(Stroke. 2000;31:493.)
© 2000 American Heart Association, Inc.
Original Contributions |
Association Between Platelet Glycoprotein Ib
Genotype and Ischemic Cerebrovascular Disease
From the Departments of Laboratory Medicine (A.S., M.M., A.O., Y.T., E.T., K.W.), Hematology (M.M., Y.I.), Neurology (D.I., N.T., Y.F.), and Health Center (T.Y., I.S.), School of Medicine, Keio University, Tokyo, and Sankyo Inc (M.Y.), Tokyo, Japan.
Correspondence to Mitsuru Murata, MD, Division of Hematology, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail murata{at}mc.med.keio.ac.jp
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Abstract |
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Background and Purpose—Platelets play pivotal roles in the development of ischemic cerebrovascular disease (CVD). The platelet glycoprotein (GP) Ib/IX/V complex is a receptor for von Willebrand factor, which plays a major role in the initial phase of platelet activation under high shear stress conditions. This study was designed to investigate the association between a genetic variation of this receptor and the prevalence of CVD.
Methods—Two hundred patients with ischemic CVD, as
confirmed by brain CT and/or MRI, and 317 age- and sex-matched control
subjects without clinical evidence of CVD or cardiovascular
disease were analyzed for their genotype
frequencies of the 145Thr/Met dimorphism of the 
-chain
of GPIb (GPIb).
Results—Genotypes with 145Met (T/M and M/M) were more frequently found in the CVD patients (26.5%) than in control subjects (14.2%, P=0.0005). The genotype effect was more obvious in those <60 years of age or without acquired cardiovascular risk factors. The odds ratio for nonsmoking women <60 years of age was 10.6 (95% confidence intervals, 2.2 to 51.7). Although the number of patients studied was small (n=24), transient ischemic attack showed the highest odds ratio (4.3, P=0.0004), followed by lacunar infarction (OR=2.2, P=0.0024) and atherothrombotic infarction (OR=1.5, P=0.3143). Logistic regression analysis revealed that the presence of Met-allele was independently associated with CVD.
Conclusions—Our study suggests that the platelet GPIb
genotype is a genetic risk factor for ischemic CVD.
Key Words: cerebrovascular disorders • genetics • platelets • polymorphism • thrombosis
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Platelets play key roles in cerebrovascular diseases (CVD) and acute coronary syndromes, as demonstrated by histopathologic findings and clinical observations showing the efficacies of antiplatelet therapies for these disorders.1 2 3 Platelet membrane glycoproteins (GPs) are particularly important to form platelet thrombi in that they mediate platelet adhesion and aggregation. GPs are now targets of antiplatelet therapies. Several lines of evidence have suggested that different GPs are involved in platelet activation processes according to different rheological conditions.4 5 6 7 8 9 10 Platelets in flowing blood can be activated and aggregated by high shear stress without chemical agonists. Moreover, shear-induced platelet aggregation has been shown to be enhanced in patients with atherosclerotic disorders including coronary artery diseases and ischemic stroke.11 12 These observations suggest the relevance in ischemic stroke of platelet responsiveness to high shear stress. The molecular mechanisms of shear-induced platelet aggregation have been investigated extensively, and it is now believed that aggregation is initiated by the binding of an adhesive ligand von Willebrand factor (vWF) to its platelet receptor, the GPIb/IX/V complex.10 Binding of vWF to GPIb/IX/V causes intraplatelet signaling, resulting in the activation of the other platelet receptor for vWF, the GPIIb/IIIa complex, to aggregate platelets.10
GPIb/IX/V complex is composed of 4 subunits; GPIb (CD42b), GPIbß
(CD42c), which is disulfide-bonded to GPIb, GPIX (CD42a), and GPV
(CD42d).13 They are synthesized from different genes. The
genomic and cDNA sequences of each component have been
identified.14 Two genetic polymorphisms have been
reported in the coding sequence of GPIb. The first polymorphism,
a C/T transition at nucleotide 1018 (numbers
according to Wenger et al15 ), results in an amino
acid dimorphism (Thr/Met) at residue 145 of GPIb, which is located
within the vWF-binding domain of the receptor. This polymorphism is
a known molecular basis of a platelet alloantigen system, HPA
2a/2b, and is involved in the development of platelet transfusion
refractoriness.16 17 The second polymorphism is the
variable number (1 to 4) of a 13–amino acid sequence repeats. This
"size-polymorphism" is known to be strongly associated with the
first polymorphism, alleles with 1 or 2 repeats being linked to
145Thr, whereas alleles with 3 or 4 repeats
are linked to 145Met.18 Moreover,
another polymorphism, the Kozak sequence polymorphism, was
recently identified and it was suggested that this polymorphism
affected the receptor density on the platelet
surface.19 The effect of these polymorphisms on
platelet function, however, is still not well understood.
The association between GPIb genotype and the risk of
coronary artery disease was first reported in
1997.20 Subsequently, several studies were reported, but
only a few studies focused on the association of this genotype
with stroke, and the results were not
consistent.21 22 23 Therefore we performed an
allelic association study to compare genotype frequencies
between CVD patients and age- and sex-matched control subjects.
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Subjects and Methods |
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Patients and Control Subjects
We analyzed 200 unrelated Japanese patients with a history of ischemic cerebrovascular disease (mean age 58.2±7.7 years), and 317 age- and sex-matched unrelated control subjects (mean age 59.0±3.6 years, Table 1
).
Patients were those who visited the outpatient clinic of Keio
University Hospital in Tokyo for regular follow-up. Diagnosis of CVD
was made by neurologists at the onset of the disease on the basis of
the classification of cerebrovascular diseases III established by the
National Institute of Neurological Disorders and Stroke.24
CVD was classified as transient ischemic attack (TIA; n=24),
atherothrombotic infarction (n=51), and lacunar infarction (n=125). The
distribution of patient number for each subtype is compatible with the
reported incidence of CVD in Japan,25 where lacunar
infarction is predominant. Patients with cardioembolic cerebral
infarction and cerebral hemorrhage were not included in this
study. Brain CT and/or MRI were performed for each patient. Magnetic
resonance angiography and/or extracranial duplex ultrasonography were
available in >80% of cases. For TIA, all patients were evaluated by
echocardiography, ECG, magnetic resonance
angiography, and extracranial duplex ultrasonography. Control subjects
were personnel working in Keio University Hospital. For the recruitment
of control subjects, we first registered all subjects between the ages
of 50 and 65 years who visited for a regular check-up and gave informed
consent. We next excluded those with histories or physical signs of CVD
or any cardiovascular disorders. Informed consent was
obtained from every patient and control subject after a full
explanation of the study. Cardiovascular risk factors
were evaluated for both patients and control subjects on the basis of
the criteria shown below. Hypertension was defined as systolic
blood pressure >140 mm Hg or diastolic pressure
>90 mm Hg or current treatment with antihypertensive drugs.
Diabetes mellitus was defined by World Health Organization
criteria.26 Hypercholesterolemia
was defined as a cholesterol level >220 mg/dL or any
cholesterol level under cholesterol-lowering
treatment.
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Polymerase Chain Reaction and Restriction Enzyme Analysis
Identification of GPIb genotype was performed by the
polymerase chain reaction (PCR)–restriction fragment length
polymorphism method with the use of Ampdirect (Shimadzu Co), which
could eliminate the DNA extraction process and amplify the genomic DNA
directly from whole blood. PCR was performed with the use of a Gene Amp
PCR System 9600-R (Perkin Elmer). Previously described
oligonucleotide primers, 5'-GGACGTCTCCTTCAACCGGC and
5'-GCTTTGCTGGGGAACTTGAC, were used in this study.20
Reaction mixture contained 10 µL Ampdirect, 10 µL Ampaddition,
250 µmol/L dNTP, 0.5 µmol/L each specific primer, 1 U
AmpliTaq DNA polymerase, 0.5 to 1 µL whole blood, with a final volume
of 50 µL. After the initial denaturation at 80°C for 15 minutes and
at 94°C for 4.5 minutes, 40 amplification cycles were carried out,
each consisting of denaturation at 94°C for 30 seconds, annealing at
60°C for 1 minute, extension at 72°C for 1 minute, followed by a
final extension step at 72°C for 7 minutes. A 588-bp PCR product
was digested with 2 U of restriction end-nuclease Hin1 l,
and genotypes were determined as
described.20
Statistical Analysis
The unpaired Student’s t test was used to compare
the continuous variables between CVD patients and control subjects.
Differences in proportion were analyzed by the
2 test. Calculation of odds ratio (OR) and
95% confidence intervals (95% CI) estimated the association strength
between GPIb genotype and CVD. OR (95% CI) >1 was
considered to be significant. A logistic regression analysis
was performed to evaluate the interaction between the GPIb
T/M genotype and other variables in relation to
the prevalence of CVD. Independent variables included in this
analysis were age (quantitative), sex (male or female),
hypertension (yes or no), hypercholesterolemia
(yes or no), diabetes (yes or no) and GPIb genotypes
(T/T vs T/M+M/M). A probability value
<0.05 was considered to be statistically significant. All statistical
analyses were performed with the use of Statview (version 5.0,
for Macintosh, SAS Institute, Japan).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Characteristics of Control Subjects and CVD Patients
Table 1
shows the number, mean age, sex distribution, and
the prevalences of selected risk factors for CVD in the patients and
control subjects. No statistically significant differences were
observed for age and sex distribution between the patients and control
subjects. As expected, there were significant differences in the
frequencies of current smoking, hypertension, and diabetes mellitus
between the 2 groups.
Genotype Frequencies Were Different Between Control
Subjects and CVD Patients
Genotype and allele frequencies of the CVD patients
and control subjects are shown in Table 2. Genotypes with
145Met (T/M or M/M) were
14.2% in control subjects. On the other hand, CVD patients showed a
significantly higher percentage of these genotypes (26.5%,
P=0.0005). Statistically significant differences were also
observed when separate analyses were performed for men (26.1%,
P=0.0153) and women (27.9%, P=0.0068).
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Effect of GPIb Genotype Was More Obvious in Those <60
Years of Age or Without Acquired Cardiovascular
Risk Factors
Table 3 summarizes the subpopulation
analyses for the relation between GPIb and CVD. In this
table, crude ORs (T/T vs T/M+M/M) are
described. In all subpopulations analyzed, the ORs were
universally higher in those groups without the selected
cardiovascular risk factors. The ORs were 3.58 and 1.06
for nonsmokers and smokers, respectively. The OR for nonsmokers <60
years of age was 4.48, for women <60 it was 4.89, and for nonsmoking
women <60 it was 10.60 (not shown in this table).
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GPIb Genotype Was Associated With Lacunar Infarction
and TIA
We next analyzed genotype frequencies for subtypes
of CVD; that is, TIA, atherothrombotic stroke, and lacunar infarction
(Table 4). TIA patients showed
significantly higher prevalence of T/M or M/M
genotypes as compared with control subjects (41.7%,
P=0.0004). A similar association was recognized for lacunar
infarction (26.4%, P=0.0024). By contrast, the frequency
for T/M or M/M genotypes in
atherothrombotic stroke patients did not differ from the control
subjects (19.6%, P=0.3143). When patients were divided into
2 groups on the basis of the number of cerebral lesions (single or
multiple), frequencies of T/M+M/M
genotypes were higher in both groups (27.0% for multiple
cerebral lesions, P=0.0121, and 23.0% for single cerebral
lesion, P=0.0303, Table 4) as compared with control
subjects. Thus GPIb genotype was associated with both single
and multiple cerebral lesions.
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No Differences Were Seen Between GPIb Genotypes in Terms
of Prevalences of Acquired Vascular Risk Factors
We compared the prevalences of acquired
cardiovascular risk factors between different
genotypes of GPIb. In control subjects, there were no
statistically significant differences in the distribution of sex, age,
frequencies of smoking, hypertension,
hypercholesterolemia, and diabetes mellitus
between the 2 GPIb genotype groups (T/T vs
T/M+M/M). Also, in CVD patients there were no
statistically significant differences in these parameters
except that the prevalence of smoking was slightly higher in the
T/T genotype, which is, however, the "non-risk"
genotype (not shown in tables).
Logistic Regression Analysis Revealed That Presence of the
Met-Allele Was an Independent Risk Factor for CVD
In the logistic regression analysis, age, sex,
hypertension, hypercholesterolemia, diabetes,
and GPIb genotypes (T/T vs
T/M+MM) were included as independent
variables. This analysis revealed that the presence of the
Met-allele (T/M or M/M) was one of the
independent risk factors for CVD (OR=1.94, P=0.0176).
Current smoking (OR=3.28, P<0.0001), hypertension (OR=4.63,
P<0.0001), and diabetes mellitus (OR=5.41,
P<0.0001) were also shown to be independent risk factors
(not shown in tables).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study, we clearly demonstrated that the genotypes with Met-allele (T/M and M/M genotypes) were associated with CVD in the Japanese population and that it might be a new genetic risk factor for CVD. Our results agree with those obtained by Gonzalez-Conejero et al21 but contradict the results reported by Carlsson et al,22 who failed to show any association between the GPIb
genotype and stroke. We performed a careful association
study with age- and sex-matched control subjects living in the same
area in Japan and carried out detailed analyses for the
association. We have found that the effect of GPIb genotype
varies significantly among subpopulations studied. As shown in Table 3, the genotype effect was stronger in those populations
who have less acquired vascular risk factors; that is, the ORs were
apparently higher in women, those <60 years of age, and nonsmokers.
When nonsmoking women <60 years of age were compared, the OR of the
Met-allele for CVD was 10.60. This finding is compatible with a
published study on the association of GPIb genotype with
coronary artery disease,20 in which the effect of
GPIb genotype was significant only in those 
60 years of
age, and with the 2 previous studies on the relation between CVD and
another platelet receptor polymorphism, the PlA1/A2
polymorphism of platelet GPIIb/IIIa.27 In one of
these studies, the genotype effect of the PlA1/A2
polymorphism was more obvious among women,28 and in
the other study, the genotype effect was stronger in
nonsmokers.23 Thus the relative contribution of genetic
factors might differ significantly, depending on the populations
analyzed. This might in part explain the conflicting results of
the published studies. Although our results suggest that the 145T/M polymorphism is associated with the risk of CVD, we did not find the gene-dose effect; that is, frequencies of heterozygote T/M differed significantly between control subjects and patients (14.2% and 26.5%, respectively), but frequencies of homozygote M/M were not significantly different (0.6% and 1.0%, respectively). This might suggest that there could be a deleterious interaction between 145Thr and Met. However, because the M/M genotype is so rare, further studies with larger cohorts are necessary to test this hypothesis.
In the subtype analysis, the GPIb genotype was
associated with the risks for TIA and lacunar infarction but not for
atherothrombotic stroke. We initially assumed that platelet
polymorphisms would be more closely related to atherothrombotic
stroke and TIA because these two types of ischemic CVD are
believed to have a common pathogenesis, and lacunar infarction is
mostly dependent on the presence of hypertension. However, this
assumption was in part based on the clinical observation that lacunar
infarction was relatively resistant to antiplatelet drugs
such as aspirin. If one considers that shear-induced,
GPIb/IX/V-mediated platelet activation is insensitive to
aspirin,10 our results are not surprising, and it could be
speculated that the relative contribution of GPIb/IX/V complex for the
pathogenesis of CVD might be different among subtypes of CVD.
The roles of vWF-GPIb/IX/V interaction in the development of atherosclerosis and arterial thrombosis have been implicated in several reports.29 30 31 32 33 Agents that block either vWF or GPIb/IX/V inhibited and delayed coronary occlusion in animal models.31 Elevated plasma levels of vWF is a poor prognostic factor of coronary heart disease as well as an independent risk factor for subsequent acute coronary events in patients with angina pectoris.32 33 Participation of vWF-GPIb/IX/V in CVD, however, is not well understood, although shear-induced platelet aggregation was enhanced in ischemic CVD.12
To date, there is no direct evidence showing a relation between the
GPIb genotype and the functional difference of
platelets. It is possible that replacement of threonine by
methionine at residue 145, which is located within the vWF and
thrombin-binding domain of this receptor, might affect the structure
and function of this receptor. It is also possible that the effect of
145T/M genotype is merely a
reflection of the functional differences caused by the other
polymorphism on the coding sequence, the "repeat
polymorphism," located in the macroglycopeptide portion, which is
in linkage disequilibrium with 145T/M.
Moreover, participation of the third polymorphism of GPIb, the
Kozak sequence polymorphism that is reportedly associated with the
receptor density on platelets,19 also should be
considered.
Polymorphisms of platelet integrins have also been studied for
the association with CVD. These are the PlA1/A2 polymorphism of
GPIIb/IIIa (IIbß3) and a collagen receptor GPIaIIa
(2ß1).28 34 GPIIb/IIIa is the final common pathway of
activation signals generated by various stimuli and is a key molecule
for platelet aggregation, thus being a recent target of
antiplatelet therapy. However, because the PlA2 allele (the
less frequent allele) is very rare in Japan35 (our
unpublished results indicated that PlA2 type is <1% in the normal
Japanese), we did not include this polymorphism in our
analysis.
Although antiplatelet therapies are widely used for the treatment and prevention of stroke, the efficacy is not always consistent and sufficient, and the participation of platelets in the pathogenesis of different subtypes of CVD still remains to be elucidated. Our present study suggested that vWF and GPIb/IX/V receptor might be involved in lacunar infarction and TIA and would further direct a new strategy for antiplatelet therapy targeting GPIb/IX/V receptor and/or vWF.
Received October 15, 1999; revision received November 23, 1999; accepted November 23, 1999.
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H. Ulrichts, K. Vanhoorelbeke, S. Cauwenberghs, S. Vauterin, H. Kroll, S. Santoso, and H. Deckmyn Von Willebrand Factor But Not {alpha}-Thrombin Binding to Platelet Glycoprotein Ib{alpha} Is Influenced by the HPA-2 Polymorphism Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1302 - 1307. [Abstract] [Full Text] [PDF]
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J. F. Meschia Addressing the Heterogeneity of the Ischemic Stroke Phenotype in Human Genetics Research Stroke, December 1, 2002; 33(12): 2770 - 2774. [Abstract] [Full Text] [PDF]
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 D Ito, N Tanahashi, M Murata, H Sato, I Saito, K Watanabe, and Y Fukuuchi Notch3 gene polymorphism and ischaemic cerebrovascular disease J. Neurol. Neurosurg. Psychiatry, March 1, 2002; 72(3): 382 - 384. [Abstract] [Full Text] [PDF]
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S. Bak, D. Gaist, S. H. Sindrup, A. Skytthe, and K. Christensen Genetic Liability in Stroke: A Long-Term Follow-Up Study of Danish Twins Stroke, March 1, 2002; 33(3): 769 - 774. [Abstract] [Full Text] [PDF]
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T. J. Kunicki The Influence of Platelet Collagen Receptor Polymorphisms in Hemostasis and Thrombotic Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 14 - 20. [Abstract] [Full Text] [PDF]
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J.Y. Streifler, N. Rosenberg, A. Chetrit, R. Eskaraev, B.A. Sela, R. Dardik, A. Zivelin, B. Ravid, J. Davidson, U. Seligsohn, et al. Cerebrovascular Events in Patients With Significant Stenosis of the Carotid Artery Are Associated With Hyperhomocysteinemia and Platelet Antigen-1 (Leu33Pro) Polymorphism Stroke, December 1, 2001; 32(12): 2753 - 2758. [Abstract] [Full Text] [PDF]
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 D. E. Kandzari and P. J. Goldschmidt-Clermont Platelet polymorphisms and ischemic heart disease: moving beyond traditional risk factors J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1028 - 1032. [Full Text] [PDF]
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 J. Mikkelsson, M. Perola, A. Penttila, and P. J. Karhunen Platelet Glycoprotein Ib{alpha} HPA-2 Met/VNTR B Haplotype as a Genetic Predictor of Myocardial Infarction and Sudden Cardiac Death Circulation, August 21, 2001; 104(8): 876 - 880. [Abstract] [Full Text] [PDF]
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 R. I. Baker, J. Eikelboom, E. Lofthouse, N. Staples, V. Afshar-Kharghan, J. A. Lopez, Y. Shen, M. C. Berndt, and G. Hankey Platelet glycoprotein Ib{alpha} Kozak polymorphism is associated with an increased risk of ischemic stroke Blood, July 1, 2001; 98(1): 36 - 40. [Abstract] [Full Text] [PDF]
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 M. S. Williams and P. F. Bray Genetics of Arterial Prothrombotic Risk States Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419. [Abstract] [Full Text]
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M. B. Frank, A. P. Reiner, S. M. Schwartz, P. N. Kumar, R. M. Pearce, P. G. Arbogast, W. T. Longstreth Jr, F. R. Rosendaal, B. M. Psaty, and D. S. Siscovick The Kozak sequence polymorphism of platelet glycoprotein Ib{alpha} and risk of nonfatal myocardial infarction and nonfatal stroke in young women Blood, February 15, 2001; 97(4): 875 - 879. [Abstract] [Full Text] [PDF]
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D. Ito, M. Murata, N. Tanahashi, H. Sato, A. Sonoda, I. Saito, K. Watanabe, and Y. Fukuuchi Polymorphism in the Promoter of Lipopolysaccharide Receptor CD14 and Ischemic Cerebrovascular Disease Stroke, November 1, 2000; 31(11): 2661 - 2664. [Abstract] [Full Text] [PDF]
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A. P. Reiner, P. N. Kumar, S. M. Schwartz, W. T. Longstreth Jr, R. M. Pearce, F. R. Rosendaal, B. M. Psaty, and D. S. Siscovick Genetic Variants of Platelet Glycoprotein Receptors and Risk of Stroke in Young Women Stroke, July 1, 2000; 31(7): 1628 - 1633. [Abstract] [Full Text] [PDF]
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