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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2186-2190
Synergistic Effects of Prothrombotic Polymorphisms and Atherogenic
Factors on the Risk of Myocardial Infarction in Young Males
By
Aida Inbal,
Dov Freimark,
Baruch Modan,
Angela Chetrit,
Shlomi Matetzky,
Nurit Rosenberg,
Rima Dardik,
Zvia Baron, and
Uri Seligsohn
From the Institute of Thrombosis and Hemostasis, Department of
Hematology, the Institute of Cardiology, and the Institute of Clinical
Epidemiology, Chaim Sheba Medical Center, Tel-Hashomer and Sackler
School of Medicine, Tel-Aviv University and the Israeli Defense
Forces, Israel.
 |
ABSTRACT |
Several recent studies evaluated a possible effect of the
prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C  T, factor V (F V) nt 1691G
A (F V Leiden), and factor II (F II) nt 20210 G A
on the risk of myocardial infarction. In the present study, we analyzed
the effect of these prothrombotic polymorphisms, as well as
apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and
hypercholesterolemia, on the risk of myocardial infarction in young
males. We conducted a case-control study of 112 young males with first
acute myocardial infarction (AMI) before the age of 52 and 187 healthy
controls of similar age. The prevalences of heterozygotes for F V
G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among
cases and controls, respectively). In contrast, the prevalence of MTHFR
677T homozygosity and the allele frequency of Apo E4 were significantly
higher among patients (24.1% v 10.7% and 9.4% v
5.3% among cases and controls, respectively). Concomitant presence of
hypertension, hypercholesterolemia, or diabetes and one or more of the
four examined polymorphisms increased the risk by almost ninefold (odds
ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5)
and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed
simultaneously by a logistic model, the combination of prothrombotic
and Apo E4 polymorphisms with current smoking increased the risk
25-fold (OR = 24.7; 95% CI, 7.17 to 84.9).The presented data suggest
a synergistic effect between atherogenic and thrombogenic risk factors
in the pathogenesis of AMI, as was recently found in a similar cohort
of women.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
ACUTE MYOCARDIAL INFARCTION (AMI)
frequently results from a rupture of an atherosclerotic plaque that is
followed by thrombus formation.1 Major risk factors for
atherosclerosis include current smoking, hypertension, diabetes
mellitus, and dyslipidemia, including the apolipoprotein (Apo) E4
isoform.2,3
The contribution of thrombogenic risk factors to the development of AMI
has been less well characterized. The investigation of such factors is
of particular interest in young patients with AMI whose coronary
arteries are angiographically intact. Potential thrombogenic risk
factors that have been studied include abnormalities of blood
flow,4 platelet hyperreactivity,5 reduced
fibrinolysis,6 and increased plasma levels of fibrinogen,
factor VII, von Willebrand factor, tissue plasminogen activator, and
tissue plasminogen activator inhibitor.7,8
Polymorphism in the 5,10 methylenetetrahydrofolate reductase (MTHFR)
gene that involves a nt 677C T transition is associated in
the homozygous state with an increased level of homocysteine, particularly when plasma folic acid level is reduced.9,10 The association between homozygous MTHFR 677T and myocardial infarction was intensely studied during the last 2 years. However, the results of
these studies range from no effect11-17 to a mild to
moderate effect.18-20
Resistance to activated protein C due to a substitution of arginine by
glutamine at amino acid residue 506 in coagulation factor V (F V) nt
G1691A21-23 is commonly observed in patients with venous
thromboembolic disorders.23,24 No association of this
polymorphism with myocardial infarction was established in the American
Physician Health Study25 and in smaller scale
studies.26,27 However, other studies showed that mutant F V
G1691A was more frequent in patients with myocardial
infarction.28,29 Recently, Rosendaal et al demonstrated
that F V G1691A did exert a profound risk of myocardial infarction in
young women who were smokers or who had other atherogenic metabolic
risk factors.30 Similar observations were made in the same
study group regarding another newly described prothrombotic
polymorphism in factor II (F II).31 This polymorphism
involves a G A transition at position 20210 of the 3'
untranslated region of the F II gene.32 This substitution is associated with increased plasma levels of F II and was found to
confer an excessive risk of venous thrombosis.32,33 Few recent reports suggest that F II G20210A is not associated with increased risk for myocardial infarction.34,35
The studies reported by Rosendaal et al30,31 are the only
ones that established a synergistic effect of atherogenic and thrombogenic risk factors. Similar studies in young men, in whom myocardial infarction is much more frequent, have not been published. In the present case-control study of young males with AMI, we evaluated
the combined risks exerted by atherogenic risk factors, namely,
smoking, hypertension, diabetes mellitus, hypercholesterolemia, and Apo
E4, and by thrombogenic risk factors, ie, F V G1691A, F II G20210A, and
homozygous MTHFR 677T.
| |
MATERIALS AND METHODS |
Cases and controls.
The study group consisted of male patients aged less than 52 years who
were consecutively admitted to the Coronary Care Unit from March 1994 to March 1998 with an established diagnosis of first AMI as defined by
the Cardiovascular Health Study.36 Of 169 eligible
patients, five were deceased at the time of the study and 112 were
willing to participate in this retrospective study. The control group
consisted of 187 healthy male subjects of similar age who were enrolled
during routine annual examinations at the clinic of the Israeli Defense
Forces. None of the controls had a history or evidence of coronary
artery disease (CAD) as determined by medical history, resting ECG, and
ergometry. The study was approved by the Human Subject Ethics Committee
of the hospital and written consent was obtained from all subjects.
Demographic characteristics.
Demographic data were obtained for each subject from the medical
records of the Medical Center and Israeli Defense Forces. The
information included current age (for controls), age at the time of the
AMI, ethnic background, smoking history, blood pressure, total serum
cholesterol, diabetes status, and history of coronary events.
Seventy-one of 112 patients underwent coronary angiography and the
severity of CAD was determined by visual estimation. Stenosis of above
70% was defined as severe.
Determination of prothrombotic polymorphisms and Apo E4.
Genomic DNA was isolated from 5 mL whole blood by a standard
method.37 The G1691A in F V was detected by polymerase
chain reaction (PCR) amplification of a 267-bp fragment and
MnlI digestion as previously described.38 The C677T
mutation in MTHFR gene was identified using HinfI cleavage of
an 198-bp PCR-amplified product as described by Frosst et
al.9 For detection of Apo E isoforms, a 242-bp fragment of
the Apo E gene was amplified by PCR and digested simultaneously with
AflIII and HaeII as described by Zivelin et
al.39 For identification of the G20210A substitution in the
F II gene, a slightly modified method of Poort et al32 was
used. A 253-bp fragment of the 3' untranslated region of the gene
was amplified by PCR and digested simultaneously with HindIII and MspI. The A20210 and G20210 alleles were discernible by
this procedure, since the A20210 allele bears a restriction site for both enzymes, whereas the G20210 allele bears restriction site only for
MspI.
Statistical analyses.
Differences in baseline characteristics between patients and healthy
controls were assessed by the chi-square test for categorical variables
and t-test for continuous parameters. Univariate odds ratio
(OR) and 95% confidence intervals (CIs) were estimated for each
prothrombotic or Apo E4 polymorphism. Further analyses were undertaken
to assess the effect of combinations of the polymorphisms on the risk
of myocardial infarction. To estimate the effect of various risk
factors on the occurrence of myocardial infarction, an unconditional
logistic regression model was designed that included age, ethnic
origin, smoking status, and presence of metabolic risk factors such as
hypertension, hypercholesterolemia, or diabetes as controlling
variables. It also included prothrombotic and Apo E4 polymorphisms.
Combinations of the polymorphisms with smoking and metabolic factors
were also included in the logistic regression model, and the adjusted
OR with 95% CIs was estimated.
| |
RESULTS |
Characteristics of the study population.
The demographic information and the prevalence of selected risk factors
for CAD among cases and controls are shown in Table 1. Two thirds of AMI patients were of
European-American origin, compared with 44% of the controls. As
expected, major risk factors for coronary disease were more common in
the patients than in the controls (Table 1).
Prevalence of prothrombotic and Apo E4 polymorphisms.
Table 2 summarizes the prevalence of
heterozygotes for F V G1691A and F II G20210A, homozygotes for MTHFR
(677T), and of the Apo E4 allele frequency among cases and controls.
None of the patients or controls was found to be homozygous for the F V
or F II polymorphisms. The prevalences of heterozygotes for F V G1691A
and F II G20210A were not significantly different between cases and
controls. In contrast, the prevalence of MTHFR 677T homozygosity and
the allele frequency of Apo E4 were higher among patients (24.1%
v 10.7% and 9.4% v 5.3% among cases and controls, respectively). When the prevalence of any combination of the four studied polymorphisms was analyzed, the difference between cases and
controls reached statistical significance (Table
3). It is notable that 45% of cases bore
at least one of the four polymorphisms, whereas among controls only
23% carried one of these markers (P = .0003).
Among patients with AMI, 55% were current smokers and 57% had at
least one atherogenic metabolic risk factor (hypertension, diabetes, or
hypercholesterolemia). The corresponding figures among controls were
24.1% for current smoking and 24.6% for atherogenic risk factors.
Further analyses were undertaken to identify possible interactions
between the atherogenic and prothrombotic risk factors. To overcome the
differences between the cases and controls with regard to ethnic origin
and age, these variables, as well as metabolic variables, were included
in a multivariate stepwise logistic regression model. The results
presented in Table 4 were adjusted for age and ethnic origin and ORs were estimated for each combination of risk
factors. The presence of atherogenic metabolic risk factors increased
the risk of myocardial infarction fourfold (OR = 4.37; 95% CI, 2.20 to
8.70), whereas the combination of these factors with the prothrombotic
polymorphisms and Apo E4 resulted in an almost ninefold increased risk
(OR = 8.66; 95% CI, 3.49 to 21.5).
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Table 4.
ORs for Cardiovascular Risk Factors and Risk of AMI
With and Without the Simultaneous Presence of Prothrombotic and Apo
E4 Polymorphisms
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Current smoking with none of the polymorphisms present was associated
with an almost fourfold increase in the risk for myocardial infarction
(OR = 3.86; 95% CI, 1.94 to 7.68), whereas the combination of current
smoking and the polymorphisms increased the risk almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9).
When the atherogenic metabolic risk factors and current smoking were
analyzed simultaneously by the logistic model, the combination of
prothrombotic and Apo E4 polymorphisms with current smoking increased
the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9). The prothrombotic
and Apo E4 polymorphisms in the absence of smoking or atherogenic
metabolic risk factors exerted only a threefold effect (OR= 3.0; 95%
CI, 1.57 to 5.73).
The prevalence of the prothrombotic or Apo E4 polymorphisms in patients
with angiographically defined CAD was similar to the prevalence in
patients with angiographically normal coronary arteries. Thus, 21 of 57 patients (36.8%) with severe CAD bore one or more of the
polymorphisms, compared with 6 of 14 patients (42.9%) who had normal
coronary arteries (P = .6).
| |
DISCUSSION |
In young patients with AMI, the evidence for atherosclerotic CAD is not
always discernible, which highlights a potential importance of
prothrombotic risk factors. We therefore chose to evaluate the effect
of several recently described prothrombotic polymorphisms and Apo E4 in
relatively young patients with AMI and estimate their interaction with
major atherogenic risk factors. Similarly to other
investigators,25-27,34,35,40,41 we found that neither F V
G1691A nor F II G20210A was associated with an increased risk of AMI.
In contrast, Rosendaal et al did demonstrate an association between F
II G20210A and F V G1691A polymorphisms and increased risk of AMI in
young women.30,31 Conceivably, these differences may stem
from variable prevalences of other risk factors in different populations.
Several studies have examined the association of homozygous 677T MTHFR
and AMI, but the results have been inconsistent. Some studies,
including our present study, demonstrated a higher prevalence of
homozygous MTHFR 677T in patients with AMI,18-20 whereas
others showed no difference in the prevalence of the mutation between coronary patients and controls.11-17 Conceivably, these
inconsistencies stem from differences in the examined populations with
respect to other genetic factors and intake of folic acid, which is
known to ameliorate the effect of homozygous MTHFR 677T.17
Our study supports the previous observations that indicated that Apo E4
polymorphism is associated with an increased risk for coronary heart
disease, probably by alterations in lipid metabolism.3
When the presence of one or more of the three prothrombotic and Apo E4
polymorphisms was analyzed, only a mildly increased risk of AMI was
observed. However, the relative risk increased significantly when major
cardiovascular risk factors were also present. Thus, the estimated risk
increased ninefold when the polymorphisms were associated with
hypertension, hypercholesterolemia, or diabetes and almost 18-fold when
associated with current smoking. Moreover, the estimated risk increased
25-fold when adjustment for atherogenic metabolic risk factors was
undertaken. These results are in accordance with the studies of
Rosendaal et al in which a similar synergism was established in a group
of young women with myocardial infarction.30,31 Also
consistent with our data is the finding of a synergistic effect that
was recently reported in a cohort of older patients with myocardial
infarction.42 Thus, it may well be that the presence of one
or more of polymorphisms studied in combination with major
cardiovascular risk factors plays a synergistic role in the etiology of AMI.
The prevalence of normal coronary arteries is higher in young adults
with AMI than in older patients.43 In the present study, among 71 patients with AMI who underwent coronary angiography, we were
unable to demonstrate a difference in the prevalence of the four
polymorphisms between patients who had normal or abnormal coronary
arteries. If these findings will be confirmed in a larger cohort of
young patients with AMI, it may suggest that prothrombotic polymorphisms confer a significant risk of AMI, which is
accentuated in young patients with angiographically normal coronary
arteries. In accordance with this suggestion, two recent reports showed no difference in the prevalence of homozygous MTHFR 677T44
or F V G1691A45 among subjects with normal or abnormal
coronary arteries.
| |
FOOTNOTES |
Submitted February 17, 1998; accepted November 16, 1998.
The first two authors contributed equally to the study.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Aida Inbal, MD, Institute of Thrombosis and
Hemostasis, Department of Hematology, Sheba Medical Center,
Tel-Hashomer, Israel 52621; e-mail: Zeligson{at}post.ccsg.tau.ac.il.
| |
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J. Grunenfelder, M. Umbehr, A. Plass, L. Bestmann, F. E. Maly, G. Zund, and M. Turina
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B. Voetsch and J. Loscalzo
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F Burzotta, K Paciaroni, V De Stefano, F Crea, A Maseri, G Leone, and F Andreotti
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F-J Munoz-Rodriguez, J-C Reverter, J Font, D Tassies, G Espinosa, R Cervera, F Carmona, J Balasch, M Ingelmo, and A Ordinas
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[Abstract]
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M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group
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[Abstract]
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K. Juul, A. Tybjarg-Hansen, R. Steffensen, S. Kofoed, G. Jensen, and B. G. Nordestgaard
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S. M. Boekholdt, N. R. Bijsterveld, A. H.M. Moons, M. Levi, H. R. Buller, and R. J.G. Peters
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[Abstract]
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N. Drabe, G. Zund, J. Grunenfelder, M. Sprenger, S. P. Hoerstrup, L. Bestmann, F. E. Maly, and M. Turina
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C. Russo, D. Girelli, O. Olivieri, P. Guarini, F. Manzato, F. Pizzolo, B. Zaia, A. Mazzucco, and R. Corrocher
G20210A Prothrombin Gene Polymorphism and Prothrombin Activity in Subjects With or Without Angiographically Documented Coronary Artery Disease
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G. Endler, P. A. Kyrle, S. Eichinger, M. Exner, and C. Mannhalter
Multiplexed Mutagenically Separated PCR: Simultaneous Single-Tube Detection of the Factor V R506Q (G1691A), the Prothrombin G20210A, and the Methylenetetrahydrofolate Reductase A223V (C677T) Variants
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T C F Sykes, C Fegan, and D Mosquera
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P. M Ueland, H. Refsum, S. A. Beresford, and S. E. Vollset
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TOP
ABSTRACT
INTRODUCTION