Download Matched Case-Control Study on Factor V Leiden

Matched Case-Control Study on Factor V Leiden and the
Prothrombin G20210A Mutation in Patients With Ischemic
Stroke/Transient Ischemic Attack Up to the Age of 60 Years
Wolfgang Lalouschek, MD; Martin Schillinger, MD; Kety Hsieh, MD; Georg Endler, MD;
Susanne Tentschert; Wilfried Lang, MD; Suzanne Cheng, PhD; Christine Mannhalter, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on June 11, 2017
Background and Purpose—The role of the factor V Leiden mutation (FVL) and the G20210A mutation of the prothrombin
(factor II [FII]) gene for arterial thrombosis is not clear.
Methods—We investigated the prevalence of these mutations in 468 patients with an acute stroke or transient ischemic
attack (TIA) before the age of 60 years and in a healthy control population individually matched for age and gender.
We also analyzed interactions between the mutations, gender, standard vascular risk factors, and stroke risk.
Results—The prevalence of the FVL did not differ significantly between patients and control subjects. However, we found
a significant interaction between the FVL, smoking, and risk of stroke in women: female smokers without FVL had a
somewhat increased risk of stroke of 2.6 (95% CI, 1.5 to 4.6; P⫽0.001) compared with nonsmoking noncarriers of the
FVL. Stroke risk was markedly higher in female smokers who had the FVL (OR, 8.8; 95% CI, 2.0 to 38.0; P⫽0.004)
after multivariate adjustment. No such interaction was observed in men. In contrast, the frequency of the FII G20210A
mutation was significantly higher in male patients compared with controls (6% versus 1%; adjusted OR, 6.1; 95% CI,
1.3 to 28.3; P⫽0.021). In females, the prevalence of the mutation was 3% in both groups. We found no significant
interactions of the FII G20210A mutation with other vascular risk factors and stroke risk.
Conclusions—Our data indicate a highly increased risk of ischemic cerebrovascular events in women up to 60 years who
smoke and have FVL. We also found evidence for an increased risk of stroke/TIA in men who have the FII G20210A
mutation but not in women in this age group. (Stroke. 2005;36:1405-1409.)
Key Words: factor V 䡲 mutation 䡲 prothrombin 䡲 stroke
T
he factor V Leiden mutation (FVL) (Arg506Gln) and the
G20210A mutation of the prothrombin gene (factor II
[FII] G20210A mutation) are the most common genetic risk
factors of venous thrombosis.1 Their importance for arterial
events, in particular myocardial infarction and ischemic
stroke, is less clear. In unselected adult populations with a
mean age of 65 years or older, no or only a modest
association between these mutations and the risk of ischemic
stroke has been found by recent meta-analyses.2,3 Some
studies reported an association between one or both mutations
and the risk of stroke in young patients (younger than 45
years in most studies), whereas others did not.4 –15 Interactions of these mutations with exogenous vascular risk factors,
particularly smoking, probably modulate the risk of arterial
vascular events.16,17
In the present study, we investigated the prevalence of the
FVL and the FII G20210A mutation in a large population of
patients with ischemic cerebrovascular events (ischemic
stroke or transient ischemic attack [TIA]) before the age of 60
years. We compared the occurrence of these variants in
patients to healthy controls individually matched for age and
gender. We also investigated interactions of these mutations
with standard vascular risk factors and the effect on the risk
of cerebrovascular events.
Materials and Methods
Patients and Control Subjects
468 consecutive patients with an acute ischemic stroke or TIA before
age 60 years (177 female, 291 male; median age, 53 years;
interquartile range [IQR], 45 to 57) who were documented in the
Vienna Stroke Registry18 were included in the study. The diagnosis
was established clinically by a neurologist and all patients underwent
cranial CT or MR. The patients were documented according to a
standardized protocol18comprising the following information: vascular risk factors including hypertension, diabetes, cigarette smoking,
body mass index, hyperlipidemia, oral contraception, or other hormone intake; medical history including general medical diseases (eg,
previous cardiac, pulmonary, neurological, endocrine, gastrointesti-
Received January 10, 2005; final revision received April 13, 2005; accepted April 21, 2005.
From the University Clinic of Neurology (W.L., S.T.), Department of Angiology (M.S.), Clinical Institute of Medical and Chemical Laboratory
Diagnostics (K.H., G.E., C.M.), Medical University Vienna (W.L., M.S., K.H., G.e., S.T., W.L., S.C., C.M.), Hospital Barmherzige Brueder (W.L.),
Vienna, Austria; and the Department of Human Genetics (S.C.), Roche Molecular Systems, Inc, Alameda, Calif.
Correspondence to Wolfgang Lalouschek, MD, University Clinic of Neurology, Clinical Department of Clinical Neurology, Waehringer Guertel 18-20,
1097 Vienna, Austria. E-mail [email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000170635.45745.b8
1405
1406
Stroke
July 2005
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nal diseases) and previous medication with particular reference to
vascular diseases (TIA/stroke, coronary artery disease, peripheral
artery disease, venous thrombosis); laboratory and technical investigations including blood chemistry and blood count taken during
hospitalization, cerebrovascular investigations (eg, carotid and vertebral ultrasound), cardiac investigations (eg, electrocardiography,
echocardiography); and stroke cause and stroke severity as measured
by validated scales.18,19
The patients included in the present study represent a subset of a
larger cohort of patients documented in the Vienna Stroke Registry
during the period from October 1998 until June 2001.18 During this
period, 732 patients with an acute cerebrovascular event before age
60 years were admitted to one of the participating departments. From
these, 69 patients with a hemorrhagic stroke or sinus thrombosis and
13 patients with a rare cause of stroke (confirmed arterial dissection
or drug abuse) were excluded. Of 468 of the remaining 650 patients
(72%), written informed consent and a blood sample could be
obtained.
The 468 control individuals matched for age (⫾2 years) and
gender (median age, 52; IQR, 45 to 57 years) were participants in an
official health care program.20 All were free of clinically manifest
arterial vascular disease and reported no vascular diseases in firstdegree relatives. Medical history, vascular risk factors, and results of
laboratory investigations were documented according to a standardized protocol.
The study complied with the Declaration of Helsinki and was
approved by the local ethics committee. All patients and control
subjects gave their written informed consent for participation in the
study.
Genotyping
The presence of FVL and FII G20210A were tested by one of two
published methods: a mutagenic separated allele-specific polymerase
chain reaction test21 or a multiplex polymerase chain reaction in
combination with a hybridization to sequence-specific oligonucleotides immobilized on nylon membrane strips.22 The reagents for the
latter test were kindly provided by Roche Molecular Systems,
Alameda, Calif.
Statistical Methods
Continuous data are given as median and IQR (range from the 25th to
the 75th percentile). Discrete data are given as counts and percentages. The McNemar test for dependent samples was used to compare
groups of categorical data. Groups of continuous data were compared by the Wilcoxon Test.
Associations between the 2 polymorphisms and the risk of stroke
were analyzed by means of conditional binary logistic regression
models with adjustment for the conventional risk factors hypertension, diabetes, hyperlipidemia, current smoking, obesity (defined as
a body mass index ⬎27), and intake of female hormones (oral
contraception or hormone replacement therapy)
The linearity of the logit assumption was checked for continuous
predictor variables and an analysis of residuals was performed.
Regression diagnostics and overall model fit were performed according to standard procedures.
Calculations were performed using SPSS for Windows (Version
10.0; SPSS Inc) and Stata (release 8.0; Stata).
Results
Baseline parameters of patients and controls are given in
Table 1. Most conventional risk factors were more prevalent
in the patient group.
FVL Mutation
In men, 11 of 291 patients (4%) and 20 of 291 controls (7%)
had FVL (OR, 0.6; 95% CI, 0.3 to 1.1; P⫽0.111). In women,
18 of 177 patients (10%) and 10/177 controls (6%) were FVL
carriers (OR, 2.0; 95% CI, 0.9 to 4.7; P⫽0.109). Adjustment
TABLE 1.
Subjects
Baseline Characteristics of Patients and Control
Age median (IQR)
Patients
(n⫽468)
Controls
(n⫽468)
53 (45–57)
52 (45–57)
P
0.011*
Female (%)
177 (38)
177 (38)
1.0†
Hypertension (%)
279 (60)
175 (37)
⬍0.001†
97 (21)
14 (3)
⬍0.001†
Hyperlipidemia (%)
333 (71)
353 (75)
0.645†
BMI ⬎27 (%)
220 (47)
142 (30)
⬍0.001†
Current cigarette smoking (%)
260 (56)
137 (29)
⬍0.001†
33 (19)
47 (27)
0.081†
Diabetes mellitus (%)
Female hormone intake
(women only)
BMI indicates body mass index; IQR, interquartile range.
*McNemar test.
†Wilcoxon test.
for hypertension, diabetes, hyperlipidemia, current smoking,
obesity, and hormone intake did not significantly affect these
results. However, we found a significant interaction between
FVL, current smoking, and risk of stroke in women. In
nonsmoking women, the prevalence of the FVL was 5% in
controls (6/117) and in patients (4/86). In women who
smoked, the prevalence of FVL was 7% in controls (4/60) but
15% in patients (14/91). Clinical and demographic data of
those female patients who smoked and had FVL are shown in
Table 2. In a conditional logistic regression adjusted for other
vascular risk factors, female smokers without the FVL had an
increased risk of stroke of 2.6 (95% CI, 1.5 to 4.6; P⫽0.001)
compared with nonsmoking female noncarriers of the FVL. In
women who had FVL and who smoked the risk of stroke was
increased 8.8-fold (95% CI, 2.0 to 38.0; P⫽0.004) after
multivariate adjustment (Figure). In males, there was no
relation between FVL, smoking, and stroke risk. We also
found no other first-order interactions of the FVL with
vascular risk factors (including age and hormone intake). We
found no significant differences in the prevalence of the FVL
in etiologically distinct subgroups (Table 3).
FII G20210A Mutation
The frequency of the FII G20210A mutation was significantly higher in patients than in control subjects (5% versus
2%; unadjusted OR, 2.3; 95% CI, 1.1 to 5.1; P⫽0.033;
adjusted OR, 2.9; 95% CI, 1.1 to 7.9; P⫽0.032). This
difference was caused by a higher prevalence of the mutation
in male patients compared with controls (6% versus 1%;
unadjusted OR, 5.0; 95% CI, 1.4 to 17.2; P⫽0.011; adjusted
OR, 6.1; 95% CI, 1.3 to 28.3; P⫽0.021). In contrast, the
prevalence of the mutation in female patients and controls
was 3% in both groups (unadjusted OR, 1.0; 95% CI, 0.3 to
3.1; P⫽1.0; adjusted OR, 1.6; 95% CI, 0.4 to 5.8; P⫽0.502).
We did not observe significant interactions of the FII
G20210A mutation with other vascular risk factors and stroke
risk. We found no significant differences in the prevalence of
the FII G20210A mutation in etiologically distinct subgroups
(Table 3).
Two of 468 patients (0.4%) were combined carriers of FVL
and the FII G20210A mutation but no combined mutation
carrier was identified among the controls (P⫽0.157).
Lalouschek et al
TABLE 2.
Prothrombotic Mutations and Risk of Stroke
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Clinical and Demographic Data of Female Patients Who Smoked and Had FVL
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N
Age
Hypertension
Diabetes
BMI
⬎27
Current
Hormone Intake
TC, mmol/L
Type of
Event
Presumed
Cause
1
22
⫺
⫺
⫺
⫹
4.73
Major
CARD
2
31
⫺
⫺
⫺
⫺
2.07
Major
LVD
3
33
⫺
⫺
⫺
⫺
3.83
TIA
SVD
4
38
⫺
⫺
⫺
⫺
4.37
TIA
UNDET
5
41
⫺
⫺
⫹
⫺
7.29
TIA
LVD
6
45
⫹
⫺
⫺
⫺
3.54
Major
LVD
7
49
⫺
⫺
⫺
⫺
6.23
Major
LVD
8
49
⫹
⫺
⫹
⫺
5.74
Major
CARD
9
52
⫺
⫹
⫹
⫺
7.24
Major
UNDET
10
54
⫺
⫺
⫹
⫹
8.09
Major
SVD
11
55
⫺
⫺
⫺
⫺
3.72
Major
CARD
12
56
⫹
⫺
⫺
⫺
7.45
Minor
UNDET
13
57
⫺
⫺
⫹
⫺
8.02
Minor
SVD
14
59
⫹
⫹
⫹
⫺
6.83
Major
LVD
FVL indicates factor V Leiden; CARD, cardioembolic; LVD, large-vessel disease; SVD, small-vessel disease; major,
major stroke; minor, minor stroke; TC, total cholesterol; UNDET, undetermined.
Discussion
Our results, obtained in a large sample of patients with
ischemic cerebrovascular events with a median age of 53
years, indicate that the FVL mutation is not a general risk
factor of stroke in this population. However, the significantly
higher frequency of the mutation in female patients who
smoke indicates a highly increased risk of stroke in these
women. We also found evidence that the FII G20210A
mutation is a significant risk factor of stroke in men in this
age group, but not in women.
Recent meta-analyses suggest that the FVL and the FII
G20210A mutation do not or only slightly contribute to the
risk of stroke in older individuals.2,3
Some, but not all, investigations in young stroke patients
(usually younger than 45 years) found a higher prevalence of
these mutations in patients than in controls, particularly in
patients with cryptogenic stroke.4,5,7–15
Most of these studies were small and/or did not test for
interactions of these mutations with gender, other vascular
risk factors, and stroke risk. Margaglione et al studied 202
patients with stroke younger than 45 years and reported a
markedly higher prevalence of the FVL mutation in female
Risk of stroke in women up to age 60 years in relation to FVL
status and smoking (absolute numbers of individuals in each
subgroup are given in the text).
patients and a particularly increased stroke risk in smokers
who had the FVL mutation.11 In contrast, Nabavi et al found
no differences of the prevalence of the mutation in 225 young
men and women with ischemic stroke or TIA. Carriers of the
FV L were somewhat more frequently smokers (74% smokers among carriers versus 55% among noncarriers), but this
difference did not reach significance (P⫽0.1). In this study, a
potential interaction between the FVL mutation, smoking, and
gender was not reported. Whereas these authors found a
higher prevalence of the FVL mutation among patients with
cryptogenic stroke, we could not detect an interaction between presumed etiology and FVL or the FII G20210A
mutation.10 The FVL has previously been shown to play a role
in arterial thrombosis in smokers. In a study by Rosendaal et
al, a particularly high risk of myocardial infarction was
described in young women who smoked and had the FVL
mutation.16,17
A relationship between the FII G20210A mutation and
stroke risk in younger individuals has also been reported. In
some studies in which gender-specific calculations were
performed, the prevalence of the mutation was similar in male
and female patients,11,14 and other studies did not separate the
patient cohorts according to gender. Our observation of a
markedly increased risk of stroke at age younger than 60
years in men but not in women constitutes a new finding and
should be tested in independent populations.
There are several possible mechanisms that may underlie a
different effect of prothrombotic genetic variations in men
and women. Endogenous estrogens increase the resistance to
activated protein C regardless of the presence of the FVL
mutation.23 Also, the FVL has been shown to further increase
the risk of venous thrombosis in oral contraceptive users.24
However, we did not find a significant interaction between
hormone intake, the FVL, and stroke risk. Other possible
explanations for gender differences are higher levels of factor
VII:C and fibrinogen in women compared with men with
1408
Stroke
July 2005
TABLE 3. Prevalence of FVL and the Factor II G20210A Mutation According to
Presumed Cause
Large-Vessel
Disease (n⫽72)
Cardioembolism
(n⫽77)
Small-Vessel
Disease (n⫽101)
Undetermined
(n⫽218)
P
FVL* (%)
6 (8)
3 (4)
8 (8)
12 (6)
0.580
FII G20210A mutation* (%)
2 (3)
4 (5)
7 (7)
9 (4)
0.590
*Heterozygous and homozygous carriers combined (for each mutation there was one homozygous patient).
FII indicates factor II.
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coronary artery disease.25 Also, differences in body iron store
have been considered to account for differences in stroke risk
between men and women.26 In some studies, different effects
of conventional vascular risk factors in men and women,27
and gender-specific changes in vascular function with age28
have been discussed.
We point out some potential limitations of our study.
Our controls were not fully population-based. Therefore,
we cannot exclude certain forms of bias, eg, regarding the
distribution of vascular risk factors or the attitude toward
a healthier living style in this population compared with
our patients. However, our results remained stable after
statistical adjustment for known vascular risk factors.
Stratification into subgroups and testing for interactions
may lead to relatively small sample sizes even in a
relatively large study. Given these limitations and the
case-control design of our study, the results, particularly
the observed interactions between gender, smoking, mutations, and stroke risk, should be confirmed in other
populations and/or in a prospective study.
In conclusion, our data indicate a highly increased risk of
ischemic cerebrovascular events in women up to 60 years
who smoke and have the FVL mutation. We also found
evidence for an increased risk of stroke/TIA in men, but not
women in this age group, who have the FII G20210A
mutation. Because of the cross-sectional nature of our study,
potential implications have to be regarded with care. Yet we
believe that women who have been identified as carriers of
the FVL mutation and who smoke should be informed about
the significantly increased risk of cerebrovascular events in
female mutation carriers who smoke.
Acknowledgments
The Vienna Stroke Registry (VSR) is supported by research
grants of the Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien (project numbers 1540,
1829, 1970), of the Jubiläumsfonds der Oesterreichischen Nationalbank (project numbers 6866, 7115, 8281,9344), and the
Austrian Research Society (P13902-MED). DNA isolation and
genotyping of FVL and the FII G20210A mutation has been
supported by the Jubiläumsfonds der Oesterreichischen Nationalbank (project number 8218).
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Matched Case-Control Study on Factor V Leiden and the Prothrombin G20210A
Mutation in Patients With Ischemic Stroke/Transient Ischemic Attack Up to the Age of 60
Years
Wolfgang Lalouschek, Martin Schillinger, Kety Hsieh, Georg Endler, Susanne Tentschert,
Wilfried Lang, Suzanne Cheng and Christine Mannhalter
Downloaded from http://stroke.ahajournals.org/ by guest on June 11, 2017
Stroke. 2005;36:1405-1409; originally published online June 9, 2005;
doi: 10.1161/01.STR.0000170635.45745.b8
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2005 American Heart Association, Inc. All rights reserved.
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