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Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3562-3565
Prothrombin G20210A Mutant Genotype Is a Risk Factor for
Cerebrovascular Ischemic Disease in Young Patients
By
Valerio De Stefano,
Patrizia Chiusolo,
Katia Paciaroni,
Ida Casorelli,
Elena Rossi,
Marco Molinari,
Serenella Servidei,
Pietro A. Tonali, and
Giuseppe Leone
From the Department of Hematology, Catholic University, Rome, Italy;
the Department of Neurology, Catholic University, Rome, Italy; and the
IRCCS Santa Lucia, Rome, Italy.
 |
ABSTRACT |
The factor II G20210A mutation is a recently identified congenital
risk factor for venous thrombosis. Its role in artery disease is still
undefined. We investigated 72 patients (35 male and 37 female) with
documented ischemic stroke occurred before 50 years of age and without
risk factors such as diabetes, hypertension, and hyperlipidemia; 198 thrombosis-free individuals were investigated as the control group. We
found 7 heterozygotes (9.7%) and 2 homozygotes (2.7%) for the mutant
factor II allele among the patients and 5 heterozygotes (2.5%) among
the controls; the mutant factor II allele frequency in the patient
group (7.6%, 95% confidence interval [CI], 3.3 to 11.9) was
significantly higher than in the controls (1.2%; 95% CI, 0.1 to 2.3;
P = .0001). The prevalence of other investigated mutant
alleles (factor V G1691A, methylenetetrahydrofolate reductase C677T)
did not significantly differ between the two groups. The odds ratio for
ischemic stroke associated with the carriership of the mutant factor II
allele (both heterozygous and homozygous genotypes) was 5.1 (95% CI,
1.6 to 16.3). Heterozygous genotype was associated with a 3.8-fold
increased risk for cerebral ischemia (95% CI, 1.1 to 13.1); in
particular, assuming an expected prevalence of homozygotes in the
general population of 1.6 to 10,000 according to the Hardy-Weinberg
equilibrium, the risk associated with the homozygous genotype was
estimated exceedingly high, being increased 208-fold.
| |
INTRODUCTION |
RECENTLY, A NOVEL mutation in the
3 -untranslated region of the prothrombin gene (20210G to A)
associated with high levels of plasma prothrombin has been reported to
be a moderate risk factor for venous thrombosis, being present in
heterozygous form in 5.4% to 7.3% of the patients and in 1.2% to
2.3% of the controls, with an increase in risk by threefold to
fivefold.1-4 The association of the mutant factor II allele
with arterial thrombosis has been reported in patients with myocardial
infarction weaker than in venous thrombosis (2-fold increase in risk),
without reaching statistical significance5; in a more
recent report, the heterozygous mutant factor II genotype was found
associated with a significant increased risk (4-fold) for myocardial
infarction in young women.6 The investigations so far
conducted on unselected patients with cerebral ischemia did not show
any increase in risk associated with the mutant factor II
allele.4,7 In the present study, we investigated the
prevalence of the mutant factor II allele in selected young patients
with ischemic stroke.
| |
PATIENTS AND METHODS |
We investigated 72 patients (35 males and 37 females) with ischemic
stroke occurred before 50 years of age (mean age, 33.9; median age, 37 years; age range, 2 to 50 years) and without risk factors such as
hypertension, diabetes, and increased levels of cholesterol or
triglycerides. Complete information about smoking habit (current and
former habit and number of cigarettes smoken per day) was not available
for the totality of the patients and the controls investigated, so that
this was not considered in the final interpretation of the results. The
patients were consecutively referred for laboratory evaluation since
November 1994 through October 1997; 60 of them had been admitted to the
Catholic University hospital (Policlinico Gemelli, Rome) because of
acute cerebral ischemia, whereas the remaining 12 had a past history of
cerebral ischemia and were referred by other hospitals or by their
family physicians. The patients were selected for the laboratory
investigation only if the ischemic event was documented by computer
tomography (CT) scan and/or nuclear magnetic
resonance (NMR) of the brain; blood was collected in
sodium citrate and plasma as well as genomic DNA were stored at
 80°C until assayed. In 10 of the 37 female patients (27%),
intake of oral contraceptives was present at the moment of the acute
event; in another 2 patients, ischemic stroke occurred during pregnancy
(n = 1) or puerperium (n = 1). In all patients, the presence of the
20210 G to A substitution in the prothrombin gene was investigated on
genomic DNA prepared by standard procedures; mutant factor II was
detected by amplification by polymerase chain reaction (PCR) and
digestion of the fragment with HindIII according to the
original method of Poort et al.1 Laboratory evaluation
included also evaluation of natural coagulation inhibitors
(antithrombin and protein C functional levels and free protein S
antigen levels) as well as detection of the G1691A mutation in the
factor V gene (factor V Leiden)8 and the C677T mutation in
the methylenetetrahydrofolate reductase (MTHFR) gene (thermolabile variant), a possible cause of mild hyperhomocysteinemia in homozygous individuals.9 The mutant alleles were investigated also in a control group of 198 thrombosis-free individuals (78 males and 120 females; mean age, 49 years; median age, 49 years; age range, 16 to 81 years). All of the patients and the control individuals were of Italian
ancestry (Middle and Southern Italy).
The differences between the patient and the control groups were
evaluated using the  2 test. The univariate odds ratio
was calculated as an approximation of relative risk for putative risk
factors by simple cross-tabulation, with 95% confidence intervals
(CI).
| |
RESULTS |
No significant variation was found between the patient group and the
controls as regards the prevalence of factor V Leiden carriers, the
overall allele frequency of the factor V Leiden, the prevalence of
homozygous carriers of the MTHFR C677T mutation, and the overall allele
frequency of the MTHFR C677T mutation
(Table 1). One patient had levels of free
protein S antigen below the normal range.
View this table:
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Table 1.
Prevalence of Mutant Genotypes in 72 Individuals With
Ischemic Stroke Before 50 Years of Age and in 198 Controls
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The normal sequence of the prothrombin gene displayed a band of 345 bp
after HindIII digestion. The mutant factor II gene heterozygous
genotype is characterized by two fragments of 345 and 322 bp; the
absence of the fragment of 345 bp and the presence of only the fragment
of 322 bp is distinctive of the homozygous genotype
(Fig 1).
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| Fig 1.
Polyacrylamide gel electrophoresis of the amplified
345-bp fragment of factor II gene after HindIII digestion; the
mutant factor II gene has a restriction site for HindIII
leading to the production of two 322- and 23-bp fragments
(the latter not detectable here). The wild-type factor II gene is
characterized by the presence of the only 345-bp fragment (lane 2). The
mutant factor II gene heterozygous genotype (lane 1) is characterized
by two fragments of 345 bp (wild-type allele) and 322 bp (mutant
allele); the homozygous genotype shows only a 322-bp fragment (lane
3).
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In the patient group, we found 9 individuals carriers of the factor II
mutant allele (12.5%; 95% CI, 4.8 to 20.1): 7 heterozygotes (2 males
and 5 females) and 2 homozygotes (2 males and 0 females). In the
control group, 5 individuals were heterozygous for the mutant factor II
allele (2.5%; 95% CI, 0.3 to 4.7). One of the heterozygous patients
had associated heterozygosity for factor V Leiden mutation (Table 1).
One homozygous patient was a 26-year old man having suffered at 24 years of age from ischemic stroke in the left thalamic region. At 26 years of age, he had an ischemic recurrence in the left calcarine
cortex leading to hemianopsia and afterwards underwent aspirin
treatment. Family investigation demonstrated heterozygosity for mutant
factor II allele both in the father (54 years of age) and in the mother
(52 years of age) of the proband; also, her sister (20 years of age)
was heterozygous for mutated factor II gene. All of these family
members did not experience thrombosis. The other homozygous individual
was a 26-year-old man with acute ischemia involving the basilar artery
documented by NMR; he was treated with intravenous heparin and
afterwards with oral anticoagulants. Transesophageal echocardiography
demonstrated the presence of a patent foramen ovale. Both the
homozygous patients were nonsmokers. Three of the 7 heterozygotes
identified were nonsmokers (overall percentage of nonsmokers among the
carriers of the factor II mutant allele was 55.5%).
Among the 10 patients taking oral contraceptives at the moment of the
acute event, 1 was protein S-deficient, 1 was heterozygous for factor V
Leiden, and 2 were homozygous for MTHFR C677T mutation. No alteration
was found in the 2 women having suffered from cerebral ischemia during
pregnancy or puerperium. Among the other 25 female patients, 2 were
heterozygous for factor V Leiden and 4 were homozygous for MTHFR C677T
mutation, with a distribution of mutant genotypes almost identical to
that found in the group of women with ischemic stroke after oral
contraceptives. No significant difference was found between the
prevalence of heterozygous mutant factor II genotype among the female
patients having suffered from cerebral ischemia after exposure to a
circumstantial risk factor (1/12 [8.3%]) and the prevalence among
women without such exposure (4/25 [16%]; P = .5231).
Considering the 60 patients (35 males and 25 females) without a
concomitant risk situation, the overall prevalence of affected
individuals was 13.3% (11.4% among male patients and 16% among
female patients).
The mutant factor II allele frequency in the patient group was 7.6%,
at significant variance with the control group (1.2%, P = .0001; Table 1). The risk for ischemic stroke associated with the
carriership (both heterozygous and homozygous) of the mutant
prothrombin allele was 5.5-fold increased. After exclusion of the
patient with protein S deficiency and of the individual carriers of the
factor V Leiden, the risk for carriers of the factor II mutant allele
was substantially unchanged (Table 1). The adjusted odds ratio
associated with the isolated heterozygous factor II mutant genotype was
3.8 (95% CI, 1.1 to 13.1). No homozygous individual carrier of mutant
factor II allele was found in the control group; therefore, the odds
ratio associated with the homozygous genotype was estimated calculating
from Hardy-Weinberg equilibrium the expected number of homozygotes
among the controls, following a procedure previously described in
detail.10 According to the Hardy-Weinberg equilibrium, the
expected number of homozygous individuals in the normal population is
1.58/10,000 (mutant allele frequency 0.01262), leading to
an expected number of 0.031 homozygous individuals among the 198 controls.
Accordingly, in our series, the odds ratio associated with homozygous
mutant factor II genotype after exclusion of the 12 individuals with
protein S deficiency (n = 1), factor V Leiden (n = 4),
heterozygous factor II mutant genotype (n = 6), combined heterozygosity
for factor V Leiden and mutant factor II (n = 1) resulted in 208, with
a 95% CI of 14 to 2,957 estimated according to Rosendaal et
al10 (Table 1).
| |
DISCUSSION |
Mutation in the 3-untranslated region of the prothrombin gene is
a congenital risk factor for venous thrombosis recently identified1; it is associated with high levels of
prothrombin and is present in 1% to 3.2% of the general population
with European ancestry.1-4,7 Recently, the factor II
mutated allele was demonstrated to be associated with an increased risk
for myocardial infarction in young women, especially if they are
smokers.6 We found that 12.5% (9/72) of patients with
ischemic stroke before reaching 50 years of age and with absence of
hypertension or evident metabolic risk factors are carriers of the
factor II G20210A gene mutation; in the control group, the prevalence
of the carriers was 2.5%. The prevalence of affected individuals among
the patients is very comparable with that found in patients with venous
thrombotic disease, which has been reported to be from 5% to
7%.1-4 In the present series, the mutant prothrombin II
allele frequency is the only putative risk factor for ischemic stroke,
which was significantly different from the control group (7.6%
v 1.2%); we found an increased prevalence of factor V Leiden
carriers and of homozygous carriers of the C677T MTHFR gene mutation,
but without reaching the statistical significance. Carriership of the
mutant factor II allele (both heterozygous and homozygous genotypes)
was found to be associated with a 5.1-fold increase in risk for
ischemic stroke. The risk associated with the heterozygous genotype was
3.8-fold increased. This finding disagrees with the results of two
recent studies that failed to demonstrate in patients with cerebral
ischemia any increase in risk associated with the factor II mutant
allele.4,7 In both investigations, the patients were not
selected according to age; however, in the study of Martinelli et
al,7 the young age was not found to be associated with an
increased prevalence of the mutant factor II allele. Yet, the clinical
manifestations of such patients were not homogeneous, including also
transient ischemic attacks; moreover, no selection criterium, such as
the absence of classic vascular risk factors, was
adopted.4,7 In contrast, we investigated a population of
patients highly selected, with documented ischemic stroke, age younger
than 50 years, and no evident constitutional risk factor for arterial
disease. In the patient group, we found 2 homozygous carriers of the
factor II gene mutation (2.7%). This is quite surprising, because
pooling the data obtained from six investigations published in detail, no homozygous individual was detected among 1,741 healthy controls, 871 patients with venous thrombotic disease, and 439 patients with arterial
thrombotic disease.1-4,6,7 Moreover, we did not find any
homozygote in a series of 343 patients with venous thrombotic disease
investigated in our laboratory (unpublished results). To
the best of our knowledge, only 2 homozygous individuals have been so
far reported. One of them was the sister of a proband patient
investigated by Poort et al1; she was heterozygous for
factor V Leiden too and experienced thrombotic symptoms.1
The other one was a 18-year-old woman suffering from deep vein
thrombosis during pregnancy.11 According to the
Hardy-Weinberg equilibrium, the mutant factor II allele frequency found
in our control population leads to an expected prevalence of homozygous
carriers in Italians of 1.6 to 10,000, so that the finding of 2.7%
homozygous genotype among young patients with ischemic stroke strongly
suggests a relationship between the inherited condition and the
thrombotic symptoms. No evident risk factor for artery disease was
found in the 2 young homozygous patients that we identified; in 1 of
them, the presence of a patent foramen ovale was demonstrated, but the
role of this anatomic variant as main cause by itself of cardioembolic
stroke is controversial.12 To estimate the risk for
ischemic stroke associated with the mutant factor II homozygous
genotype, we applied a procedure previously described by Rosendaal et
al10 for investigating the thrombotic risk related to
homozygous factor V Leiden genotype. The increase in risk we found was
208-fold, which was statistically significant yet with a large range of
the 95% CI. We conclude that the 12.5% prevalence of carriers of
mutant factor II allele among young patients with ischemic stroke is at
least comparable with that found in patients with venous thrombotic
disease and that it is associated with an increase in risk, so that
genotyping for this mutation should be included in the diagnostic panel
of cerebral ischemia. In particular, the homozygous genotype seems
highly predisposing to ischemic stroke and further investigations on larger series of patients are advisable.
| |
FOOTNOTES |
Submitted November 12, 1997;
accepted January 19, 1998.
Address reprint requests to Valerio De Stefano, MD,
Divisione di Ematologia, Istituto Semeiotica Medica, Università
Cattolica, Largo Gemelli 8, 00168 Roma, Italy.
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.
| |
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Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association
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Coagulation Factors II, V, VII, and X, Prothrombin Gene 20210G->A Transition, and Factor V Leiden in Coronary Artery Disease : High Factor V Clotting Activity Is an Independent Risk Factor for Myocardial Infarction
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Abstract
Introduction
Abstract