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Keywords:

  • myocardial infarction;
  • platelet aggregation;
  • platelet glycoprotein GP IIb/IIIa complex;
  • polymorphism;
  • platelets;
  • risk factors

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Objectives.  Platelet glycoprotein (GP) receptor IIb/IIIa plays a key role in the development of myocardial infarction (MI), and PlA2 is a polymorphism in the gene encoding this receptor. The prevalence of PlA2 shows pronounced geographical variation and has to our knowledge not been presented for a Scandinavian population before. Platelets from PlA2-positive individuals show increased aggregability compared with platelets from PlA2-negative individuals, and PlA2 genotypes might be associated with MI. The purpose of this study was to investigate the relation between the PlA2 polymorphism and MI in a large Scandinavian population.

Design.  Case–control study. We included patients with angiographically verified CAD with and without previous MI and a group of healthy individuals matched for age, race, and sex.

Results.  We studied the frequency of PlA2 in 1191 healthy individuals and 1019 patients with coronary artery disease (CAD). Amongst these patients, 529 subjects had suffered an MI previously. PlA2 was present in 28% of healthy individuals, 28% of patients with CAD but no MI, and in 35% of patients with CAD and MI. The difference between healthy individuals and MI patients was significant (P = 0.002). Furthermore, a graded relationship between the number of PlA2 alleles and the risk of MI was seen (P = 0.011). Associations between PlA2 and traditional cardiovascular risk factors as well as mean platelet volume were investigated. We found a significant interaction between PlA2 and serum cholesterol.

Conclusion.  In our Scandinavian study population the common platelet polymorphism PlA2 is significantly associated with an increased risk of MI, but not of CAD. Clinically, typing for PlA2 might have implications for antiplatelet therapy of patients with MI.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Myocardial infarction (MI) most often results from the development of an acute occlusive thrombus in an atherosclerotic coronary artery. Platelets have a key role in this process, and particularly membrane platelet glycoprotein (GP) receptor IIb/IIIa is important. This receptor mediates platelet aggregation, binding primarily fibrinogen, in a final common platelet response to stimulation by all agonists [1, 2]. Mean platelet volume (MPV) is increased in patients with acute MI, and as large platelets are more hemostatically active than small ones, the increased platelet volume may reflect a prothrombotic state in patients with MI [3]. Antiplatelet therapy reduces the morbidity and mortality associated with MI, and intravenous inhibitors of GP IIb/IIIa have been shown to be beneficial in the treatment of acute coronary syndromes, especially in high-risk patients undergoing percutaneous coronary intervention (PCI) [4, 5].

Genetic factors play an important role in the development of coronary atherosclerosis and MI [6] and may modify the effect of environmental risk factors. GP IIb/IIIa is highly polymorphic and carries the PlA and other diallelic antigen systems [7]. The PlA2 allele might represent an inheritable, independent risk factor for MI [8–14], although some investigators have found no association between PlA2 genotypes and MI [15–20]. Differences in demographics, smoking habits, and case definitions may explain some of these conflicting results. Geographical variations in PlA2 prevalence are substantial [21–24], and the prevalence of PlA2 has to our knowledge not been presented for a Scandinavian population before.

Platelets from PlA2-positive individuals show increased aggregability compared with platelets from PlA2-negative individuals [25, 26]. Thus, PlA2 genotypes might be associated with MI, but not coronary artery disease (CAD). This hypothesis was tested in a large case–control study on patients with angiographically verified CAD with and without previous MI and a group of apparently healthy individuals matched for age, race and sex. Possible interactions between the PlA2 polymorphism, MPV, and other cardiovascular risk factors were also evaluated.

Selection of patients and healthy control subjects

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

The PlA2 polymorphism was analysed in 1019 patients with CAD and 1191 healthy individuals matched for age, race and sex. Because ethnic differences have been reported for PlA2 [21–24], we only included Whites. Patients were referred to elective or subacute PCI at Skejby Sygehus, Aarhus University Hospital. CAD was diagnosed visually during angiography, and a luminal narrowing of >50% in one of the three major coronary arteries or major branches was considered to be significant. The extent of CAD was classified as one-, two-, or three-vessel disease. Unfortunately, this parameter was only available for 754 patients in our database. MI was diagnosed according to WHO criteria [27]. Data concerning smoking habits and family history of coronary heart disease (CHD) were obtained from questionnaires. A family history of CHD was defined as classical angina pectoris or MI in first-degree relatives with debut of symptoms before the age of 60. Subjects were classified as active, former, or never-smokers. Blood samples for analyses of DNA, lipid profile, and platelet parameters were collected in ethylenediaminetetraacetic acid the day after PCI. MPV and platelet count were measured on an AdviaTM 120 apparatus (Bayer Corporation, Copenhagen, Denmark). Cardiovascular risk factors were assessed from data obtained during the actual hospitalization or from the patient's chart.

Control subjects were selected from a population that was identified and examined as a part of an international WHO study, MONItoring of trends and determinants in CArdiovascular diseases (MONICA 10). Details regarding the selection and examination of this population have previously been published [28, 29]. A total of 1191 individuals were matched for race, sex and age with the case subjects and had their PlA genotype analysed.

The study was approved by the Scientific Ethical Committee, and informed consent was obtained from all participants.

Genotyping

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

The PlA1/A2 polymorphism is a T to C substitution at position 1565 in exon 2 of the glycoprotein IIIa gene. Genomic DNA was extracted from whole blood, and a 266-bp fragment encoding exon 2 was amplified with the polymerase chain reaction as described previously by Weiss et al. [8]. Briefly, we used allele-specific restriction digestion to detect the polymorphism. Amplified DNA was digested with MspI, electrophoresed in 3% NuSieve agarose gels (FMC Bio Products, Rockland, ME, USA) and visualized in UV light by ethidium bromide staining. Determination of genotypes was performed in a blinded fashion with regard to DNA analyses and clinical data.

Statistical analysis

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Subjects with the PlA1/A2 or PlA2/A2 genotypes were classified as PlA2 positive, those with PlA1/A1 as PlA2 negative. Hardy-Weinberg equilibrium was tested with the chi-square test, as were the difference between categorical variables. For normally distributed variables, the between-group differences were compared with a two-sample t-test or by one-way analysis of variance (anova), when more than two mean values were compared. A possible graded relationship between the number of PlA2 alleles and the risk of MI was investigated with a test for trend in proportions using Spearman's correlation coefficient. A test for trend in strata for the relative risk was performed according to Breslow and Day [30] on cholesterol data. Platelet count values were log-transformed to allow analysis by parametric tests. Normally distributed variables are expressed as mean ± SD, and platelet count is expressed as geometric median (coefficient of variation). Logistic regression analysis was used to analyse traditional risk factors together with the PlA1/A2 genotype on MI. The relative risk of MI was estimated by odds ratio (OR) and 95% confidence interval.

PlA genotypes in relation to MI

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Patients (60.2 ± 10.1 years, 74.4% males) and control subjects (59.6 ± 9.6 years, 73.3% males) were matched for age, race and sex. Distributions of PlA genotypes are shown in Table 1. Allele frequencies in both groups are in accordance with those predicted by the Hardy-Weinberg equilibrium.

Table 1.  Genotype distributions in patients and healthy individuals
  Controls (n = 1191) Patients (n = 1019)Patients without MI (n = 490)Patients with MI (n = 529)
Genotype [% (n)]
PlA1/A172.0 (857)68.1 (694)71.8 (352)64.7 (342)
PlA1/A225.0 (299)29.0 (296)26.1 (128)31.8 (168)
PlA2/A22.9 (35)2.8 (29)2.0 (10)3.6 (19)
Allele frequency (%)
PlA184.582.684.980.5
PlA215.517.415.119.5

The prevalence of PlA2 amongst patients with CAD and MI, those with CAD but no MI, and healthy individuals was significantly different (Fig. 1). Thus, 28% of control subjects were either hetero- or homozygous for the PlA2 allele, whereas 31.9% of patients were PlA2 positive (P = 0.049). However, carriage of the PlA2 allele was more frequent in patients with MI (187/529), than in patients without MI (138/490) (P = 0.014, OR = 1.4 [1.1–1.8]). The difference between healthy individuals and CAD patients with MI was significant (P = 0.002, OR = 1.40 [1.13–1.75]). Amongst patients with MI, a graded relationship between the number of PlA2 alleles and the risk of MI was seen (see Table 1: PlA1/A1 patients; 49.3% with MI, PlA1/A2 patients; 56.8%, PlA2/A2 patients; 65.5%, P = 0.011). Men were younger than women at the time of first MI (55 years vs. 59.6 years, P < 0.00001). If PlA2 is a genetic risk factor for MI, then one would expect an even higher prevalence of this polymorphism amongst individuals in whom MI occur at an early age. However, the average age at the time of first MI did not differ significantly between PlA2-positive and -negative MI patients, although a trend was seen (55.2 years vs. 56.7 years, P = 0.098).

image

Figure 1. Relative frequency (in%) of PlA2-positive individuals. Group 1: apparently healthy individuals (n = 1191). Group 2: patients with CAD but no previous MI (n = 490). Group 3: patients with CAD and previous MI (n = 529).

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Patients with MI

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Baseline characteristics are dichotomized for patients with and without MI in Table 2. Sex distributions, prevalence of diabetes, and the average age did not differ. A family history of CHD was more prevalent in patients with MI (34% vs. 27%, P = 0.018). As described above, at least one inheritable risk factor for MI amongst these patients is the PlA2 allele. PlA2 was present in 28.2% of patients without MI and in 35.3% of patients with MI (P = 0.014, OR = 1.4 [1.1–1.8]). Patients with MI had more coronary artery stenoses than other patients (55% vs. 38% with more than one stenosis, P < 0.00001).

Table 2.  Characteristics of patients with (n = 529) and without (n = 490) myocardial infarction
 Without MI (%)With MI (%)P values
  1. aMean platelet volume data are available for 91% (480) of patients with MI and 91% (448) of patients without MI.

Age (years)60.6 ± 9.959.8 ± 10.20.204
% Males74.374.70.888
Family history of CHD134 (27)181 (34)0.018
PlA2 positive138 (28.2)187 (35.3)0.014
Diabetes58 (11.8)52 (9.8)0.302
BMI (kg m−2)26.9 ± 4.027.1 ± 4.30.407
Smokers (ever)373 (76)424 (80)0.119
Smokers (current)165 (34)171(32)0.643
Platelet count249 (0.28)239 (0.27)0.016
Mean platelet volumea8.35 ± 1.098.44 ± 1.170.263
Multiple-vessel stenosis139/363 (38)214/388 (55)<0.00001

PlA genotypes in relation to stenosis

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Characteristics of patients by extent of coronary artery stenosis are presented in Table 3. Patients with stenosis of more than one vessel were older than other patients (P < 0.0001). Sex distributions were similar in the three groups, as were the prevalence of PlA2. There was a significantly higher prevalence of MI amongst patients with two- or three-vessel disease compared with patients with one-vessel disease (P < 0.0001). Diabetes was more prevalent amongst patients with three-vessel disease than amongst patients with one- or two-vessel disease (16.7% vs. 10.2%, P = 0.032). Lipid levels and prevalence of hypertension did not differ between groups (data not shown).

Table 3.  Characteristics of patients by extent of stenosis
No. of vessels stenosedOne vessel (n = 401)Two vessels (n = 215)Three vessels (n = 138)P values
Age (years)58.7 ± 9.860.9 ± 9.762.9 ± 10.6<0.0001
% Males75.375.876.80.939
Diabetes (%)40 (10.0)23 (10.7)23 (16.7)0.095
Eversmokers (%)302 (75.3)166 (77.2)112 (81.1)0.444
Active smokers (%)141 (35.2)68 (31.6)44 (31.9)0.563
PlA2 positive (%)134 (33.4)72 (33.5)36 (26.1)0.247
MI prevalence (%)175 (43.6)125 (58.1)89 (64.5)<0.0001

PlA genotypes in relation to other cardiovascular risk factors

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Genetic and environmental factors are involved in the pathogenesis of atherosclerosis and MI and are likely to act in concert. The PlA2 polymorphism might primarily affect the risk of MI in particular subgroups of patients such as males [11, 31], young patients [8], or smokers [13]. Accordingly, we performed stratified analyses in subgroups characterized by different levels of established and putative risk factors. We tested for interactions between PlA2 and age, sex, smoking, total cholesterol, HDL cholesterol, triglycerides, hypertension, diabetes, body mass index, number of stenosed coronary arteries, MPV and platelet count. An interaction between serum total cholesterol and PlA2 was observed (Table 4). The association between PlA2 and MI was stronger in patients with low levels of serum total cholesterol, and a significant trend in strata was seen (P = 0.016). After adjusting for the use of cholesterol-lowering drugs (statins) in a logistic regression model this interaction remained significant (P = 0.038).

Table 4.  Interaction between cholesterol level and the PlA2 polymorphism
Cholesterol quartiles (n)Odds ratios [95% CI]P values for association between PlA2 and MI
  1. Cholesterol levels were available for 1011 of 1019 patients. The average cholesterol level was 5.37 ± 1.06 mmol L−1.

6.0+ (270)1.08 [0.66–1.77]0.76
5.3–5.9 (241)1.18 [0.68–2.05]0.55
4.6–5.2 (274)1.25 [0.74–2.10]0.41
[RIGHTWARDS ARROW]4.5 (226)3.67 [1.91–7.05]0.00006

Moreover, a slightly increased risk of MI was seen in smokers with the PlA2 allele (OR for MI = 1.93 [1.16–3.23]). Apart from traditional risk factors, we tested for interactions between PlA2 and platelet parameters. Neither MPV nor platelet count were associated with PlA2, when tested with one-way anova (P = 0.78 and 0.41).

Furthermore, logistic regression was used to adjust for confounding in order to investigate the independence of PlA2 as a risk factor for MI. After controlling for the above-mentioned risk factors (except from total cholesterol), the OR for the relationship between PlA2 and MI was 1.49 [1.02–2.19].

Patients with a family history of CHD

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

A family history of CHD was more prevalent amongst females than males (41% vs. 28%, P < 0.0001). Patients with a family history of CHD were younger than other patients (57 years vs. 61.7 years, P < 0.0001) (Table 5). We investigated whether any difference was seen between the two groups with regard to PlA2 prevalence and traditional cardiovascular risk factors. The prevalence of PlA2 did not significantly differ (P = 0.33). Patients with a family history of CHD had lower levels of serum total cholesterol (P = 0.011), whereas blood pressure, triglycerides, prevalence of diabetes, and smoking did not differ (data not shown). The difference in cholesterol levels was partly explained by the fact that more patients with a family history of CHD received cholesterol-lowering drugs (P = 0.002) (data not shown). However, despite no explanatory difference in risk profiles, patients with a family history of CHD had a significantly higher prevalence of MI than patients without a family history of CHD (57% vs. 49%, P = 0.018). Furthermore, they were younger at the time of their first MI (52.7 years vs. 58 years, P < 0.0001).

Table 5.  Characteristics for patients with and without a family history of CHD
 + Family history of CHD (n = 315)÷ Family history of CHD (n = 702)P values
Age (years)57.0 ± 9.961.7 ± 9.9<0.0001
% Males66.378.1<0.0001
Cholesterol (mmol L−1)5.2 ± 1.065.4 ± 1.060.011
MI prevalence (%)181 (57.5)347 (49.4)0.018
Age at first MI52.7 ± 9.558.0 ± 10.2<0.0001
PlA2 positive (%)94 (29.8)231 (32.9)0.332

Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

This study demonstrates a significantly higher prevalence of PlA2 in patients with ischaemic heart disease than in healthy individuals matched for race, sex and age. Moreover, our data confirm an association between this polymorphism and MI in patients with CAD. Amongst these patients 31.9% were PlA2 positive compared with only 28% of healthy individuals. Subgroup analyses revealed that CAD patients without MI did not have an increased prevalence of PlA2 (28.2%), whereas 35.4% of MI patients were PlA2 positive. This finding is in accordance with previous reports and supports the hypothesis that PlA2 is a risk factor for MI, but not for CAD [12, 13]. A graded relationship that adds to the biological plausibility was seen between the number of alleles and the risk of MI.

The frequency of the PlA2 polymorphism has been shown to vary considerably between different geographical areas [21–24] and, to our knowledge, has not been determined in a Scandinavian population before. The overall allele frequency was 17.4% amongst patients and 15.5% amongst healthy individuals. In a study on Anglo-Scandinavian descendants by Anderson et al. [12] a carriage rate of 33.8% for PlA2 was associated with an OR for MI of 1.4 [0.95–2.04], i.e. the same OR, which is seen in our larger population. Thus, our findings are consistent with those previously published by Anderson et al.

Patients with a family history of CHD were younger than other patients. Obviously, this difference in age is partly due to the definition of a family history of CHD in this study. However, despite a lower or similar prevalence of traditional risk factors for CHD, patients with a family history of CHD had a significantly higher prevalence of MI and were significantly younger at the time of first MI. These findings corroborate the importance of genetics in the pathophysiology of CHD. Interestingly, the presence of a family history of CHD was significantly higher amongst female patients confirming the findings in a Danish twin study [32]. PlA2 prevalence did not significantly differ between patients with and without a family history of CHD. This is surprising, but might reflect the fact that CHD is a multifactorial trait, the phenotype of which results from the interaction between environmental and several inherited risk factors.

The size of our study group allowed us to perform subgroup analyses in order to investigate the relation between PlA2 and other cardiovascular risk factors. In accordance with the study by Ardissino et al. [13], our data indicate an interaction between smoking and the PlA2 polymorphism. However, unlike Ardissino et al. [13] who found an OR for MI of 13.7, when PlA2-positive smokers were compared with PlA2-negative nonsmokers, only a minor elevation in OR was seen in our data (OR = 1.93 [1.16–3.23]). Ardissino et al. included young patients with ST-elevation MI only and, recently, it was shown that there is a significant reduction of PlA2 in smokers with non-ST-elevation acute coronary syndromes compared with nonsmokers [33]. In our study, we included both patients with ST-elevation and non-ST-elevation MI and this may explain why only a weak interaction between smoking and PlA2 was observed in our study.

We found a significant interaction between PlA2 and serum total cholesterol. The association between PlA2 and MI was strongest in patients with low levels of serum cholesterol. Thus, the OR for MI was 1.1 in the highest cholesterol quartile versus 3.7 in the lowest quartile (test for trend: P = 0.016). After adjusting for the use of cholesterol-lowering drugs the interaction between PlA2 and serum total cholesterol remained significant (P = 0.038). Subjects with high levels of cholesterol are likely to suffer from atherosclerosis and MI. Any increase in the risk of MI due to PlA2 is concealed by the high risk of MI in these patients. In contrast, patients with low levels of cholesterol have a low risk of MI, and the absolute increase in risk owing to PlA2 is seen in the relative risk estimate, the OR. This finding is in accordance with a study by Abbate et al. who found that, amongst patients with CAD, there was a higher prevalence of subjects with only one cardiovascular risk factor in PlA2-positive patients compared with PlA2-negative patients [34]. Our findings imply that in future studies one would expect to find a higher frequency of PlA2 carriers in patients with CHD not explained by traditional risk factors.

Apart from traditional risk factors, we also investigated whether any interaction between PlA2 and MPV could be demonstrated. MPV is increased in patients admitted with acute MI [3], and large platelets are more hemostatically active than small ones [35]. Platelets from PlA2-positive individuals have been reported to bind more fibrinogen [25] and need less activation to aggregate [26], and PlA2-positive individuals have a shortened bleeding time [36]. We hypothesized that MPV and PlA2, which both have been linked with an increased hemostatic potential, might be associated. However, no association between PlA2 and MPV was seen. In our study, MPV was not significantly larger in MI patients. Part of the explanation may be that we studied patients with previous and not acute MI [35].

Thrombosis is of major importance in the pathophysiology of MI, and the relative contribution of thrombosis to the coronary occlusion might be particularly important in the young [37]. Thus, any increase in the tendency to platelet aggregation due to PlA2 is most likely to affect patients with an early onset of MI. Most of our patients had only one-vessel disease and constitute a cohort in which prothrombotic risk factors are likely to play an important role in the pathogenesis of MI. We found a trend towards PlA2-positive patients being younger at the time of first MI compared with PlA2-negative patients.

Our results should be taken with some caution. First, the PlA2 allele may be in linkage disequilibrium with another yet unidentified molecular variant, which is the true risk determinant. Secondly, we used unselected, healthy individuals from the general population as control subjects, accepting that a small proportion may have silent CAD. Thirdly, as with other similar investigations, our cross-sectional design may lead to survival bias, as data on patients with a fatal MI are not provided. These patients might have a risk profile that is different from that of MI survivors. Finally, it cannot be ruled out that the role of PlA2 in the pathogenesis of MI is due to other cells than platelets, as GP IIIa is also a part of the vitronectin receptor, which is expressed on endothelial cells and smooth muscle cells. The exact pathophysiological role of PlA2 deserves further investigation.

Logistic regression analysis was performed in order to assess the independence of PlA2 as a risk factor for MI. Adjusting for other risk factors resulted in only a modest change in OR (from 1.4 to 1.5). We conclude that in our study population there is an independent association between PlA2 and MI. This finding is in line with the main conclusion of a meta-analysis conducted by Di Castelnuovo et al. [38]. Typing for the PlA2 polymorphism might have implications for clinical risk assessment as well as prophylactic and therapeutic intervention.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of patients and healthy control subjects
  6. Genotyping
  7. Statistical analysis
  8. Results
  9. PlA genotypes in relation to MI
  10. Patients with MI
  11. PlA genotypes in relation to stenosis
  12. PlA genotypes in relation to other cardiovascular risk factors
  13. Patients with a family history of CHD
  14. Discussion
  15. Conflict of interest statement
  16. Acknowledgements
  17. References
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