(Circulation. 1999;100:608-613.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Age-Dependent Association of Apolipoprotein E Genotype With Coronary and Aortic Atherosclerosis in Middle-Aged Men
An Autopsy Study
From the Medical School, University of Tampere, and Tampere University Hospital (E.I., T.L., P.J.K.); the Department of Human Molecular Genetics, National Public Health Institute, Helsinki (M.P.); the Department of Clinical Chemistry, Tampere University Hospital, and the Laboratory of Atherosclerosis Genetics, Tampere (E.I., T.L., T.K.); the Tampere School of Public Health, University of Tampere, and Tampere University Hospital (P.L.); and the Department of Forensic Medicine, University of Helsinki (V.S., J.P., A.P., K.H.L., A.M., K.K.L.), Finland.
Correspondence to Erkki Ilveskoski, MD, Medical School, University of Tampere, PO Box 607, FIN-33101, Tampere, Finland. E-mail ei46478{at}uta.fi
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Abstract |
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Background—Apolipoprotein E (apoE) polymorphism is one of the genetic determinants of serum cholesterol values. The apoE
4 allele has been
associated with advanced coronary heart disease (CHD) diagnosed
by angiography, but the role of the apoE genotype in
atherosclerosis has not been confirmed at vessel-wall
level, nor is any age-dependent effect of the apoE genotype on
the development of CHD known.
Methods and Results—The right and left anterior descending
coronary arteries (RCA and LAD) and the aorta from 700 male
autopsy cases (Helsinki Sudden Death Study) in 1981-1982 and 1991-1992
(average age 53 years, range 33 to 70 years) were stained for fat, and
all areas covered with fatty streaks, fibrotic plaques, and complicated
lesions were measured. In the RCA and LAD, the apoE genotype
was significantly associated with the area of total atherosclerotic
lesions in men <53 years old but not with that in older men
(P=0.0085 and P=0.041, respectively, for
age-by-genotype interaction). Men <53 years old with the
4/3 genotype showed 61% larger total atherosclerotic lesion
area in the RCA (P=0.0027) and 26% larger area in the
LAD (P=0.12) than did men with the 3/3. The apoE
4/3 was also associated with atherosclerotic lesions in the
abdominal (P=0.014) and thoracic (P=0.12)
aorta, but this effect, unlike that of the coronary arteries,
was not age-related.
Conclusions—In men, the apoE 4 allele is a significant
genetic risk factor for coronary
atherosclerosis in early middle age. This suggests that
at older age, other known risk factors of CHD play a more important
role in the atherosclerotic process than apoE polymorphisms.
Key Words: apolipoproteins • atherosclerosis • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Because apolipoprotein E (apoE) plays an important role in lipid metabolism, it is an important determinant in morbidity and mortality from atherosclerotic diseases.1 The apoE gene is polymorphic, resulting in 3 common alleles (
2, 3, and 4) and 6 different genotypes (2/2,
3/2, 4/2, 3/3, 4/3, and 4/4).2 3 The apoE
4 allele is associated with high serum total and LDL
cholesterol concentrations,4 5 6 7 which in turn
are well-established risk factors for coronary heart disease
(CHD).8 9 A recent meta-analysis of 14 studies
showed the apoE 4 allele to be associated with CHD in both men
and women.10 In all these studies, the phenotype
of CHD was diagnosed either by clinical observation or by
coronary angiography.11 12 13 14 15 16 These
diagnostic methods detect only advanced coronary
artery disease and coronary narrowings and are inappropriate
for study of the effect of apoE polymorphism on the early phase of
atherosclerosis characterized by fatty change and
raised lesions. Although this question could be solved by direct
examination of the coronary arteries, to the best of our
knowledge only 2 autopsy studies exist.17 18 In 1 autopsy
study, the association of apoE polymorphism with
atherosclerosis was found only in aorta17
and in another study only in coronary arteries.18
Thus, although the apoE genotype has been shown to be
associated with risk of elevated serum cholesterol
levels and CHD, the association between atherosclerosis
of the coronary artery wall and apoE polymorphism has not
yet been confirmed unequivocally. A Swedish twin study concluded that genetic susceptibility to death from CHD decreases at older ages.19 If apoE is an important genetic factor in the pathogenesis of atherosclerosis, it should exert its strongest effect in youth or early middle age. Such an association between genetic influence and age has never been studied with regard to apoE polymorphism and arterial atherosclerosis.
We studied an autopsy series of middle-aged Finnish men to investigate the association of apoE genotype with autopsy-confirmed atherosclerosis in the coronary arteries and aorta. We also investigated whether and how any effect of apoE polymorphism on atherosclerotic plaques varies with age.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Subjects
The Helsinki Sudden Death Study (HSDS) was launched to study the lifestyle and genetic factors predisposing to sudden death in Finnish middle-aged men who lived in Helsinki and its surroundings. The HSDS consists of 2 autopsy series collected at 10-year intervals. The first series (A series, n=400) was collected during 1981-1982 and the second series (B series, n=300) during 1991-1992. The 2 autopsy series included 700 men 33 to 70 years old (mean 53.07 years, SD 9.58 years, median 54 years) subjected to a medicolegal autopsy. Indications for an autopsy were out-of-hospital death of a previously healthy man, accidental death, suspected intoxication, suicide, or death in connection with medical treatment. A forensic autopsy is performed in this area in 42% of all deaths in people <65 years old. More than half the men died of disease, 68% of cardiac origin (Table 1
). The second most common causes
of death were intoxication and violence, most of these accidental
or self-inflicted.
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The body mass index (BMI) was calculated by dividing the weight (kg) of the cadaver by height (m) squared. The proximal parts of the right coronary arteries (RCA) and left anterior descending coronary arteries (LAD), thoracic aortas, and abdominal aortas with proximal parts of the iliac arteries were collected for analysis. The study was approved by the Ethics Committee of the Department of Forensic Medicine, University of Helsinki.
DNA Extraction and ApoE Genotyping
In the A series, DNA was extracted from paraffin-embedded
samples of cardiac muscle by the method of Isola et al.20
In the B series, DNA was isolated from frozen (-70°C) cardiac
samples by the standard phenol-chloroform method, and 
25 ng of
purified DNA was used for apoE genotyping by polymerase chain reaction
and HhaI restriction enzyme digestion as described by Hixson
and Vernier.21 The digested fragments were
electrophoresed on 12% polyacrylamide gel and visualized by
silver staining. ApoE genotype could be successfully determined
in 671 cases.
Measurements of Area Involved With Atherosclerotic Lesions
We measured the areas of the different types of atherosclerotic
lesions in the RCA and LAD and thoracic and abdominal aortas. At
autopsy, the arteries were dissected free, opened, and attached to a
card, and then fixed in buffered formalin. The vessel wall was stained
with the Sudan IV fat-staining method. The definition of
atherosclerosis was based on the protocols of 2
international studies: the International
Atherosclerosis Project, Standard Operating
Protocol 1962,22 and the WHO Study Group in
Europe.23 An area stained red with Sudan IV and showing no
other types of changes underlying it was classified as fatty streak. An
elevated plaque that exhibited no ulceration or thrombosis was
considered a fibrotic lesion. Any plaque area with ulceration or
thrombosis was classified as a complicated lesion. The area involved
with fatty streaks, fibrotic plaques, and complicated lesions was
measured by computer-assisted planimetry, which is standard planimetric
equipment connected to a personal computer. It measures the exact area
of a single lesion in square millimeters. The areas of different types
of lesions were expressed in percentages by dividing the lesion area by
the total area of the artery wall and multiplying by 100%. The total
atherosclerotic lesion area of the arterial wall was the
total areas of fatty streak and fibrotic lesions. Because the
complicated lesions in the arterial wall were always
incorporated into either the fatty streak or the fibrotic lesion area,
or both, the complicated-lesion area was analyzed
separately.
Of the series of 700 men, arterial samples for the planimetric measurements were available from 596 men for the analysis of the LAD and from 440 men for the analysis of the RCA. Planimetric data of the atherosclerosis in the thoracic (n=256) and abdominal (n=259) aorta were available only for the B series.
Statistical Analyses
Data analysis was based on ANCOVA. Data were
analyzed in square-root form, but the results are displayed as
crude data. In the analysis, only the most common apoE
genotypes, 3/2, 3/3, and 4/3, were included because in
this way, the 3/3 group provides an internal control to separate the
effect of the 2 and 4 alleles. Furthermore, to study the
effect of age, the series was divided according to the average age,
53.1 years (median 54 years), of the series into 2 subgroups: men <53
and men 
53 years old. ApoE genotype status and age subgroup
were used as factors in the ANCOVA, and in addition, the series status
(A or B) was taken as a factor in the ANCOVA to eliminate its possible
confounding effect. The possible confounding effect of BMI was
controlled for, being taken as a covariate. If a significant
interaction of age and apoE was observed, a second ANCOVA was performed
for each age subgroup separately. In this analysis, age as a
continuing variable was a second covariate in addition to BMI.
Finally, the differences between 3 genotypes were
analyzed with the Scheffé post hoc test. Computation was
carried out with Statistica Version 5.1 (StatSoft Inc) on a personal
computer.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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ApoE Genotypes, Allele Frequencies, and Characteristics of the Subjects
ApoE genotype and allele frequencies for both age subgroups are shown in Table 2
, and they
are consistent with other studies of Finnish
populations.5 6 There were no differences in
genotype and allele frequencies between the age subgroups.
Age and BMI did not vary between different apoE genotypes, as
shown in Table 1
.
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Coronary Atherosclerosis and ApoE
Genotype
A significant apoE genotype–by-age interaction was
observed on fatty streak (P=0.027) and total atherosclerotic
(P=0.0085) area involvement in the RCA (see Table 3). The apoE genotype was
associated with the RCA atherosclerosis only in men
<53 years old, and in this age subgroup, the carriers of 4/3
genotype had on average a 54% increase in the area of fatty
streaks and a 61% increase in the total atherosclerotic area
involvement compared with the carriers of 3/3 (P=0.0471
and P=0.0027 for 3/3 versus 4/3; Scheffé post
hoc test). The carriers of 3/2 tended to have lower values than the
carriers of 3/3, but the differences were statistically
insignificant. The association of apoE with fibrotic lesion area was
highly significant (P=0.009) in men <53 years old, although
the interaction of apoE and age was insignificant (P=0.17).
ApoE 4/3 genotype was also associated with the highest
values of the fibrotic lesion area involvement in men <53 years old
(P=0.0089 for 3/3 versus 4/3; Scheffé post hoc
test). ApoE had no significant effect on the mean percentage area of
complicated lesions in the RCA.
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In the LAD, there was a significant interaction of apoE and age on the
total atherosclerotic lesion area (P=0.041) and a borderline
interaction on fatty streaks (P=0.10) (see Table 3).
ApoE genotype was significantly associated with the LAD
atherosclerosis only in men <53 years old, and the
4/3 carriers tended to have higher mean percentage area of fatty
streak and total atherosclerotic lesion involvement than the 3/3
group (P=0.1371 and P=0.1190 for 3/3 versus
4/3; Scheffé post hoc test). The carriers of the 4/3
genotype had on average a 26% increase in the total
atherosclerotic area involvement compared with the carriers of
3/3.
Aortic Atherosclerosis and ApoE Genotype
The association of apoE genotype with aortic
atherosclerosis was not age-dependent (P=NS
for apoE genotype–by-age interaction). In the abdominal aorta,
apoE genotype was significantly associated with fibrotic lesion
(P=0.010) and total atherosclerotic lesion
(P=0.014) area (see Table 4).
The 4/3 genotype was associated with greater fibrotic and
total atherosclerotic lesion area involvement than 3/3
(P=0.3095 and P=0.0340 for 3/3 versus 4/3;
Scheffé post hoc test) or 3/2 (P=0.0240 and
P=0.0578 for 3/2 versus 4/3; Scheffé post hoc
test). ApoE genotype had a borderline association with fatty
streaks in both thoracic and abdominal aorta. The carriers of the
4/3 genotype consistently had the highest area of
atherosclerotic lesion involvement in both parts of the aorta. In
addition, the covariate age had a major effect on the aortic
atherosclerosis. ApoE polymorphism was not related
to complicated lesions of the aorta.
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The Figure shows the effect of apoE
genotype on the mean percentage area of total atherosclerotic
lesions in thoracic and abdominal aorta and in RCA and LAD
coronary arteries. In aorta, the effect of apoE
genotype on the lesion area was similar in both age subgroups,
and the men 53 years old had higher values than younger men. In the
coronary arteries, however, age modulated the effect of apoE
genotype on the lesion area: apoE was associated with the
lesion area only in men <53 years old but not in the subgroup of older
men. In other words, the association of the apoE polymorphism with
the area of total atherosclerotic lesions varied with age in the
coronary arteries but not in the aorta.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The 2 main findings of our study are that apoE polymorphism seems to associate with atherosclerotic lesion area in both the coronary arteries and the aorta, and moreover, in the RCA and LAD, the association of apoE polymorphism is age-dependent. Our study demonstrates, at the vessel-wall level, that the apoE
4
allele is a significant risk factor for CHD and confirms the
results of several clinical and angiographic
studies.11 12 13 14 15 16 We could find no significant protective
role for the 2 allele in coronary or aortic
atherosclerosis, although the carriers of the
allele tended to have less lesion involvement than the 3/3
group.
ApoE polymorphism is known to be associated with high serum lipid
levels,4 5 6 7 which are important factors particularly in
development of early so-called type I to IV lesions that only minimally
reduce the lumen.24 Therefore, it can be hypothesized that
in the process of atherosclerosis, apoE
polymorphism affects mainly the first steps of the pathogenesis of
atherosclerosis. Coronary angiography is
usually performed only after clinically evident symptoms appear. Thus,
for investigation of early stages of (coronary)
atherosclerosis without significant stenosis,
other kinds of studies are needed, such as autopsy series. Only 2
previous autopsy studies have investigated the association of apoE with
atherosclerosis at the vessel-wall level, with
different results.17 18 In the Pathobiological
Determinants of Atherosclerosis in Youth (PDAY)
study,17 the apoE 4 allele was significantly
associated with total lesion area in thoracic and abdominal aorta of
young men. However, the PDAY group could find no relation between apoE
polymorphism and atherosclerotic lesions in the RCA.17
Conversely, an autopsy study on 130 Alaskan Natives reported an
association between the 4 allele and
atherosclerosis in the LAD and RCA, but not in the
aorta.18 In our autopsy study, we found an association
between the apoE 4 allele and atherosclerosis
both in the coronary arteries and in the aorta. Differences
between results of these 2 autopsy studies and ours can be explained by
different kinds of study structure, study population, or age
distribution, as well as by differences in methods. In the PDAY study,
subjects were young men 15 to 34 years old, whereas the Alaskan Natives
were both men and women 9 to 85 years old. Our subjects were
middle-aged men, 33 to 70 years old, prone to
atherosclerosis and sudden death. In both the PDAY and
the Alaskan Natives studies, the percentage area of atherosclerotic
lesions was graded visually, whereas we used computer-assisted
planimetry. In our technique, we measured the area of atherosclerotic
lesions in the arteries. In addition, Finns are particularly suitable
for genetic studies of coronary atherosclerosis
because of their high, although declining, prevalence of
CHD25 26 as well as their genetic homogeneity, a result of
geographic isolation and the founder effect.27
Our study suggests that the effect on coronary
atherosclerosis of the apoE 4 allele is
age-dependent. This finding is in agreement with the conclusions of the
Swedish twin study that when people die of CHD at younger ages, genetic
mechanisms play a greater role than in deaths at an older
age.19 A prospective population-based study on the elderly
found no relationship between apoE 4 and CHD incidence or mortality,
which also supports our finding.28 In addition, there is
evidence that the effect of the 4 allele on serum
cholesterol is also age-dependent and that it decreases at
older ages.29 Our findings imply that this decrease in
effect also applies to the effect of apoE polymorphism on
coronary atherosclerosis as confirmed by
autopsy.
Why, then, does the apoE 4 allele seem to be associated with
coronary atherosclerosis only in the younger
age subgroup? If a trait is age-dependent, with risk increasing with
age (as in CHD), selection for younger affected individuals probably
increases the genetic contribution to the disease status of the
individual in question. With age, accumulation of other risk factors
and phenocopies dilutes the effect of initial participants in
the pathogenic cascade. So, when younger subjects are selected for the
study, the proportion of individuals at genetic risk rises and trait
differences should be seen more clearly, as did occur in our study.
Further, at older age, the extent of the
atherosclerosis reduces the variability, and therefore,
an association of a single genetic factor with the disease might be
prevented.
The association of apoE polymorphism with aortic atherosclerosis, in turn, was not age-dependent. This might be due to differences in the hemodynamic conditions between the coronary artery and the aorta. The mechanical forces determine, in large part, the susceptibility of a lesion to progress.24 In the coronary arteries, the lesions may be more progression-prone than in the aorta. This could also partly explain the lack of association of apoE polymorphism with coronary atherosclerosis at older age. It has been shown that the fatty streak lesions in the coronary arteries increase throughout life, but in the aorta, the lesions tend to remain at the same level after middle age.30 This suggests that the development of atherosclerotic lesions in the coronary arteries differs from that in the aorta.
In conclusion, in the present autopsy study of middle-aged men, the
apoE 4/3 genotype had a larger area of
atherosclerosis both in the coronary arteries
and in the aorta than the 3/3 genotype. In the LAD and RCA,
the association was age-dependent. The fact that the apoE 4
allele was associated with coronary
atherosclerosis only before the age of 53 years
suggests that at older age, other known or at present still unknown
risk factors may play a more important role in the atherosclerotic
process than apoE polymorphisms. We thus conclude that apoE
polymorphism is one of the genetic factors that participate in the
process of atherosclerosis in men. It might prove
useful to determine the apoE genotypes of men at high risk of
CHD already at early middle age so as to take preventive measures
against coronary atherosclerosis, particularly
for those carrying the 4 allele. The 4 allele is known to
be associated with sensitivity to dietary interventions to lower serum
cholesterol.31 32
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Acknowledgments |
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This study was supported by grants from the Medical Research Fund of the Tampere University Hospital, the Yrjö Jahnsson Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Medical Foundation, the Finnish Foundation of Alcohol Research, and the Elli and Elvi Oksanen Fund of the Pirkanmaa Fund under the auspices of the Finnish Cultural Foundation. Dr Lehtimäki was supported by a fellowship from the Emil Aaltonen Foundation. The authors thank Seppo Tyynelä for planimetric measurements, Antti Lammi for technical help with the DNA extraction procedure, and Mervi Niittylahti and Outi Lumme for skillful laboratory assistance.
Received February 3, 1999; revision received April 20, 1999; accepted May 19, 1999.
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A.J. C. Slooter, M. Cruts, A. Hofman, P. J. Koudstaal, D. van der Kuip, M.A. J. de Ridder, J.C. M. Witteman, M.M. B. Breteler, C. Van Broeckhoven, and C. M. van Duijn The impact of APOE on myocardial infarction, stroke, and dementia: The Rotterdam Study Neurology, April 13, 2004; 62(7): 1196 - 1198. [Abstract] [Full Text] [PDF]
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A. E. Roher, C. Esh, T. A. Kokjohn, W. Kalback, D. C. Luehrs, J. D. Seward, L. I. Sue, and T. G. Beach Circle of Willis Atherosclerosis Is a Risk Factor for Sporadic Alzheimer's Disease Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2055 - 2062. [Abstract] [Full Text] [PDF]
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P. J. Pollanen, P. J. Karhunen, J. Mikkelsson, P. Laippala, M. Perola, A. Penttila, K. M. Mattila, T. Koivula, and T. Lehtimaki Coronary Artery Complicated Lesion Area Is Related to Functional Polymorphism of Matrix Metalloproteinase 9 Gene: An Autopsy Study Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1446 - 1450. [Abstract] [Full Text] [PDF]
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