPL gene
HindIII polymorphism has been found in association with
hypertriglyceridemia,17 18 19 decreased HDL cholesterol
levels,20 increased apo B levels,19 coronary
heart disease (CHD),19 21 and some features of the insulin
resistance syndrome.22 Because these metabolic
complications are also characteristic features of visceral obesity, we
have investigated the possibility that the LPL-HindIII
polymorphism may be involved in the relation of visceral obesity to
plasma insulin and lipoprotein concentrations.
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Methods
|
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Subjects
A cohort of white men were recruited to participate in studies
that
were designed to investigate associations between obesity,
regional
adipose tissue (AT) distribution measured by CT, and plasma
lipoprotein
levels.
11 Fifty-two subjects of this cohort
agreed to participate
in this study involving DNA analysis. They
were all nonsmokers
and free from metabolic disorders that required
pharmacological
treatment. All subjects were sedentary, and their body
weight
was stable at the time of investigation. The study was approved
by
the Ethics Committee on Human Research of Laval University.
DNA Analysis
Approximately 30 mL of peripheral venous blood was collected in
tubes containing EDTA and kept frozen at -20°C until processing. DNA
was extracted from leukocytes by standard methods after digestion with
proteinase K and extraction with phenol/chloroform. Polymerase chain
reaction (PCR) amplification was performed by using primers for the
HindIII restriction site located in intron 8 of the LPL
gene.18 Reactions were performed in a Perkin-Elmer Cetus
thermal cycler (model TC) under the following conditions: initial
denaturation at 95°C for 3 minutes; followed by 30 cycles at 95°C
for 1 minute, 60°C for 30 seconds, and 72°C for 1 minute; and a
final extension of 10 minutes at 72°C. The reaction volume of 50 µL
contained 1.0 U Taq polymerase (Perkin-Elmer Cetus), 150 ng
genomic DNA, 50 pmol of each oligonucleotide, and 3 µmol dNTP in the
buffer recommended by the manufacturer. After amplification, 12 U
HindIII was added to the PCR products and digested for 3
hours at 37°C. The resulting fragments were separated by size on an
8% nondenaturing polyacrylamide gel. The gels were run for 2 hours at
200 V, stained with ethidium bromide, and then photographed under UV
transmitted light. The size of DNA fragments was estimated using PUC
19digested Sau3A as molecular-weight standards. The
amplified fragment had a size of 1.3 kb, and after digestion with
HindIII, the + allele cut by HindIII resulted in
fragments of 600 and 700 bp, whereas the - allele not cut by
HindIII retained the size of 1.3 kb.
Measurements of Total Body Fat
Body density was measured by the hydrostatic weighing
technique.23 Percent body fat was estimated from density
by using the Siri equation.24 Fat mass was obtained by
multiplying percent body fat by body weight. Pulmonary residual volume
was measured with the helium-dilution method of Meneely and
Kaltreider.25 Waist and hip circumferences were measured
by standardized procedures recommended by the Airlie
conference.26
CT
Cross-sectional abdominal subcutaneous and visceral AT areas
were determined by CT with a Siemens Somatom DRH scanner as previously
described.27 Briefly, the subjects were examined in the
supine position with both arms stretched above the head. CT scans were
performed at the abdominal level between the fourth and fifth lumbar
vertebrae by using a radiograph of the skeleton as a reference to
establish the position of the scan to the nearest millimeter. Total and
visceral AT areas were calculated by delineating these areas with a
graph pen and then computing the AT surfaces by using an attenuation
range of -190 to -30 Hounsfield units.28 29 Abdominal
visceral AT area was measured by drawing a line within the muscle wall
surrounding the abdominal cavity.
Oral Glucose Tolerance Test
A 75-g oral glucose tolerance test (OGTT) was performed in the
morning after an overnight fast. Blood samples were collected through a
venous catheter from an antecubital vein at 15 minutes before and at 0,
15, 30, 45, 60, 90, 120, 150, and 180 minutes after glucose ingestion
for determination of plasma glucose and insulin concentrations. Plasma
glucose was measured enzymatically,30 whereas plasma
insulin was measured by radioimmunoassay with polyethylene glycol
separation.31 Plasma glucose and insulin areas under the
curve during the OGTT were determined by the trapezoid method.
Plasma Lipoprotein Measurements
Blood samples were obtained in the morning after a 12-hour fast
from an antecubital vein into Vacutainers (Becton Dickinson) containing
EDTA. Cholesterol and triglyceride levels in plasma and lipoprotein
fractions were measured enzymatically on an RA-1000 analyzer (Technicon
Instruments Corp). VLDLs (d<1.006 g/mL) were isolated by
ultracentrifugation,32 and the HDL fraction was obtained
after precipitation of apo Bcontaining lipoproteins in the
infranatant (d>1.006 g/mL) with heparin and
MnCl2.33 The cholesterol content of
HDL2 and HDL3 subfractions was
determined after precipitation of HDL2 with dextran
sulfate.34 Apo B and LDLapo B concentrations were
measured in the plasma and infranatant, (d>1.006 g/mL)
respectively, by using the rocket immunoelectrophoretic method of
Laurell35 as previously described.36
AT Biopsies and AT LPL Activity
A subsample of twenty-five subjects gave their informed consent
for AT biopsies. Approximately 500 mg of AT was surgically removed
under local anesthesia from the abdominal (lateral to the umbilicus)
and femoral (anterior mid-thigh) adipose depots. AT samples were kept
frozen at -80°C for later measurements of heparin-releasable
activity37 as previously described.38 Another
sample of AT was digested with collagenase,39
and isolated adipocytes were measured to determine mean fat cell
size.40 The density of triolein was used to transform AT
cell volume into fat cell weight. AT LPL activity was expressed in
micromoles of free fatty acid per hour per 106
cells.
Plasma Postheparin LPL Activity
After a 12-hour fast, blood was collected from subjects 10
minutes after they had received an injection of heparin (10 IU/kg body
wt IV). Assays for enzyme activity were performed with a modification
of the method of Nilsson-Ehle and Ekman,41 as previously
described.42 Briefly, plasma LPL activity was measured by
using glycerol tri[14C]oleate as the substrate in an
artificial emulsion prepared in 0.1 mol/L Tris-HCl buffer (pH 8.0)
containing Triton X-100, and the delipidated human serum samples were
incubated at 30°C for 20 minutes in the presence or absence of 1.0
mol/L NaCl. Free fatty acids released during incubation were
selectively extracted, and an aliquot was counted for 14C
radioactivity. LPL activity was calculated as the lipase activity
sensitive to 1.0 mol/L NaCl from the total lipase activity (without
NaCl). LPL activity is expressed as nanomoles of oleic acid released
per milliliter of plasma per minute.
Statistical Analysis
Comparisons between the two genotype groups were
performed with Student's t test. Associations between
variables were analyzed within each group by using Pearson's
correlation coefficient. Subjects were subdivided into groups of low
versus high body mass index (BMI), low versus high visceral AT areas,
and low versus high fasting insulin levels, with a BMI of <25
kg/m2 as the low value and a BMI of >27 kg/m2
as the high value.43 For visceral AT areas, the
100-cm2 value proposed by Després and
Lamarche44 was used as the cutoff point, as it
represents the lower limit value associated with significant
but moderate disturbances in the CHD risk profile. The median value
(71.5 pmol/L) of the fasting plasma insulin distribution in the overall
group was selected as an arbitrary cutpoint to define subjects with low
or high insulin levels. Subjects were also further subdivided on the
basis of LPL-HindIII genotype. A 2x2 ANOVA was then
performed to assess BMI, visceral AT, or insulin effects versus the
effect of the LPL-HindIII genotype. Comparisons
among subgroups were performed by using multiple-comparison ANOVA
analyses and the Duncan post hoc test in situations where a significant
group effect was observed. All statistical analyses were performed with
the SAS statistical package (SAS Institute).
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Results
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Fifty-two subjects were analyzed for the LPL-
HindIII
polymorphism.
The relative allele frequencies were .24 and .76 for
the - allele
(noncarrier of the restriction site) and the + allele,
respectively.
Subjects were classified into two groups: (1) those who
were
heterozygous for the
HindIII polymorphism (+/-
group, n=23)
and (2) those who were homozygous for the + allele (+/+
group,
n=28). One subject who was homozygous for the - allele was
excluded
from analysis. The subjects' characteristics according to
LPL
genotype are presented in Table 1

. The
two genotype groups were
comparable for age, BMI, fat mass,
waist-to-hip ratio, visceral
AT areas, fasting insulin, and glucose and
insulin areas during
OGTT. Results of Table 2

show no
difference in plasma lipoprotein
levels between the two groups.
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Table 1. Anthropometric and Metabolic Characteristics of the
Two Groups of Men Defined on the Basis of Lipoprotein Lipase
(LPL)HindIII Polymorphism
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Associations between BMI, visceral AT area, and triglyceride
concentration in the two genotype groups are shown in Fig 1
. Whereas plasma triglyceride concentrations were
positively associated with BMI, visceral AT area, and fasting insulin
levels in the +/+ genotype group, no significant associations
were found in men with the +/- genotype. Significant negative
correlations were also observed between BMI, visceral AT area, fasting
insulin, and plasma HDL2 cholesterol concentration
in the +/+ genotype group (Fig 2
). These
associations were not found in the +/- group, with the exception of
BMI. We then tested the hypothesis that this polymorphism could
modify the relationship between visceral obesity and fasting plasma
insulin level and the insulin response during the OGTT. Essentially
similar associations among these variables were found in both
genotypes (.60
r
.75, P<.001; data
not shown). No significant correlation was observed between visceral AT
area and plasma LDL cholesterol, LDLapo B, and total apo B in both
genotypes (data not shown).

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Figure 1. Scatterplots showing correlations between body mass
index (BMI), visceral adipose tissue (AT) area measured by computed
tomography, fasting plasma insulin level, and fasting plasma
triglyceride concentration in groups of men defined on the basis of
their lipoprotein lipase (LPL)HindIII genotype.
Individuals homozygous for the + allele (allele cut by the restriction
enzyme HindIII) were included in the +/+ group (n=26),
whereas subjects heterozygous for the - allele (no HindIII
restriction site) were included in the +/- group (n=23).
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Figure 2. Scatterplots showing correlations between body mass
index (BMI), visceral adipose tissue (AT) area measured by computed
tomography, fasting plasma insulin level, and plasma
HDL2 cholesterol concentration in the two groups of
men subdivided on the basis of their lipoprotein lipase
(LPL)HindIII genotype (n=20 and 25 for the +/-
and +/+ genotypes, respectively).
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To further examine the potential interaction between BMI, fasting
insulin level, visceral AT area, and LPL HindIII
genotype with plasma lipoprotein levels, subjects in both
genotypes were then subdivided according to BMI (low BMI<25
kg/m2; high BMI>27 kg/m2). No significant
differences were observed in plasma triglyceride levels among the four
subgroups, although a trend was noted for higher triglyceride
concentrations among overweight men with the +/+ genotype (Fig 3
). When subjects were subdivided on the basis of
visceral AT areas, men with elevated levels of visceral AT (area
100
cm2) and with the +/+ genotype had higher plasma
triglyceride levels compared with +/+ subjects with low levels of
visceral AT (Fig 3
). In the +/- group, variation in the amount of
visceral AT was not associated with differences in triglyceride
concentration. Thus, the hypertriglyceridemic effect associated with
visceral obesity appeared to be restricted to the +/+ genotype.
Subgroups were also formed on the basis of fasting insulin levels (low
versus high) by using the median value (71.5 pmol/L) of the fasting
insulin distribution of the whole sample as the cutoff point. Elevated
triglyceride levels were observed in the hyperinsulinemic state,
irrespective of LPL genotype.

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Figure 3. Bar graphs showing comparison of plasma triglyceride
levels within each lipoprotein lipase (LPL)HindIII
genotype between men with low vs high body mass index (BMI),
low vs high fasting insulin level, and low vs high visceral adipose
tissue (AT) area. The median value of the insulin distribution in the
overall group was used to define subjects with low or high insulin
levels. The number within each bar identifies each subgroup, whereas
the number above the SE indicates a significant difference with the
corresponding group (P .05). Numbers of subjects in each
subgroup (from left to right) were n=7, 16, 8, and 18 for BMI; n=7, 16,
9, and 17 for visceral AT area; and n=11, 12, 11, and 15 for fasting
insulin level.
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Similar analyses were also performed for the cholesterol-toHDL
cholesterol ratio (not shown). No significant differences were observed
among the four subgroups on the basis of low or high BMI. Visceral
obesity had a tendency to be associated with a higher
cholesterol- toHDL cholesterol ratio in the presence of the +/+
genotype, whereas in +/- subjects, high or low visceral AT
areas could not discriminate between a high and low cholesterol-toHDL
cholesterol ratio. Finally, a higher cholesterol-toHDL cholesterol
ratio was observed in the two groups with high insulin levels,
suggesting that this relation may be independent of the
HindIII genotype.
Although the LPL polymorphism identified with HindIII is
found in a noncoding DNA sequence (intron 8) of the gene, we tested
whether it would influence AT and postheparin LPL activities (Table 3
). No significant differences were found between the
two genotypes, suggesting that the presence or absence of the
HindIII restriction site does not alter plasma and AT LPL
activities. When subgroups were formed on the basis of low and high
BMI, visceral AT areas, and fasting insulin, no significant differences
were observed between subgroups for AT and postheparin LPL activities
(data not shown).
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Discussion
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Abdominal obesity combined with an increased accumulation of
visceral
AT is associated with alterations in indices of plasma
glucose-insulin
homeostasis and in the plasma lipoprotein
profile.
10 11 45 However, because substantial
heterogeneity remains among abdominally
obese subjects,
we have proposed that visceral obesity represents
a condition
that may exacerbate the genetic susceptibility to
noninsulin-dependent
diabetes mellitus, dyslipoproteinemia, and
CHD.
4 13 In this
regard, we have previously shown that
genetic variation at two
major genes involved in lipoprotein metabolism
has divergent
effects on dyslipidemia in visceral obesity. An
EcoRI variant
in the apo B gene appeared to be associated
with elevated apo
B and LDLapo B concentrations in visceral
obesity,
16 whereas the apo E polymorphism seemed to
influence plasma triglyceride
levels in abdominally obese,
hyperinsulinemic subjects,
14 15 in contrast to its usual
effect on LDL cholesterol in the general
population.
46
Because LPL activity is an important correlate
of plasma
triglyceride
47 48 and HDL cholesterol
49
levels,
the main objective of this study was to verify whether the
LPL-
HindIII
polymorphism could influence the magnitude
of dyslipidemia (hypertriglyceridemia
and low HDL cholesterol
concentrations) generally observed in
visceral obesity. Results of the
present study suggest that
visceral obesity may be associated with
hypertriglyceridemia
and low HDL cholesterol concentrations in subjects
who are homozygous
for the + allele of the
HindIII
restriction site in intron 8
of the LPL gene. The + allele of
LPL-
HindIII has been previously
associated with
hypertriglyceridemia and premature CHD
17 18 19 21 and with
low HDL concentrations.
20 To the best of our
knowledge,
this is the first time that an interaction with visceral
obesity, a
common correlate of the high triglyceridelow
HDL cholesterol
dyslipidemic phenotype, has been reported.
In a sample of 370 normoglycemic Hispanic and 520 normoglycemic
non-Hispanic white subjects, Ahn et al22 have recently
reported that individuals with the +/+ genotype at the
LPL-HindIII restriction site had higher fasting plasma
insulin and triglyceride concentrations and reduced HDL concentrations
compared with subjects with the +/- genotype. In the
present study, the +/+ genotype was associated with
hypertriglyceridemia and low HDL concentrations in the presence of
visceral obesity. However, essentially similar correlations were noted
between visceral AT accumulation and plasma insulin levels in the two
genotype groups, suggesting that the hyperinsulinemic effect
associated with visceral obesity was not altered by the
HindIII polymorphism at the LPL locus. Thus, the
magnitude of the hyperinsulinemic/insulin-resistant state associated
with visceral obesity appears to be independent of HindIII
genotype. In contrast to the study of Ahn et al,22
the present results do not support the notion that the
LPL-HindIII genotype may be a marker for
susceptibility to develop an insulin-resistant/hyperinsulinemic state.
With regard to hypertriglyceridemia and a decreased HDL cholesterol
level, the polymorphism may exacerbate the dyslipidemic state that
is associated with excess visceral AT. At this time, we cannot rule out
the possibility that the difference between the two studies is caused
by low power level resulting from the small sample size on which the
present report is based.
The +/+ HindIII genotype altered the association
between BMI, insulinemia, and visceral obesity with fasting
triglyceride levels because significant correlations were found only in
the +/+ group. Essentially similar results were observed when plasma
HDL2 cholesterol was used as the dependent variable.
These effects on triglyceride and HDL2 cholesterol
levels are consistent with a hypothesis of a physiological role for
LPL, which not only hydrolyzes triglyceride-rich lipoproteins but also
modulates plasma HDL levels. Several metabolic and experimental studies
have shown that a high LPL activity is generally associated with high
plasma HDL levels, especially the HDL2
subfraction.49 For these reasons, it is not surprising
that triglycerides and HDL2 cholesterol were altered
in a reciprocal manner, but our results emphasize that the magnitude of
this effect is much greater in the homozygous +/+ genotype.
The LPL-HindIII polymorphism is located in intron 8 of
the LPL gene and therefore should not be associated with differences in
enzyme activity and theoretically, should not be the cause of the
observed effects. Accordingly, femoral and abdominal AT LPL activities
were not different between the two genotypes; postheparin
plasma LPL activity was also similar in the two groups. Thus, it is
likely that the LPL-HindIII polymorphism is in linkage
disequilibrium with a functional mutation in the LPL gene or in another
gene that could predispose individuals to dyslipidemia. In addition,
the observed effect may also be due to differences in regulation of the
LPL gene between the two genotypes. Insulin is an important
regulator of the LPL enzyme, and this hormone may regulate LPL at the
mRNA50 and/or posttranscriptional51 level.
For example, the + allele could be associated with a functional LPL
enzyme that is less sensitive to insulin and may result in a reduced
response of LPL to insulin in visceral obesity. Other regulators could
also be involved in mediating the effects described here.
In conclusion, these results indicate that the dyslipidemia associated
with abdominal visceral obesity, particularly plasma triglycerides and
HDL2 cholesterol, may be modulated to a significant
extent by variation in the LPL gene, despite its lack of effect on
measurable LPL activity. Thus, this LPL polymorphism may be
considered as another genetic marker that influences plasma lipoprotein
levels and presumably CHD risk in relation to the level of visceral
fat. Obviously, it will be necessary to examine interactions among
several candidate genes for a proper assessment of CHD risk. However,
studies based on large cohorts will be needed to examine even simple
interactions among apo E, apo B, and LPL genes.
 |
Acknowledgments
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This study was supported by the Medical Research Council of
Canada
(MRC), the Heart and Stroke Foundation of Canada, and the
Canadian
Diabetes Association. M.-C. Vohl and B. Lamarche received MRC
fellowships
during the course of this study. The authors wish to
express
their gratitude to the research personnel involved in
collection
of the data. The contribution of the staff of the Lipid
Research
Center, Diabetes Research Unit, and Physical Activity Sciences
Laboratory
is acknowledged.
Received December 10, 1994;
accepted March 1, 1995.
 |
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