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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2771-2776
Polymorphisms of Platelet Membrane Glycoprotein Ib Associated
With Arterial Thrombotic Disease
By
Rocio Gonzalez-Conejero,
Maria L. Lozano,
Jose Rivera,
Javier Corral,
Juan A. Iniesta,
Jose M. Moraleda, and
Vicente Vicente
From the Unit of Hematology and Hemotherapy, and the Department of
Neurology, School of Medicine. Hospital General Universitario, Murcia,
Spain.
 |
ABSTRACT |
Platelet membrane glycoprotein Ib (GPIb) is a major receptor
for von Willebrand factor and thrombin, which plays a key role in the
initial development of thrombi. Two polymorphisms (HPA-2 and VNTR) that
affect phenotype have been described in GPIb. The relevance of these
polymorphisms to thrombotic disease was investigated by genotypic
identification in three case-control studies: 104 case patients with
acute cerebrovascular disease (CVD), 101 case patients with acute
coronary heart disease (CHD), 95 patients with deep venous thrombosis
(DVT), and one control age-, sex-, and race-matched for each case
patient. Results show that the C/B genotype of the VNTR and the HPA-2b
polymorphisms of GPIb are strongly associated with increased risk of
coronary heart disease and cerebral vascular disease but not with deep vein thrombosis. These two polymorphisms of GPIb may represent newly
identified risk factors for arterial thrombotic disease, but not for
venous thrombosis.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
ARTERIAL THROMBOSIS is a
principal human affliction causing approximately 50% of the
nonaccident deaths in developed nations. Over the past 2 decades,
numerous studies have reported platelet hyperaggregability in patients
with coronary heart disease (CHD), thrombotic cerebrovascular disease
(CVD), and peripheral vascular disease.1-4 Shear-induced
binding of von Willebrand factor (vWF) to platelet glycoprotein (GP)
Ib, which occurs at high levels in diseased arteries and arterioles
partially obstructed by atherosclerosis or vasospasm, induces the
activation and aggregation of platelets without the addition of any
agonist.5-9
GPIb is a transmembranous platelet glycoprotein having a molecular
weight (Mr) of 143,000 that forms a
noncovalent complex with GPIb , GPIX, and GPV. There are
approximately 25,000 GPIb molecules per platelet.10 Two
polymorphisms of GPIb have been described. Size polymorphism was
first described by Moroi et al,11 who noted four variants
of GPIb, which were designated A, B, C, and D in order of decreasing
molecular mass, from 168 kD for variant A to 153 kD for variant D. The
polymorphism was shown to result from a variable number of tandem
repeats (VNTR) of 39 bp in the macroglycopeptide region of GPIb:
either one (D allele), two (C allele), three (B allele), or four (A
allele). Each repeat leads at the protein level to additions of
13-amino acids and, thus, moves the vWF-binding domain farther out of
the platelet membrane.12,13 A potential consequence of this
structural change is to expose the molecule to greater shear forces,
which may lower the threshold for shear-induced interaction with vWF
and subsequent platelet activation.
Another polymorphism within the GPIb coding region, a Thr in HPA-2a
(Kob; Sib[b] negative)  Met in HPA-2b (Koa; Sib[a]) at
position 145,14 is related to the antigenicity of
HPA-2,15 which suggests that the aminoacidic change should
cause a variation in the structure of the GPIb molecule. The HPA-2
polymorphism is located close to the vWF and the high-affinity thrombin
binding sites16,17 and might therefore influence the
receptor function of these variants. DNA typing has recently showed
that the HPA-2 polymorphism is in linkage disequilibrium with the VNTR
polymorphism described above.18 HPA-2a is associated with
the D or C variants, whereas HPA-2b is linked with the longest B and A
alleles.
Different frequencies of these GPIb variants have been found among
distinct populations.10 In Caucasians, the C (HPA-2a) allele is the most prevalent, with a frequency of 80%, followed by the
D (HPA-2a) and B (HPA-2b) alleles with a similar 10% frequency, whereas the largest variant A (HPA-2b) is uncommon.10,19-22
The aim of the present study was to perform an analysis of the two
polymorphisms of GPIb, one affecting the distance by which the
active sites of platelet GPIb extend from the surface and the other
altering the vicinity of the GPIb active sites, in relation with the
development of arterial thrombotic disorders. Thus, we conducted two
retrospective case-control studies both in survivors from acute
cerebrovascular events and in patients diagnosed of acute coronary
syndromes and examined the relevance of those polymorphisms in a venous
thromboembolism setting.
| |
MATERIALS AND METHODS |
Selection of case patients and control subjects.
Studies on case patients and control subjects were approved by the
local ethics committee, and all participants gave their informed
consent. Genotypic analyses were performed on 104 consecutive CVD
patients referred to our institution and diagnosed with transient ischemic attack (TIA; n = 31), minor stroke (n = 44), or cerebral infarction (n = 29). Diagnosis was attained according to the
classification of cerebrovascular diseases of the National Institute of
Neurological Disorders and Stroke ad Hoc Committee.23 One
hundred one consecutive patients who survived a primary acute coronary
event and were admitted to the Coronary Unit with an established
diagnosis of myocardial infarction (n = 69) or unstable angina (n = 32), according to the World Health Organization criteria,24
were also enrolled in the CHD study. Moreover, 95 consecutive patients
with a confirmed diagnosis (by compression ultrasonography or contrast
venography) of deep venous thrombosis (DVT) were evaluated. All
included cases of CHD, CVD, or DVT were age- and sex-matched to a
different control who had no documented history of vascular disease.
All case patients and control subjects were Mediterranean Caucasians.
CVD and CHD controls were additionally chosen approximating criteria to
match selected risk factors for arterial thrombotic disease (smoking history, blood pressure, total serum cholesterol level, and diabetes status) with their respective case patient. These 300 distinct controls
were selected by reviewing patient charts from a population of patients
admitted to the hospital who had no documented history of vascular
disease. Prespecified subgroup analyses were performed with
stratification by age ( 60 or >60 years of age), sex, type of
coronary acute event (myocardial infarction or unstable angina), and
type of cerebrovascular acute event (TIA, minor stroke, or cerebral
infarction). For the DVT case/control study, the intake of oral
contraceptives, the presence of lupus anticoagulant, and the prevalence
of two genetic risk factors for this disease (factor V Leiden and
prothrombin 20210 A allele) were investigated. The identification of
such genetic markers was performed as previously described.25,26
Blood collection and DNA isolation.
Blood samples were obtained by atraumatic venipuncture collection into
1:10 volume of EDTA (Vacutainer; Becton Dickinson, Meylon, France).
Total genomic DNA was obtained from peripheral blood after lysis with
sodium dodecyl sulfate (SDS) and proteinase K treatment of
buffy coat. DNA was purified using phenol/chloroform and ethanol
precipitation.
DNA amplification of the macroglycopeptide region (VNTR) and
genotyping of HPA-2.
Identification of the VNTR polymorphism of the GPIb gene was
performed by genomic polymerase chain reaction (PCR) of the macroglycopeptide region using two oligonucleotide primers: VNTR-F3 and
VNTR-B4 (corresponding to nucleotides 4202-4223 and 4378-4400, respectively; nucleotide number according to Wenger et
al27), with modifications from Ishida et al.13
To confirm these results, we performed a second genomic PCR using a
different set of primers: VNTR-F2 (nucleotides 3915-3938) and VNTR-B5
(4372-4393). PCR products were electrophoresed through acrylamide gels
and stained with AgNO3, as previously
described.25
Two oligonucleotide primers, HPA-2F and HPA-2B (nucleotides 3435-3455 and 4001-4021, respectively), were used in a PCR to generate a 587-bp
fragment of the GPIb gene involving the HPA-2 polymorphism (modified
from Ishida et al13). Amplified products were digested with
BsaHI (New England BioLabs, Beverly, MA), electrophoresed through 7% acrylamide gels, and stained with AgNO3.
Confirmation of the HPA-2 genotype was achieved in all cases using
single-strand conformation polymorphism analysis (SSCP).28
Genotyping of both VNTR and HPA-2 was always performed blinded as to
whether the DNA sample was from a case patient or a control.
Statistical analysis.
The Student's t-test was used to compare age. All other
variables were analyzed by the  2 test. A P value
.05 was considered to indicate statistical significance. The strength
of the association of the polymorphisms with the occurrence of
thrombotic events was estimated by calculation of the odds ratio (OR)
with the EpiInfo software (Division of Surveillance and Epidemiology,
CDC, Atlanta, GA) and the Cornfield method for the calculation of 95%
confidence intervals (CI).
| |
RESULTS |
Characteristics of the study population.
Table 1 shows the age and sex of the study
subjects. No significant differences were found in the prevalence of
selected risk factors for arterial thrombosis (hypercholesterolemia,
diabetes, hypertension, or smoking) among patients and controls in the
CVD and CHD case/control studies. However, significant differences were
observed for the family history of CVD and/or CHD between these
patients and controls.
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Table 1.
Age and Sex of Subjects of Study and Prevalence of
Selected Risk Factors for Arterial and Venous Thrombosis Among Case
Patients and Controls
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Genotyping of VNTR polymorphism and frequency of genotypes.
The amplification by PCR of the region of GPIb encoding the VNTR
polymorphism with the VNTR-F3 and VNTR-B4 oligonucleotide primers
resulted in the identification of three visible fragments of 276, 237, and 198 bp on acrylamide gels, corresponding to the alleles B, C, and
D, respectively (Fig 1A). To confirm the
VNTR genotype, we performed a second PCR of the region using
oligonucleotide primers VNTR-F2 and VNTR-B5 and amplified three
different fragments of 557 bp (B allele), 518 bp (C allele), and 479 bp
(D allele) (Fig 1B). The genotype obtained by these two PCR coincided
in all samples tested. No allele A carriers were found.
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| Fig 1.
Genetic determination of the VNTR and HPA-2 regions of
GPIb. PCR analysis of the VNTR polymorphism was performed with two
different sets of primers: VNTR F3/B4 (A) and VNTR F2/B5 (B). HPA-2
identification was performed by PCR-ASRA-BsaHI digestion (C)
and confirmed by SSCP (D). Amplified products were resolved by
acrylamide gel electrophoresis and stained with AgNO3. The
genotype of the VNTR and HPA-2 polymorphisms is indicated at the top of
each lane. MW represents the 1-kb marker ladder (GIBCO-BRL, Life
Technologies, Barcelona, Spain).
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The genotypes and allelic frequencies of the VNTR polymorphism in the
case/control studies are summarized in
Table 2. Genotype analyses showed an
association of the C/B genotype and CVD (P = .0114; OR, 2.83;
95% CI, 1.16 to 7.07). A similar association was observed between the
C/B genotype and CHD (P = .0047; OR, 2.84; 95% CI, 1.28 to
6.41). The prevalence of the B allele was significantly higher in the
group of CVD patients than in the respective control group (12.02%
v 5.77%; P = .0256; OR, 2.23; 95% CI, 1.04 to 4.86).
The B allele was also more frequently identified among CHD case
patients than in controls, although this difference did not reach
significant levels (14.36% v 8.91%; P = .0878; OR, 1.71; 95% CI, 0.88 to 3.35). No statistically significant difference related to age, sex, and type of coronary or cerebrovascular acute event was detected in relationship to the VNTR genotype (data not
shown).
By contrast, the DVT group of patients did not differ from the control
group either in the C/B genotype frequency (10.53% v 9.47%;
P = .8089) or in the B allele frequency (6.32% v
8.42%; P = .4322).
Genotyping of HPA-2 polymorphism and frequency of genotypes.
The HPA-2a allele displayed a restriction pattern with BsaHI of
270, 201, and 116 bp, whereas the presence of two bands (386 and 201 bp) was distinctive of the HPA-2b allele (Fig 1C). HPA-2 genotyping, as
determined by the SSCP method, was in complete concordance with results
obtained with BsaHI digestion (Fig 1D).
Table 3 summarizes the genotyping data for
all subjects of study. We found a significant association between
HPA-2b and acute cerebrovascular events. Thus, of the 104 such
patients, 22.11% carried at least one b allele, as compared with
10.58% of the controls (OR, 2.40; 95% CI, 1.04 to 5.63; P = .0244). Similarly, the prevalence of HPA-2b (percentage of subjects
that were either heterozygous [a/b] or homozygous [b/b]) was
significantly higher among CHD subjects than among controls (OR, 2.09;
95% CI, 0.98 to 4.49; P = .0375). No statistically significant
difference related to age, sex, and type of coronary or cerebrovascular
acute event was detected in relationship to the HPA-2 genotype (data
not shown).
The prevalence of the HPA-2b allele was 12.63% in DVT patients and
14.74% in controls, a value that was not significantly different
(P = .6729).
Finally, the frequencies of the VNTR and HPA-2 polymorphisms detected
in the control groups did not differ from those previously observed in
Caucasian population.10,19-22
| |
DISCUSSION |
The study of genetic variations determining arterial thrombosis has
already shown polymorphisms of plasma proteins29-37 or endothelial cell surface glycoproteins38-40 that can give
rise to independent risk factors for thrombosis and/or
atherosclerosis. Considering the interest to know whether polymorphisms
of platelet glycoprotein receptors also represent risk factors in
arterial thrombosis, to date only the association between the HPA-1b
(PlA2) polymorphism of the GPIIIa has been reported in
acute coronary thrombosis.41 However, we,42
like others,43-48 found that association controversial.
To assess the association between the VNTR and HPA-2 polymorphisms of
the GPIb gene and arterial thrombosis, we compared the risk of CVD
or CHD among case and control subjects matched for sex, race, and age.
Considering that genetic and environmental factors act additively or
synergistically to determine that individual's risk of arterial
thrombosis, our strategy for identification of polymorphisms
predisposing to the disease was to avoid overrepresentation of classic
vascular risk factors in the CVD and CHD groups compared with controls.
Thus, we tried to approximate risk factors between every case patient
and a single control who was age- and sex-matched. The association
between the presence of the C/B genotype and arterial thrombosis was
remarkably significant: for CHD and CVD, the presence of the C/B
genotype was associated with almost a threefold increase in risk. The
HPA-2b polymorphism of GPIb, which is in linkage disequilibrium with
A and B variants of the VNTR polymorphism,18 was also
significantly associated with the occurrence of acute coronary events
and with the development of CVD. By contrast, no statistically
significant differences in the prevalence of the VNTR or HPA-2
polymorphisms were found between the case patients with DVT and the
control subjects. Interestingly, the C/B (HPA-2a/b) genotype was found
in 60% of subjects with a family history of CVD and/or CHD,
whereas all other genotypes were present in 40% of those individuals.
Thus, the findings of the present study suggest that the VNTR C/B and
the HPA-2a/b genotypes of GPI are associated with arterial
thrombotic events. In agreement with our results, during the
preparation of this manuscript, data from the Japanese population
showed that the largest VNTR A and the HPA-2b alleles increased, in a
way similar to that in our study, the risk of coronary
heart disease,49 confirming that these GPIb
polymorphisms represent newly identified genetic risk factors for
arterial thrombosis in Caucasian and Japanese populations.
Considering the present case/control studies, several points should be
borne in mind when interpreting results. First, the study was performed
in arterial thrombotic events survivors. Therefore, a survival bias
cannot be avoided in the disease-association study, and it is likely
that early mortality from CHD or CVD in patients could
lead to an underestimation of the prothrombotic polymorphisms. Second,
our study refers to the association between the VNTR and HPA-2
polymorphisms of GPIb and arterial thrombosis, specifically in the
Mediterranean Caucasian population. The relevance of these polymorphisms should be investigated in other populations and with
prospective and family studies.
We cannot exclude the possibility that the VNTR and HPA-2 polymorphisms
of the GPIb gene could be simply genetically linked to the causative
gene. Nevertheless, these two changes in the GPIb could influence
the susceptibility to arterial thrombosis. The single amino acid
substitution (Thr145/Met145) in the
neighbouring of the active sites of GPIb16,17 and the
alloantibody formation,15 determined by the HPA-2
polymorphism, suggest that the aminoacidic change might cause a
conformational variation in the structure of the GPIb molecule that
may therefore be able to affect its function. On the other hand, the
addition of repeats to the macroglycopeptide region of GPIb,
determined by the VNTR polymorphism, increases the distance between the
ligand-binding domains of GPIb and the platelet plasma membrane. The
key question, as suggested by others,10,50 is whether
variations in the distance by which the active sites of GPIb extend
from the surface influence platelet adhesion and the predisposition for
pathologic thrombi to form by altering the susceptibility of platelets
to shear-induced activation. Our study shows a significant association
of C/B genotype carriers with the development of acute arterial
thrombotic events. These findings support the previous hypothesis
suggesting that the higher or lower number of repeats, and thus the
greater or smaller overall length of the macroglycopeptide region of
GPIb, would have a prothrombotic or antihemostatic effect,
respectively.12 Being that the HPA-2 polymorphism is
genetically linked to the VNTR polymorphism, whether the HPA-2b is per
se associated with arterial events or by means of its linkage
disequilibrium with the size polymorphism of GPIb remains to be
elucidated. The finding of a stronger association of the
C/B genotype with either CVD (OR, 2.83) or CHD (OR, 2.84), than between
HPA-2 (a/b + b/b) and CVD (OR 2.40) or CHD (OR, 2.09; 95% CI, 0.98 to
4.49), could suggest a more relevant role of the VNTR polymorphism.
To date, very few studies have attempted to assess the influence of the
HPA-2 and VNTR polymorphisms in platelet function. Mazzucato et
al22 have reported no functional abnormalities in the
binding of vWF to the platelet GPIb as a function of the HPA-2
genotype, and we have found comparable basal activation, aggregability,
and ristocetin-induced binding of vWF in platelets from three subjects
VNTR B/B (HPA-2 b/b) and in platelets from three individuals VNTR C/C
(HPA-2 a/a) (data not shown). By contrast, a chronic, but not
transient, enhanced platelet aggregation response to shear stress in
stroke patients has been recently reported,4 which suggests a genetic predisposition of platelets in the development of arterial vascular disease. Further studies under conditions that
resemble those found in arterial circulation and diseased arteries,
such as the in vitro shear-induced platelet activation, could be
helpful to appropriately explore GPIb function and the role of VNTR
and HPA-2 polymorphisms.
The proposed involvement of a structural change that exposes the
GPIb to greater shear forces opens up the possibility of identifying
individuals who would most benefit from drug therapy with agents that
interfere with shear-stress-induced platelet responses that have been
shown to beneficially affect arterial thrombosis51-55 and,
thus, to improve clinical outcome.
| |
FOOTNOTES |
Submitted December 22, 1997;
accepted June 12, 1998.
Supported by FIS 97/1150. J.C. is Contratado de Reincorporación
en la Universidad de Murcia. R.G.-C. is a FIS Fellow (95/1401).
Address reprint requests to Vicente Vicente, MD, Centro Regional de
Hemodonación. C/. Ronda de Garay s/n, 30003 Murcia, Spain; e-mail: vvg{at}fcu.um.es.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract