A2 Alelle of GpIIIa Gene Is a Risk Factor for Stroke
Caused by Large-Vessel Disease in Males
Agnieszka Slowik, MD; Tomasz Dziedzic, MD; Wojciech Turaj, MD; Joanna Pera, MD;
Lidia Glodzik-Sobanska, MD; Pawel Szermer, MD; Maciej T. Malecki, MD;
Denise A. Figlewicz, PhD; Andrzej Szczudlik, MD, PhD
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Background and Purpose—Glycoprotein IIIa (GpIIIa) is a platelet membrane receptor for fibrinogen and von Willebrand
factor. It plays a key role in platelet aggregation. Previous studies in stroke patients, without analysis based on specific
subtypes of stroke cause, have not shown any link between GpIIIa A1/A2 polymorphism and stroke risk. We studied
the significance of the GpIIIa gene A1/A2 polymorphism in stroke patients with different stroke causes.
Methods—We genotyped 92 patients with stroke caused by large-vessel disease (LVD stroke) and 184 matched controls;
103 patients with stroke caused by small-vessel disease (SVD stroke) and 206 controls; and 182 patients with
cardioembolic stroke (CE stroke) and 182 controls (TOAST criteria). The GpIIIa A1/A2 polymorphism was analyzed
by polymerase chain reaction followed by restriction enzyme digestion and electrophoresis.
Results—The genotype distribution of the GpIIIa gene in patients with LVD stroke (A1/A1, 63%; A1/A2, 34.8%; A2/A2,
2.2%) differed significantly from their controls (A1A1, 79.3%; A1/A2, 20.1%; A2/A2, 0.6%). The distribution of the
GpIIIa A1/A2 polymorphism in patients with SVD stroke and CE stroke was similar to that of their controls. In contrast
to females with LVD stroke, we found that males with LVD stroke presented with an overrepresentation of at least 1
A2 allele of the GpIIIa gene when compared with their controls (39.7% versus 23.0%; P⫽0.003). Conditional logistic
regression analysis showed that possession of at least 1 A2 allele of the GpIIIa gene was an independent risk factor for
LVD stroke in males (OR, 2.51; 95% CI, 1.21 to 5.20).
Conclusion—A2 allele of the GpIIIa gene is an independent risk factor for LVD stroke in males. (Stroke. 2004;35:15891593.)
Key Words: etiology 䡲 stroke 䡲 platelet glycoprotein GPIIb/IIIa complex 䡲 gene expression 䡲 polymorphism
G
lycoprotein IIb/IIIa is a platelet receptor involved in a
final step of platelet-mediated thrombus formation on
the injured vessel wall.1 It binds fibrinogen and von Willebrand factor, causing platelet aggregation.2 The glycoprotein
IIb/IIIa receptor consists of a 2-chain glycoprotein IIb subunit
noncovalently associated with a single-chain glycoprotein
IIIa subunit.1 The genes encoding glycoprotein IIb and IIIa
are located on chromosome 17q21.3 The A1/A2 polymorphism of glycoprotein IIIa (GpIIIa) gene caused by a T-to-C
nucleotide substitution at position 1565 that is associated with
the occurrence of the amino acid Leu 3 Pro variant at residue
33 of the mature protein4 has been widely studied in cardiovascular diseases.5 These studies have shown that possession
of an A2 allele increases the risk for myocardial infarction,6 – 8
coronary artery disease,9 and restenosis after stent placement.10 Most of the studies on stroke patients have yielded
negative results, but they did not analyze different stroke
causes.11–13
Two studies on subgroups of stroke patients have
demonstrated a relation between GpIIIa gene polymorphism and stroke risk.14,15 They revealed that possession of
at least 1 A2 allele of GpIIIa gene was a risk factor for
atherothrombotic stroke in young patients14 and a risk
factor for symptomatic carotid stenosis.15 Based on data
from studies of patients with cardiovascular diseases and
studies of stroke patients with atherothrombotic stroke,14,15
we hypothesized that the GpIIIa gene polymorphism might
increase the risk of stroke caused by large-vessel disease
(LVD stroke) only. LVD, unlike other causes of stroke,
shares pathophysiological features with acute coronary
syndromes.16 Both diseases result from the formation of a
platelet-rich thrombus at the site of the ruptured atherosclerotic plaque.16
We studied the significance of the GpIIIa gene polymorphism as a risk factor for stroke caused by LVD,
small-vessel disease (SVD), or cardioembolism.
Received December 22, 2003; final revision April 15, 2004; accepted April 23, 2004.
From the Department of Neurology (A.S., T.D., W.T., J.P., L.G.-S., P.S., A.S.) and the Department of Metabolic Diseases (M.T.M.), Jagiellonian
University, Krakow, Poland; and the Department of Neurology (D.A.F.), University of Michigan, Ann Arbor, Mich.
Correspondence to Dr Agnieszka Slowik, Department of Neurology, Jagiellonian University, 31-503 Krakow, Botaniczna 3, Poland. E-mail
[email protected]
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000132194.24663.3d
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Stroke
July 2004
Subjects and Methods
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The study population consisted of 632 unrelated patients with
ischemic stroke diagnosed, established according to World Health
Organization (WHO) criteria,17 prospectively recruited at the Stroke
Unit, University Hospital, Krakow, Poland between 1998 and 2002.
This unit serves as a stroke emergency center for 1 district of Krakow
and as a referral center for South East Poland (10% to 15% of
patients).
All stroke patients underwent cranial computed tomography.
Magnetic resonance imaging was performed in 133 cases (21.0%),
when indicated. Five hundred twenty (82.3%) patients underwent
extracranial arterial ultrasound examination and 431 (68.2%) patients had echocardiography performed. In patients younger than age
45 years (n⫽61), we performed transesophageal echocardiography
and screening for hypercoagulable state. According to the clinical
features and the results of diagnostic workup, the following causes of
stroke were diagnosed based on TOAST criteria: LVD stroke, SVD
stroke, cardioembolic (CE) stroke, and stroke of unknown or rare
etiology.18 Only patients with established stroke etiology were
included for further analysis.
We also studied unrelated control individuals, free of clinically
detectable cerebrovascular disease and without any stroke history.
They were recruited from consecutive spouses of the patients (30%),
or from the community, to maintain the control to case ratio 2:1 for
LVD and SVD strokes and control-to-case ratio 1:1 for CE stroke.
Controls were randomly matched from the beginning of the study for
age (⫾1 year) and sex with the patients. All stroke patients and
controls were whites.
This study was performed according to the Helsinki Declaration
with approval of the Ethical Committee of the Jagiellonian University. All individuals included in this study gave informed consent
before their inclusion in the study.
Demographic data were collected from stroke patients and their
controls. An individual was classified as having arterial hypertension
if he/she met 1 of the following criteria: (1) the diagnosis of
hypertension in the medical history; (2) antihypertensive treatment
before entry into the study; or (3) systolic or diastolic blood pressure
ⱖ140 mm Hg or ⱖ90 mm Hg, respectively, on at least 2 different
occasions (the first 3 days of hospitalization were not considered for
the stroke patients). The history of ischemic heart disease and
myocardial infarction was established using medical history, examination of previous and current electrocardiograms, and laboratory
data. The diagnosis of atrial fibrillation was established on electrocardiogram findings during a hospitalization or on data from medical
documentation with electrocardiogram-documented atrial fibrillation. Diabetes mellitus was defined by WHO criteria.19 Family
history of stroke was defined as the occurrence of stroke in
first-degree relatives. Smoking habits were defined as current smokers of ⱖ1 cigarette per day, former smokers, or nonsmokers. For
statistical analysis, “current” and “former” smokers were pooled
together.
The history was taken from patients or their proxies. To determine
patients’ ability to be interviewed, we asked questions about their
name, date, and orientation. Irrespective of the information we were
able to obtain from the patients, we also questioned all the proxies
and studied medical documentation to assemble the most detailed
medical history.
For the control subjects, data were collected according to a
detailed clinical questionnaire, including information on vascular
risk factors, current medication, and physical examination at the time
of drawing the blood sample for DNA analysis.
Laboratory personnel, blinded for sample identity, performed the
genetic analyses. Uncuffed venous blood samples for extraction of
DNA were drawn from each subject within 2 days of stroke onset.
Leukocyte DNA was extracted using a commercially available kit
(High Pure PCR template Preparation Kit; Boehringer Mannheim).
The A1/A2 genotyping for the GpIIIa polymorphism was established using polymerase chain reaction and restriction enzyme
digestion, modified from Weiss et al.6
Data on quantitative characteristics are expressed as means⫾SD.
Data on qualitative characteristics are expressed as percent values or
absolute numbers, as indicated. Comparisons between the groups
were made with ␹2 test (nominal data) or Student t test (interval
data). A value of P⬍0.05 was considered statistically significant.
Hardy–Weinberg equilibrium was tested by the ␹2 method. The
sample size for LVD stroke was calculated to have a power of 80%
to detect the difference between the frequencies of alleles at the 0.05
significance level. The expected proportion of carriers of at least 1
A2 allele of GpIIIa among controls for LVD stroke was 23%.
The association of the GpIIIa genotype with risk for LVD stroke
was tested using conditional logistic regression analysis, considering
potential confounding risk variables including age, sex, and other
conventional risk factors. A backward elimination procedure was
used for multivariable analysis. For multivariate risk predictors, the
adjusted odds ratios are given with the 95% CIs.
The calculations were performed using the data analysis software
program SPSS 10 for Windows.
Results
Stroke cause was established in 398 of 632 (63%) consecutive patients. SVD stroke was diagnosed in 108 patients, LVD
stroke in 99 patients, and CE stroke in 191 patients. Three
hundred seventy-seven of 398 (94.7%) patients agreed to
participate in the study: 103 patients with SVD stroke, 92
with LVD stroke, and 182 patients with CE stroke. Demographic data and risk factor profiles of patients and their
controls are presented in Table 1.
A1/A2 genotypes of the GpIIIa gene, determined in 949
individuals, were in Hardy–Weinberg equilibrium for the total
group and each group separately (P for each group ⬎0.1).
GpIIIa genotype distribution was similar in patients with
SVD stroke when compared with their controls, and in CE
stroke when compared with their controls. The only significant difference in the GpIIIa genotype distribution was found
between patients with LVD stroke and their controls. The
possession of at least 1 A2 allele was found in 37% of patients
with LVD compared with 20.7% of the controls (P⫽0.003)
(Table 2).
Possession of at least 1 A2 allele of GpIIIa gene was found
significantly more often in males with LVD stroke than in
their controls. No such difference was found between females
with LVD stroke and their controls. Risk factor profiles of
male and female patients with LVD stroke and their controls
are presented in Table 3.
Conditional logistic regression analysis showed that the
presence of at least 1 A2 allele of GpIIIa gene, hypertension,
and current or previous smoking history were independent
risk factors for LVD stroke in males (Table 4).
Presence of at least 1 A2 allele of GpIIIa gene was not an
independent risk factor for LVD stroke in females (OR adjusted
for all studied risk factors, 1.51; 95% CI, 0.42 to 5.49).
Discussion
This study shows that possession of at least 1 A2 allele of
GpIIIa gene is an independent risk factor for LVD stroke in
males, but not for SVD stroke or CE stroke.
Analysis based on specific stroke cause is crucial in genetic
studies. There is a growing body of evidence that stroke causes
differ in the age of onset, male/female ratio, and risk factor
profile.20,21 Jerrard-Dunne et al revealed that a family history of
stroke was a risk factor for LVD and SVD strokes, but not for CE
stroke.21 We used TOAST criteria18 to determine stroke etiology,
because they are thought to be the best available clinical criteria to
Slowik et al
TABLE 1.
GpIIIa Gene A1/A2 Polymorphism and LVD Stroke
1591
Demographics and Risk Factors Profile in Patients With Different Stroke Etiologies and Their Matched Controls
Risk Factor
SVD Stroke
(n⫽103)
Controls for
SVD Stroke
(n⫽206)
Age, y (⫾SD)
62.5⫾11.2
63.2⫾11.5
1.00
Male/female ratio
P*
LVD Stroke
(n⫽92)
Controls for
LVD Stroke
(n⫽184)
0.57
66.4⫾12.4
65.9⫾11.3
56/47
112/94
63/29
126/58
Hypertension, n (%)
74 (71.8)
108 (52.4)
0.0001
74 (80.4)
98 (53.3)
Ischemic heart disease, n (%)
35 (34.0)
62 (30.1)
0.49
39 (42.4)
65 (35.3)
P*
CE Stroke
(n⫽182)
Controls for
CE Stroke
(n⫽182)
P*
0.75
69.0⫾13.6
69.1 ⫾13.4
0.97
1.00
⬍0.00001
0.25
Atrial fibrillation, n (%)†
History of myocardial infarction, n (%)
82/100
82/100
153 (84.1)
101 (55.5)
⬍0.00001
1.00
141 (77.5)
80 (44.0)
⬍0.00001
126 (69.2)
18 (9.9)
⬍0.00001
⬍0.00001
2 (1.9)
17 (8.3)
0.02
3 (3.3)
13 (7.1)
0.20
45 (24.7)
14 (7.7)
Diabetes mellitus, n (%)
21 (20.4)
33 (16.0)
0.38
18 (19.6)
30 (16.3)
0.50
33 (18.1)
29 (15.9)
0.58
Family history of stroke, n (%)
24 (23.3)
36 (17.5)
0.22
13 (14.1)
28 (15.2)
0.98
31 (17.0)
29 (15.9)
0.78
Smoking (current/previous), n (%)
37 (35.9)
68 (33.0)
0.61
36 (39.1)
32 (17.4)
0.001
50 (27.5)
51 (28.0)
0.90
*Between-group comparison between studied stroke subgroup and their controls with Student t test (age) and ␹ test.
†Atrial fibrillation was not considered to be a risk factor for SVD stroke and LVD stroke.
SVD indicates small-vessel disease; LVD, large-vessel disease; CE, cardioembolic.
2
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separate different stroke etiologies, although they present an imperfect relationship to the underlying inherited disease mechanism.22
To prove that GpIIIa polymorphism is involved as a risk
for LVD stroke and not for other stroke etiologies, we
compared patients with LVD stroke, SVD stroke, and CE
stroke with each groups’ matched controls. We did not use
the same control group for different stroke causes, as did the
author of a previously published article on this topic.23 The
issue of precise matching of patients’ populations with their
controls is important particularly for the genes having possible deleterious, time-dependent impact on overall health and
longevity in humans, such as the GpIIIa gene.24 Thus, even a
few years of difference in age of controls may influence the
frequency of the alleles in this group and may influence the
final results when comparing patient populations with
controls.
Several reports have established that LVD stroke affects
mostly males, whereas the sex distribution in SVD stroke
patients and CE stroke patients did not differ significantly.21
We confirmed this observation showing the male-to-female
ratio of 2:1 in patients with LVD.
We did not find any correlation between the possession of
at least 1 A2 allele of GpIIIa gene and the age of stroke onset.
This correlation has been reported in patients with myocardial
infarction6,25 and once in stroke patients.14 Carter et al, who
studied 37 young patients with probable atherothrombotic
stroke, showed that at least 1 A2 allele of GpIIIa gene was
present twice as often as compared with 74 controls matched
by age and sex.14 Studies of young stroke females yielded
negative results;23,26 this may be related to the protective role
of estrogens in female GpIIIa A2 carriers.27 In our study, the
small number of patients with LVD stroke younger than age
50 years (n⫽8) does not allow us to draw conclusions
concerning the relation between the age of stroke onset and
GpIIIa polymorphism.
A number of potential biases may have influenced our final
results. The most important is the fact that we were not able
to establish stroke cause in 37% of consecutive stroke
patients fulfilling the entry criteria. This value is similar to the
percentage of patients with undetermined stroke causes reported by other authors.20 Nevertheless, this could have
influenced the distribution of GpIIIa genotype within the
studied groups. We were able to genotype 74% of patients
with unknown or rare stroke etiology, and we found that the
distribution of the GpIIIa genotype was similar to that of the
whole control group (data not shown).
Another weakness of our study may have been the lack of
carotid ultrasound examination in the control subjects. We are
aware that up to 10% of asymptomatic individuals may have
carotid stenosis.28 However, in light of data published by
Streifler et al15 showing that the possession of at least 1 A2
allele of GpIIIa gene in asymptomatic patients with significant carotid stenosis was 20.3%, which is similar to our
controls, we believe that the lack of this examination in
controls does not influence the final results.
TABLE 2. GpIIIa Genotype Distribution in Patients With Different Stroke Etiologies and Their
Matched Controls
SVD Stroke
(n⫽103)
SVD Controls
(n⫽206)
A1/A1, n (%)
71 (68.9)
151 (73.3)
A1/A2, n (%)
29 (28.2)
53 (25.7)
32 (34.8)
A2/A2, n (%)
3 (2.9)
2* (1.0)
2 (2.2)
Genotype
LVD Stroke
(n⫽92)
58 (63)
LVD Controls
(n⫽184)
CE Stroke
(n⫽182)
CE Controls
(n⫽182)
146 (79.3)
142 (78.1)
131 (72)
37 (20.1)
35 (19.2)
50 (27.5)
1† (0.6)
5 (2.7)
1* (0.5)
Statistical calculation based on the comparison of A1/A1 vs A1/A2 and A2/A2 genotypes.
*P⫽NS.
†P⫽0.003 (␹2 test).
1592
Stroke
TABLE 3.
July 2004
Demographics and Risk Factor Profile in Males and Females With LVD Stroke and Their Matched Controls
Males With
LVD Stroke
(n⫽63)
Male Controls
for LVD Stroke
(n⫽126)
65.7⫾11.2
65.0⫾10.8
0.99
A1/A2 or A2/A2 genotype, n (%)
25 (39.7)
29 (23.0)
0.017
9 (31.0)
9 (15.5)
0.097
Hypertension, n (%)
48 (76.2)
68 (54.0)
0.003
27 (93.1)
30 (51.7)
0.0001
Ischemic heart disease, n (%)
25 (39.7)
41 (32.5)
0.33
14 (48.3)
24 (41.4)
0.63
3 (4.8)
16 (12.7)
0.1
0
2 (3.4)
0.43
Age, y (⫾SD)
History of myocardial infarction, n (%)
P*
Females With
LVD Stroke
(n⫽29)
Female Controls
for LVD
Stroke (n⫽58)
67.9⫾12.2
67.9⫾12.1
P*
0.99
Diabetes mellitus, n (%)
10 (15.9)
25 (19.8)
0.51
8 (27.6)
4 (6.9)
0.01
Family history of stroke, n (%)
10 (15.9)
18 (14.3)
0.54
3 (10.3)
11 (19.0)
0.28
Smoking (current/previous), n (%)
30 (47.6)
28 (22.2)
0.0001
5 (17.2)
3 (5.2)
0.08
*Between-group comparison between studied stroke subgroup and their controls with Student t test (age) and ␹ test.
2
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Finally, the lack of association of the presence of A2 allele
of GpIIIa gene in female patients with LVD should be
discussed. Women could be protected from the atherothrombotic effect of A2 allele by the action of estrogens. Data exist
demonstrating that physiological concentrations of estrogens
inhibit the A2-bearing platelets more than the A1-bearing
platelets.27 However, taking into account that our study may
lack the power to detect some, possibly minor, role of the A2
allele in females, it should be pointed out that this problem
warrants further study.
Identification of a subgroup of stroke patients, ie, male
patients with LVD stroke, having an overrepresentation of A2
allele of GpIIIa gene may have implications for planning their
future treatment strategies. Studies show that there is a
relationship between the effectiveness of aspirin treatment
and GpIIIa polymorphism.29,30 Further studies are needed to
elucidate the significance of aspirin in acute treatment and
secondary stroke prevention in A1 and A2 carriers with LVD
stroke, separately.
Acknowledgments
This research was supported by State Committee for Scientific
Research Grant 6PO5B 049 20. We thank Anna Dziubek, Halina
Kaliszuk, and Malgorzata Sado from the Department of Neurology,
Jagiellonian University, Krakow, Poland and Amanda Haeffele from
the Department of Biochemistry and Molecular Biology, State
University of New York, Upstate Medical University, Syracuse, NY
for invaluable technical assistance. We are grateful to Julienne
Kenton for her help in the preparation of this manuscript.
TABLE 4. Independent Predictors of LVD Stroke in Male
Patients (Conditional Logistic Regression Model)
Age, y
OR
95% CI
P
1.004
0.97–1.04
NS
A1/A2 or A2/A2 genotype
2.51
1.21–5.20
0.01
Hypertension
2.77
1.31–5.81
0.007
Smoking (current/previous)
3.81
1.88–7.73
0.0002
Results are presented as ORs (adjusted for age, the presence of at least 1
A2 allele of GpIIIa gene, hypertension, smoking, history of myocardial infarction,
ischemic heart disease, diabetes mellitus, and family history of stroke).
OR indicates odds ratio; NS, nonsignificant.
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A2 Alelle of GpIIIa Gene Is a Risk Factor for Stroke Caused by Large-Vessel Disease in
Males
Agnieszka Slowik, Tomasz Dziedzic, Wojciech Turaj, Joanna Pera, Lidia Glodzik-Sobanska,
Pawel Szermer, Maciej T. Malecki, Denise A. Figlewicz and Andrzej Szczudlik
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Stroke. 2004;35:1589-1593; originally published online June 3, 2004;
doi: 10.1161/01.STR.0000132194.24663.3d
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