(Circulation. 2000;102:1645.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Homozygosity for 807 T Polymorphism in 
2 Subunit of Platelet 2ß1 Is Associated With Increased Risk of Cardiovascular Mortality in High-Risk Women
From the Julius Center for Patient Oriented Research (M.R., D.E.G., Y.T.v.d.S.), the Department of Hematology (M.R., P.G.d.G., J.J.S., M.J.T.), Graduate School of Biomembranes, and the Department of Internal Medicine (M.R., J.D.B.), Utrecht University Medical School, Utrecht, the Netherlands.
Correspondence to Mark Roest, MSc, Julius Center for Patient Oriented Research, Utrecht University Medical School, Heidelberglaan 100, 3584 CX Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Platelet adhesion to collagen is the initial step in both hemostasis and thrombosis; this adhesion is mediated by
2ß1 on the surface
of platelet membranes. An 807 C to T single nucleotide
exchange polymorphism close to the gene coding for the
2 subunit of 2ß1 is
associated with the density of 2ß1 on the
platelet membrane.
Methods and Results—We studied the relation of the
2ß1 807 C/T genotype to
cardiovascular mortality in a prospective cohort study
of 12 239 women who were invited for the breast cancer screening
program of Utrecht, the Netherlands. The initial age was
between 52 and 67 years. Women were followed on vital status between
1976 and 1995 (168 513 women-years). Data were analyzed by
using a nested case-control design. The
2ß1 807 C/T genotype was not
associated with cardiovascular mortality in the total
population: the rate ratio for cardiovascular mortality
in 807 TT homozygotes compared with 807 CC wild types was 1.2 (95% CI
0.8 to 1.7). However, the 2ß1 807 T
polymorphism was associated with an increased risk of
cardiovascular mortality in women who smoked or in
women who had indications of compromised endothelium,
such as diabetes and microalbuminuria. In those who were
exposed to 
2 of these factors, the risk ratio (95% CI) between
2ß1 807 TT homozygotes and 807 CC wild
types was 14.1 (5.0 to 39.9).
Conclusions—2ß1 807 TT homozygosity,
coding for increased 2ß1 density on the
platelet membrane, is associated with an increased risk of
cardiovascular mortality in those women with
indications of compromised endothelium.
Key Words: platelets • genes • cardiovascular diseases • women
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemostasis and thrombosis are initiated by the adhesion of platelets to collagen.1 Platelet adhesion to collagen is a multistep process depending on the availability and function of von Willebrand factor (vWF), collagen, and the platelet integrins glycoprotein Ib and
2ß1. Briefly, vWF
binds to collagen in the subendothelium.
Glycoprotein Ib on the platelet surface can interact
with vWF, which is attached to collagen.2 3 This reduces
the velocity of circulating platelets and allows the binding of
2ß1, an integrin also
present on the platelet surface, to collagen, which is
necessary for firm attachment.4 5 The availability of
integrin 2ß1 on the
platelet surface may play an essential role in platelet
adhesion to collagen in the vessel wall (types I, III, IV, V, and
VI).6
Patients deficient of the 2 subunit of
2ß1 suffer from
prolonged bleeding times and chronic mucocutaneous bleeding and have
increased platelet adhesion to collagen types I, III, IV, and VI in
vitro, under flow conditions.7 8 Moreover, individuals
with autoimmune platelet dysfunction have been found to express
serum antibodies against the 2 subunit of
2ß1 that block in
vitro platelet adhesion to collagens and collagen-induced
aggregation.9 10 11
Large studies on the relation of platelet reactivity and
cardiovascular disease are scarce because they are
laborious and expensive. With molecular genetic techniques, candidate
genes for platelet activity were identified. The role of
variability of specific platelet integrins in
cardiovascular disease can now be studied in large
populations. Most studies on genetic variability of platelet
function and cardiovascular disease have been performed
on the PlA1/A2 polymorphism in
IIbß3. Some studies
showed an increased risk for arterial thrombosis for the
PlA2 allele,12 13 whereas
another study did not indicate any association.14 The
interpretation of a relationship between the
PlA1/A2 polymorphism and arterial
thrombosis is difficult because there is no difference in platelet
function between the genotypes. Recently, an 807 C to T single
nucleotide exchange polymorphism has been identified in
the gene encoding the 2 subunit of
2ß1, which is
associated with increased
2ß1 density on the
platelet membrane and with increased platelet adhesion to
collagen types I and IV.15 16 17 This has led to the
hypothesis that subjects with the 807 T genotype of
2ß1 express more
2ß1 on the
platelet surface, leading to an increased potential of platelet
adhesion and a tendency to arterial thrombosis and, hence,
an increased risk of cardiovascular disease. This
hypothesis is supported by findings of 2 independent case-control
studies, which reported an increased risk of nonfatal myocardial
infarction in men with the
2ß1 807 T allele
compared with men with the 807 C allele.18 19 The
strongest relationship was found in smokers.19 The latter
finding suggests that the effect of the 807 T polymorphism may be
particularly pronounced in subjects with arterial damage
due to other risk factors.
We studied the relationship between genetic variability in
2ß1 and
cardiovascular mortality in a cohort study of 12 239
women, initially aged 50 to 67 years, who were followed up for a
maximum of 18 years.20
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Methods |
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Population
Between December 1974 and October 1980, 20 555 women who were born between 1911 and 1925 and lived in the city of Utrecht, the Netherlands, were invited for an experimental program for breast cancer screening.20 The women were invited for repeat examination at 1- to 6-year intervals. We chose as a baseline population the 12 239 (60%) women who attended the second examination (1976 to 1978) because this examination included a questionnaire on smoking. All women gave oral consent for the use of their data and urine samples for future scientific research. The study was approved by the Institutional Review Board of the University Medical Center Utrecht, the Netherlands.
Risk Factors
Baseline examination included a questionnaire involving
medication, prescribed diets, presence of
cardiovascular disease, and smoking. In addition, blood
pressure, height (m), and body weight (kg) were measured. Women were
classified as having diabetes mellitus if they reported the use of
insulin or oral blood glucose–lowering drugs or were on a diabetes
diet. Women were classified as smokers if they reported themselves to
be current smokers. Body mass index (kg/m2) was
calculated as weight (kg) divided by height squared
(m2). Obesity was defined as body mass index >30
kg/m2. Microalbuminuria was defined
as the highest quintile of albumin excretion. The presence of
cardiovascular disease, smoking, diabetes,
hypertension, and excessive urinary albumin excretion was
considered by markers of vascular dysfunction.
End Points
Municipal registries informed the Department of
Epidemiology (presently the Julius Center
for Patient Oriented Research) about migration and mortality of the
cohort members. Causes of death were obtained from the general
practitioners. Subjects who were lost to follow-up were
censored at the time point that they were lost. The 9062 surviving
women had a median follow-up time of 17 years, with a maximum of 18
years. One thousand four hundred forty-seven women (12.3%) had moved
outside the recruitment area and had a median follow-up of 10 years,
with a maximum of 18 years. During follow-up (182 976 women-years),
1714 women died: 608 from cardiovascular diseases
(codes 390 to 459 of the International Classification of Diseases,
Ninth Revision [ICD-9]), 601 from neoplasms (ICD-9 140 to 239), 299
from other causes, and 206 from unknown causes. Mortality from
myocardial infarction was defined as ICD-9 codes 410 to 414,
cerebrovascular mortality as ICD-9 codes 430 to 439, and other
cardiovascular mortality as all remaining ICD-9 codes
between 390 and 460.
Design
A nested case-control approach was used.21
This allowed the use of all information from the entire cohort while
keeping the laboratory work within manageable bounds. The cases were
all 608 women who died of cardiovascular disease during
the follow-up period; the controls constituted a random sample of 618
of the cohort of 11 631 women who did not die of
cardiovascular disease (sampling fraction 1:18.8).
Urine samples of 59 cardiovascular cases and 49
controls were not collected at baseline or were lost during follow-up.
DNA samples of 69 cardiovascular cases and 73 controls
were not suitable for analysis. Consequently, the final study
group constituted 480 cardiovascular mortality cases
and 496 women in the reference group.
Genotyping
DNA was isolated from 50-mL urine samples.22 A
fragment containing nucleotide 807, located close to the
gene coding for the 2 subunit of
2ß1, was amplified in
20 mmol/L Tris-HCl, pH 8.0, 2.5 mmol/L
MgCl2, 50 mmol/L KCl, 0.1 mg/mL BSA, 0.4
pmol of 3' primer (5'-TGTTTAACTTGAACACATATAAAACC-3'), 0.4 pmol of 5'
primer (5'-GATTTAACTTTCCCAGCTGCCTTC-3'), 0.42 mmol/L of each
nucleotide (Pharmacia, Biotech), 0.075 U superTAQ
polymerase (HT Biotechnology LTD), and 5 µL DNA with the use of a
PTC200 multicycler (MJ Research). Temperature cycles were as follows: 4
minutes at 94°C and 33 cycles of 40 seconds at 94°C, 40 seconds at
55°C, and 2 minutes at 72°C. The reaction was terminated with a
10-minute incubation at 72°C. Genotype was determined from
each DNA fraction by dot blotting and hybridization with
antigen-specific oligonucleotides.22 The
antigen-specific oligonucleotide was
5'-
32P-AATTGCTCCGAA-TGTGTT-3' for the 807 C
allele and
5'-32P-AATTGCTC-CAAATGTGTT-3' for 807 T
allele. Dots were visualized on x-ray films (DuPont) after
overnight radiation. Mutation analysis was performed by 2
independent readers blinded for case or control status of the
samples.
Data Analysis
Means and proportions of baseline
cardiovascular risk factors were computed for women
with the 2 subunit genotypes of 807
CC, 807 CT, and 807 TT. The significance of mean difference was tested
by ANOVA, and significance in proportions was tested by
2 statistics. The 2
goodness of fit test was used to determine whether the observed
genotype distribution was in Hardy-Weinberg
equilibrium.23 24
A nested case-control approach was used to estimate incidence rates and
rate ratios.22 Because controls were selected at random at
a known sampling fraction, all data from this group provide unbiased
estimates of the entire cohort of women without
cardiovascular mortality. We first determined the
genotype of the 2 subunit of
2ß1. Subsequently, we
estimated the follow-up years for each genotype in the entire
cohort by weighting the follow-up years of the reference group with a
factor of 18.8 (the inverse of the sampling fraction) and applying the
follow-up years from the cardiovascular mortality
cases. Incidence rates were calculated as the number of incidents per
genotype divided by the estimated follow-up years for that
genotype.22 The incidence rate ratio was
calculated as the incidence rate for cardiovascular
disease in heterozygotes divided by the incidence rate in wild types.
Poisson regression was used to estimate incidence rates and risk
ratios; 95% CIs were calculated by the method of
Hubers.25
Similarly, crude relative risks, incidence rates, and rate ratios were estimated separately for women who died of myocardial infarction (ICD-9 410 to 414), cerebrovascular disease (ICD-9 430 to 438), and other cardiovascular disease (all remaining ICD-9 codes between 390 to 459). Potential confounding by age at entry in the cohort, hypertension, body mass index, and smoking was investigated by adding these variables individually and once simultaneously to the Poisson containing the 807 T genotype to see whether the crude rate ratio of the 807 T genotype changed. The presence of effect modification was investigated by subgroup analysis on age (above or below the median), current smoking at baseline, diabetes, history of cardiovascular disease, and microalbuminuria.
Further subgroup analysis was performed on the numbers of indicators of endothelial perturbation, which were defined as 0 if subjects were nonsmokers and nondiabetic and had no microalbuminuria, as 1 if they had 1 of these indicators, and as 2 if they had 2 or 3 of these indicators. The significance of modifying effects was tested in a multivariate model, which includes interaction terms.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The genotype distribution of the control group was in Hardy-Weinberg equilibrium (
2=0.30; 1
df, P=0.58). The
2ß1 807 C/T
genotype was not associated with age, diabetes mellitus,
smoking, body mass index, or systolic and diastolic
blood pressure or with a history of cardiovascular
disease either in cardiovascular cases or in the
control group (Table 1
).
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The follow-up time of our cohort was 148 209 women- years: 58 443
years for women with the 807 CC genotype, 67 532 for women
with the 807 CT genotype, and 22 234 for women with the 807 TT
genotype. The estimated incidence rates for overall
cardiovascular mortality and for fatal myocardial
infarction, cerebrovascular mortality, and other
cardiovascular mortality were similar among the
2 807 C/T genotypes (Table 2).
|
The possibility that the relationship between the 807 C/T polymorphism and cardiovascular mortality was a consequence of confounding by age, blood pressure, body mass index, and smoking was excluded because adjustment for these variables individually or simultaneously did not change the crude mortality rate ratio of the 807 T genotype.
Subgroup analysis according to history of
cardiovascular disease showed no modifying effect on
the relationship between the 2
genotype and cardiovascular mortality. However,
in those women who reported themselves to be current smokers at
baseline, an increased risk of cardiovascular mortality
was found for 2 807 TT homozygotes compared
with 807 CC wild types (Table 3); the
mortality rate for women who were both smokers and
2 807 TT homozygotes was 7.1 (95% CI 3.8 to
12.9) per 1000 years compared with 3.5 (95% CI 2.8 to 4.4) per 1000
years for women who were 807 wild types and nonsmokers, 3.2 (95% CI
2.3 to 4.6) per 1000 years for women who were 807 wild types and
smokers, and 3.2 (95% CI 2.3 to 4.6) per 1000 years for women who were
807 TT homozygotes but nonsmokers. In smokers, the risk ratio for
cardiovascular mortality between 807 TT homozygotes and
807 CC wild types was 2.2 (95% CI 1.1 to 4.4). This risk tended to be
increased for fatal myocardial infarction as well as cerebrovascular
mortality and all other causes of cardiovascular
mortality. Similarly, in those subjects who had diabetes or
microalbuminuria, the mortality rate appeared to be
increased in 2 807 TT homozygotes compared
with 807 CC wild types, but these risk ratios did not reach statistical
significance.
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Further subgroup analysis on the number of risk
indicators of endothelial perturbation is
presented in Table 4. If
anything, in subjects who were nonsmokers and had no diabetes and
microalbuminuria, the mortality rate appeared to be lower
for 2ß1 807 CT
heterozygotes and 807 TT homozygotes than for 807 CC wild types.
However, in subjects with one of those indicators, a significantly
increased risk was found for cardiovascular mortality
between 807 TT homozygotes and 807 CC wild types, whereas in subjects
with 2 or 3 of these indicators, a markedly increased risk for
cardiovascular mortality was found in 807 TT
homozygotes compared with 807 CC wild types. The total follow-up time
in the subgroup of subjects with 2 or 3 factors of compromised
endothelia was 2493 years (1673 years in 807 C wild types, 792 years in
807 CT heterozygotes, and 28 years in 807 T homozygotes). In the 807 CC
homozygotes, 17 women died during the 1673 follow-up years (mortality
rate 10.4 per 1000 years), 20 women died during the 792 follow-up years
in the 2ß1 807 CT
heterozygotes (mortality rate 25.3 per 1000 years), and 4 women died
during the 28 follow-up years in the
2ß1 807 TT homozygotes
(mortality rate 143 per 1000 years). The incidence rates for the
different subgroups are presented in the
Figure.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our findings in a large population-based study on platelet collagen receptor
2ß1
genotype and cardiovascular mortality show that
the 2ß1 807 C/T
genotype has no overall association with
cardiovascular mortality in women. However, in women
who were current smokers at baseline, a significantly increased risk of
cardiovascular mortality was found compared with 807 C
wild types (relative risk 2.2, 95% CI 1.1 to 4.4). The relationship
between 807 TT homozygotes and cardiovascular mortality
was most pronounced in women who had 2 indicators of compromised
endothelium: the risk ratio between 807 TT homozygotes
and 807 CC wild types was 14.1 (95% CI 5.0 to 39.9). To appreciate our findings, some characteristics of the study need to be addressed. Our data are obtained from a large prospective cohort study and are therefore not subject to selection bias because cases and controls were members of the same cohort. In addition, we do not expect information bias because questionnaire data, anthropometric data, and urine samples were collected at baseline before the cardiovascular events occurred. The prospective nature of the present study enabled us to investigate cardiovascular mortality, whereas conventional case-control studies rely on retrospectively collected data and are therefore limited to morbidity of cardiovascular disease or to intermediate markers of disease.
The probability of measurement error or misclassification on
genotype is negligible because the 2 independent investigators
who performed DNA diagnostics were blinded for case or
control status of the DNA sample, and all measurements were performed
in duplicate. The genotype distribution of
2ß1 in our reference
population was in Hardy-Weinberg equilibrium.
A disadvantage of full cohort study analyses is the large
number of DNA samples to be screened on the 2
807 C/T genotype. This problem was solved by adopting a nested
case-control approach: DNA samples of 480 women who died of
cardiovascular disease were analyzed together
with DNA samples of a random cohort sample of 496 women who did not die
of cardiovascular disease. Because of random sampling,
our control group constituted an unbiased estimate of the population
time experience in the entire cohort. Nested case-control
analysis takes full advantage of a cohort study, but it has the
cost and labor effectiveness of a case-control
study.21
Our findings of an increased risk of cardiovascular
disease for 2 807 T homozygotes in women with
compromised endothelium due to smoking, diabetes, and
microalbuminuria are in agreement with the a priori
hypothesis that women with the 807 T genotype of
2ß1 express more
2ß1 on the
platelet surface, leading to an increased potential of platelet
adhesion and, hence, an increased risk of
cardiovascular disease. Normally, the vessel wall is
protected against platelet-collagen interaction by the intact
endothelium. This may explain the lack of association
between the 807 T allele of the 2 subunit
of 2ß1 in the
population at large. In smokers and in subjects with diabetes or with
microalbuminuria, the compromised
endothelium may allow platelet-collagen interaction
and subsequent platelet activation.
Our findings build on 2 studies that have reported that the 807 T allele is associated with nonfatal myocardial infarction in men.18 19 Similar to our findings, smoking appeared to be a risk-modifying factor in the relationship between the 807 C/T polymorphism and cardiovascular mortality.19 Our findings are further supported by studies on indirect platelet adhesion to collagen via vWF.26 27 These studies suggested an association between plasma levels of vWF and increased risk of myocardial infarction in patients with angina pectoris or with reinfarction in a population of survivors of myocardial infarction.
We found evidence that genetically determined expression of excess
2ß1 on the
platelet surface may be associated with increased risk of
cardiovascular mortality in subjects with perturbed
endothelia, which is associated with diabetes,
microalbuminuria, and smoking. Further research on the
relationship between
2ß1 and
cardiovascular disease in high-risk populations, such
as patients with angina pectoris, coronary stenosis,
diabetes, microalbuminuria, and smokers, is indicated.
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Acknowledgments |
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The study was supported by the Netherlands Heart Foundation (grant NHS 95-165). We thank Thomas Kunicki, MD, PhD, Paul de Jong, MD, PhD, and Dick de Zeeuw, MD, PhD, for reviewing the manuscript and their critical comments.
Received February 16, 2000; revision received April 28, 2000; accepted May 8, 2000.
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T. J. Kunicki, A. B. Federici, D. R. Salomon, J. A. Koziol, S. R. Head, T. S. Mondala, J. D. Chismar, L. Baronciani, M. T. Canciani, and I. R. Peake An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees Blood, October 15, 2004; 104(8): 2359 - 2367. [Abstract] [Full Text] [PDF]
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J. Lahav, E. M. Wijnen, O. Hess, S. W. Hamaia, D. Griffiths, M. Makris, C. G. Knight, D. W. Essex, and R. W. Farndale Enzymatically catalyzed disulfide exchange is required for platelet adhesion to collagen via integrin {alpha}2{beta}1 Blood, September 15, 2003; 102(6): 2085 - 2092. [Abstract] [Full Text] [PDF]
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Z. Wang, T. M. Leisner, and L. V. Parise Platelet {alpha}2{beta}1 integrin activation: contribution of ligand internalization and the {alpha}2-cytoplasmic domain Blood, August 15, 2003; 102(4): 1307 - 1315. [Abstract] [Full Text] [PDF]
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B. Nieswandt and S. P. Watson Platelet-collagen interaction: is GPVI the central receptor? Blood, July 15, 2003; 102(2): 449 - 461. [Abstract] [Full Text] [PDF]
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L. Pontiggia, R. Lassila, S. Pederiva, H.-R. Schmid, M. Burger, and J. H. Beer Increased Platelet-Collagen Interaction Associated With Double Homozygosity for Receptor Polymorphisms of Platelet GPIa and GPIIIa Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2093 - 2098. [Abstract] [Full Text] [PDF]
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 T. Maeno, H. Koyama, H. Tahara, M. Komatsu, M. Emoto, T. Shoji, M. Inaba, T. Miki, Y. Okuno, and Y. Nishizawa The 807T Allele in {alpha}2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes Diabetes, May 1, 2002; 51(5): 1523 - 1528. [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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 T. J. Kunicki and Z. M. Ruggeri Platelet Collagen Receptors and Risk Prediction in Stroke and Coronary Artery Disease Circulation, September 25, 2001; 104(13): 1451 - 1453. [Full Text] [PDF]
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