807C/T polymorphism in the platelet glycoprotein Ia gene in young patients with ischemic stroke of undetermined etiology.

Platelet membrane glycoprotein receptors mediate key reactions in arterial thrombosis. The relationship between glycoprotein Ia polymorphisms and the risk of ischemic stroke, however, remains controversial. A matched case-control study was conducted to evaluate this question in young patients. Seventy patients with ischemic stroke of undetermined etiology, with ages ranging from 15 to 50 years, and 70 healthy control individuals, matched by age, gender and ethnicity, were tested for the 807C/T genotypes. Patients were excluded if they had systemic diseases known to predispose to thrombosis or any defined etiology of ischemic stroke. The frequencies of the 807T glycoprotein Ia variant and of conventional risk factors for arterial thrombosis (hypertension, smoking, diabetes mellitus, use of oral contraceptives, levels of serum cholesterol and body mass index) were compared in stroke patients and control individuals. The 807T allele was found in 61% of patients and 53% of control individuals (matched-pair odds ratio, 1.38; 95% confidence interval, 0.69-2.74; P = 0.42). Arterial hypertension and smoking were more frequent in patients than control individuals (matched-pair odds ratio, 2.83; 95% confidence interval, 1.05-8.02; P = 0.04; and odds ratio, 3.20; 95% confidence interval, 1.10-9.97, P = 0.03, respectively). In conclusion, our results do not support an independent association between the 807C/T polymorphism and stroke of undetermined etiology. The interplay of this polymorphism with arterial hypertension in the causation of ischemic stroke requires further evaluation.     

Variability in platelet aggregation following sustained aspirin and clopidogrel treatment in patients with coronary heart disease and influence of the 807 C/T polymorphism of the glycoprotein Ia gene

A broad variability in patient response to dual antiplatelet treatment has been described during the first month of treatment. Data on platelet function profiles in patients on dual antiplatelet therapy for a more sustained period are limited. Whether gene sequence variations of the glycoprotein Ia/IIa receptor influence platelet aggregation in these patients is also unknown. The aim of this study was to characterize platelet aggregation profiles in patients on dual antiplatelet treatment (aspirin plus clopidogrel) for >1 month and to assess whether these may be influenced by the C807T polymorphism of the glycoprotein Ia gene. We included 82 patients, who were divided into 2 groups: carriers (CT + TT genotypes; n = 51) and noncarriers (CC genotype; n = 31) of the mutant T allele. Platelet aggregation was assessed using light transmittance aggregometry after stimuli with adenosine diphosphate (20 micromol/L), collagen (6 microg/ml), and epinephrine (20 micromol/L). A significant variability in the distribution of platelet aggregation was observed in the overall study population, as well as in carriers and noncarriers of the T allele. T allele carriers had increased platelet aggregation compared with noncarriers after stimuli with adenosine diphosphate, collagen, and epinephrine (p <0.05 for all platelet aggregation assays). Thus, platelet aggregation varied significantly in patients on long-term dual antiplatelet treatment and was increased in T allele carriers of the 807C/T polymorphism of the glycoprotein Ia gene. These findings may contribute to the increased ischemic risk observed in these patients.     

The C807T/G873A polymorphism in the platelet glycoprotein Ia gene and the risk of acute coronary syndrome in the Italian population

Membrane glycoprotein (GP) Ia/IIa mediates platelet adhesion to collagen. The linked C807T/G873A polymorphisms in the GP Ia gene are correlated with a variable expression of the platelet surface receptor, the 807 TT/873 AA genotype being associated with a higher receptor density. Our study aimed to evaluate the possible role of the GP Ia C807T/G873A polymorphism as a risk factor for acute coronary syndrome in the Italian population. We investigated 157 patients with acute coronary syndrome (117 with myocardial infarction and 40 with severe unstable angina) as the first manifestation of coronary disease occurring before 65 years of age, compared with 312 healthy controls. All individuals were of Italian ancestry and were genotyped for the GP Ia C807T/G873A polymorphism. Complete linkage between the 807 and 873 sites was found in all samples. The 807 TT genotype was present in 12.7% of cases and in 4.8% of controls; the odds ratio for acute coronary syndrome was 2.9 (95% CI 1.4--5.8) for the 807 TT genotype compared with C-allele carriers and 0.6 (95% CI 0.4--0.9) for the 807 CC genotype compared with T-allele carriers. For the TT genotype, compared with CC homozygotes, the increase in risk was 3.4-fold in patients with at least one risk factor (smoking, hypercholesterolaemia, diabetes, systemic hypertension) and 4.1-fold in patients with angiographically diagnosed two- or three-vessel disease. We conclude that the GP Ia 807 TT (873 AA) genotype is associated with an increased risk of acute coronary syndrome in the Italian population; conversely, the GP Ia 807 CC (873 GG) genotype seems to represent a protective factor.     

血小板糖蛋白受体I a C807T基因多态性与心肌梗死关系的研究

目的：检测中国人群血小板糖蛋白(GP)受体Ia C807T基因多态性，以明确中国人群血小板GP Ia C807T的基因型，并探讨其多态性与心肌梗死(MI)之间的关系。方法：提取人基因组DNA，应用引物序列特异性多聚酶链反应(SSP—PCR)技术对小于60岁的MI患者72例和对照者70例分别进行血小板GP受体Ia C807T基因多态性检测。结果：中国人群血小板GP Ia C807T具3种基因型(TC，CC，TT)，MI患者T等位基因携带频率明显高于对照组(64％vs47％，P＜0．05)。结论：年龄小于60岁的MI患者T等位基因携带频率高，血小板膜GP Ia受体的遗传性差异在MI发病中可能具有重要作用。     

The prevalence of C807T mutation of glycoprotein Ia gene among young male survivors of myocardial infarction: a relation with coronary angiography results

INTRODUCTION: The glycoprotein complex Ia/IIa (GP Ia/IIa) is a major collagen receptor on platelets and other cell types. Recently, linked polymorphisms within the coding region of the GP Ia gene (C807T and G873A) related to GP Ia/IIa surface expression have been identified. The 807T/873A allele is associated with high expression, whereas the 807C/873G allele is associated with low surface expression of GP Ia/IIa. Subsequently, the 807T allele was found to be associated with coronary artery disease (CAD) and cerebral infarction in younger patients. Moreover, platelet thrombus formation is significantly influenced by genetic variations of the GPIb alpha and GPIa receptors and is dependent on the blood flow rate. AIM: 1. To determine the frequency of C807T polymorphism of the GPIa gene in young survivors of myocardial infarction (MI) and 2. to evaluate the relationship between the intensity of CAD in the coronary angiography examination and the 807C/T genetic status of the patients. METHODS: 102 young male survivors of MI (YSMI) -- mean age 43, range 29-49 years, mean age at the time of the first episode 37+/-3 years -- were studied. Obesity was found in 15%, diabetes in 14%, hyperlipidemia in 87%, hypertension in 22% and smoking history in 90% of cases. Familial CAD and/or MI were confirmed in 50% of patients. The control group consisted of 106 healthy volunteers with a negative family history of CAD, both medical staff members and blood donors (mean age 40, range 18-42 years). The genetic study was performed using genomic DNA obtained from peripheral blood leukocytes. The C807T polymorphism of platelet glycoprotein Ia (GPIa) was investigated using the PCR method introduced by Santoso et al. RESULTS: Coronary angiography (Siemens Bicor system) revealed single-artery disease in 34%, two-artery disease in 36% and three-artery disease in 26% of patients. In two patients there were no signs of CAD. The C807T polymorphism of GPIa was found in 73.5% of investigated patients (heterozygotes CT 59.8%, homozygotes TT 13.7%). The CC genotype was confirmed in 26.5% of patients. A similar analysis performed in the group of healthy men showed C807T polymorphism of the GPIa gene in 73.6% (CT in 58.5% and TT in 15.1% of persons, ns). CC genotype was found in 26.4% of persons. Interestingly, the T genotype frequency was similar in patients with three- or two-artery disease in comparison with patients with single-vessel or without CAD (49.3% vs. 50.7%, respectively, ns). In 75 YSMI carrying C807T polymorphism of the GPIa gene additional genetic abnormalities were confirmed in 21 patients - BclI polymorphism of b-chain fibrinogen gene, G4070A and G1691A (FV Leiden) mutation of factor V gene and C677T polymorphism of methylenetetrahydrofolate reductase gene. Partial occurrence of combined polymorphisms was found. This was confirmed independently of the number of coronary arteries involved.CONCLUSIONS: Our results may question the potential role of C807T the GPIa anomaly as a single genetic abnormality predisposing young men to coronary artery disease.     

The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women

Several platelet membrane glycoprotein polymorphisms have been identified as potential risk factors for cardiovascular disease. Recently a nucleotide -5T/C dimorphism in the translation initiation site (Kozak sequence) of the platelet glycoprotein Ibalpha (GPIbalpha) gene was associated with increased platelet surface levels of the GPIb-IX-V receptor complex. The role of this GPIbalpha Kozak sequence polymorphism in the occurrence of arterial thrombotic disease is unknown. We performed genotype analysis of the Kozak sequence polymorphism of GPIbalpha in a population-based study of 18- to 44-year-old women with nonfatal myocardial infarction (MI) (n = 78), nonfatal stroke (n = 106), and 384 demographically similar female control subjects. Analysis of -5T/C genotypes revealed that at least one copy of the C allele was present in 14.1% of MI cases, 23.6% of stroke cases, and 23.7% of controls. The age-adjusted odds ratio for MI in women carrying at least one copy of the C allele was 0.53 (95% confidence interval [CI] 0.27-1.05). The age-adjusted odds ratio for stroke in women carrying at least one copy of the C allele was 0.99 (95% CI 0.59-1.65). Analyses stratified by stroke type (ischemic, hemorrhagic) yielded similar results. In conclusion, young women carrying the C allele of the Kozak sequence polymorphism of GPIbalpha are not at increased risk of MI or stroke. Paradoxically, the C allele may even be associated with a reduced risk of MI in this population. This finding requires further study.     

807 C/T Polymorphism of the glycoprotein Ia gene and pharmacogenetic modulation of platelet response to dual antiplatelet treatment.

Glycoprotein (GP) Ia/IIa is a major platelet-collagen receptor playing a key role in thrombosis following collagen exposure. The 807 C/T polymorphism of the GP Ia gene (ITGA2) has been associated with platelet GP Ia/IIa receptor expression, having T-allele carriers, increased receptor density and thrombotic risk. The aim of the study was to assess the role of the 807 C/T polymorphism on modulating platelet function in patients undergoing coronary stenting receiving a 300 mg clopidogrel loading dose. Platelet aggregation was assessed in 44 patients by light transmittance aggregometry following adenosine diphosphate and collagen stimuli at baseline, and 10 min, 4 h and 24 h after clopidogrel front loading. The T allele was found in 73% of patients. Clopidogrel reduced adenosine diphosphate-induced platelet aggregation (P < 0.01), which was similar in carriers and non-carriers of the T allele throughout the study (P = 0.73). Clopidogrel reduced collagen-induced platelet aggregation only in non-carriers of the T allele (P = 0.03), which resulted in an increase in T allele carriers during the overall study (P = 0.04). In conclusion, the T allele of the GP Ia gene modulates platelet aggregation and clopidogrel antiplatelet effects, suggesting an enhanced reactivity to fibrillar collagens (exposed during coronary stenting) in T allele carriers and might contribute to an increased thrombotic risk in these patients.     

血小板膜糖蛋白I b的基因多态性与心肌梗塞发生关系的研究

目的　评价我国人群心肌梗塞的发生与血小板膜糖蛋白 (glycoprotein,GP)Ib基因多态性的关系。方法　采用病例对照研究 ,选择 10 0例确诊心肌梗塞的患者 (急性或陈旧性 )和 10 4例无心脏病史者作对照 ,用PCR SSP的方法进行血小板GPIbα链的基因多态性检测。结果　对照组无Met/Met纯合子 ,Thr/Met占 16.3 % ;心肌梗塞组Thr/Met Met/Met共占 3 0 % ,与对照组相比 ,P =0 .0 2 ,比数比 (oddsratio,OR)为 2 .2 (95 %可信区间 1.1～4 .3 )。在≤60岁发生心肌梗塞的患者Thr/Met Met/Met之和的频率(42 .2 % )更明显高于≤ 60岁的对照组 (14 .5 % ) (P =0 .0 0 2 ,OR =4 .3 ,95 %可信区间1.7～10 .8)。结论　血小板GPIb中Met等位基因与心肌梗塞之间呈显著的相关性 ,在≤60岁的人中 ,此种相关性更强。     

Glycoprotein Ia C807T polymorphism and risk of restenosis following coronary stenting

Platelets are thought to contribute to development of restenosis following percutaneous coronary interventions. The glycoprotein Ia/IIa complex is a major platelet collagen receptor, its surface expression being influenced by two, linked single nucleotide polymorphisms (C807T and G873A) in the glycoprotein Ia gene. T807 is associated with increased expression of this integrin receptor. We assessed whether T807 is associated with an increased risk of restenosis in 1769 consecutive patients treated with coronary stenting. 6-month follow-up angiograms were available in 82.4% of the patients. C807T genotype distribution was CC in 35.8%, CT in 47.6% and TT in 16.6% of the patients. Restenosis (diameter stenosis > or =50% at follow-up angiography) occurred in 32.9% of CC, 31.5% of CT and 32.1% of TT patients (P=0.87). The rate of major adverse cardiac events (death, myocardial infarction or need of reintervention) within 1 yr was 21.6% for CC, 21.7% for CT and 21.2% for TT patients (P=0.98). Thus, carriage of the GP Ia T807 allele is not associated with an increased risk of restenosis or unfavorable late outcome following coronary artery stenting.     

Platelet glycoprotein Ia 807C/T and 873G/A polymorphisms in patients with venous thromboembolism.

Two silent polymorphisms (807C/T and 873G/A) within glycoprotein Ia (GPIa) gene have been implicated in increased risk of developing thrombosis and myocardial infarction in affected individuals. The aim of this study was to investigate the GPIa gene polymorphism in patients with venous thromboembolism (VTE). A multiplexed allele specific-polymerase chain reaction (AS-PCR)-based method was used to determine the GPIa 807T/873A allele frequency in 77 patients with VTE and 106 healthy controls. The allelic frequency for 807T/873A was 33% in the patient group and 38% in the control group. The allelic frequency for 807C/873G was 66% in the patient group and 62% in the control group. The genotypic frequencies were 8% for 807TT/873AA, 42% for 807CC/GG, and 50% for 807CT/GA in the patient group. In the control group, the frequencies were 12% for 807TT/873AA, 35% for 807CC/873GG, and 52% for 807CT/873GA. As a result, the glycoprotein Ia 807C/T and 873G/A dimorphisms were not shown as risk factors for VTE.     

Association of the ScaI atrial natriuretic peptide gene polymorphism with nonfatal myocardial infarction and extent of coronary artery disease

Background There is growing evidence from recent studies that atrial natriuretic peptide (ANP) plays an important part in coronary blood flow regulation and in atherosclerosis. Transition T2238→C in the atrial natriuretic peptide (ANP) precursor gene, which leads potentially to the translation of ANP with 2 additional arginines, has been suggested to be associated with salt-sensitive hypertension. According to our knowledge, this study is the first to look for the potential association of the ScaI ANP gene polymorphism with the history of nonfatal myocardial infarction and the extent of coronary artery disease (CAD).Methods The study was performed in 847 consecutive, white patients (719 men and 128 women) with significant coronary artery stenosis confirmed by means of elective coronary angiography (at least 1 coronary artery with ≥50% lumen narrowing). Screening for the T2238→C substitution was performed by means of polymerase chain reaction of genomic DNA, followed by ScaI digestion and agarose gel electrophoresis.Results We found a significant association of the A2A2 ScaI ANP genotype with a higher incidence of positive history of nonfatal myocardial infarction (odds ratio 1.85, 95% CI 1.33-2.58) and multiple-vessel CAD (odds ratio 1.45, 95% CI 1.02-2.06). The ScaI ANP genotype distribution did not differ with age, sex, body mass index, plasma lipids, hypertension, diabetes mellitus, and family history of CAD in studied groups.Conclusions Our results suggest that the ScaI ANP polymorphism may be associated with nonfatal myocardial infarction and the extent of CAD. However, the precise mechanism of this association remains to be determined. (Am Heart J 2003;145:125-31.)     

C677T gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) in patients with myocardial infarction

Hyperhomocysteinemia is thought to be an independent risk factor for coronary heart disease. Increased plasma homocysteine level can result from malnutrition (e.g. folate deficiency) and/or genetic-related disturbances. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the synthesis of 5-methyltetrahydrofolate, the methyl donor for homocysteine remethylation to methionine. Transition of cytosine (C) to thymidine (T) at nucleotide position 677 of MTHFR gene causes alanine 226-to-valine substitution, and in consequence results in decreased enzyme activity and increased homocysteine level. Therefore, the aim of our study was to estimate the frequency distribution of C677T MTHFR polymorphism in patients with past myocardial infarction (MI), and to evaluate the association between this polymorphism and age of MI onset or left ventricular mass (LVM). The study was performed in 100 MI patients aged from 34 to 76 years and in control group consisted of 100 age- and gender-matched non-MI subjects. Applying PCR followed by Hinf I digestion of amplification products no significant difference in the frequency distribution of C677T MTHFR genotypes has been found between both groups (MI patients: 46% CC, 45% CT and 9% TT, and control group: 39% CC, 50% CT and 11% TT, respectively). No significant association between MTHFR genotypes and age of MI onset or LVM has been found in MI group. The results of our study suggest that C677T polymorphism of MTHFR gene is not a risk factor for myocardial infarction in Polish population.     

Genetic polymorphism of platelet glycoprotein IIIa in patients with acute myocardial infarction and acute ischaemic stroke

BACKGROUND: It has recently been suggested that the Leu33Pro polymorphism of the platelet glycoprotein IIIa affects the risk of coronary thrombosis. Finland is genetically isolated and has an incidence of cardiovascular disease among the highest in the world. Interestingly, the prevalence of ischaemic heart disease also varies in different parts of the country, being highest in eastern Finland. METHOD: We studied the Leu33Pro polymorphism using polymerase chain reaction in 133 patients with coronary artery disease, 234 patients with cerebrovascular disease and 326 control subjects originating from two areas of Finland. RESULTS: The frequencies of the Pro33 allele in the patients with acute myocardial infarction and cerebrovascular attack were 13% and 14%, respectively, and did not differ from the controls (13%). Among patients with acute myocardial infarction from the Helsinki area, the family history of premature coronary artery disease was more often positive in carriers of the Pro33 allele than in non-carriers, but after adjustment for multiple comparisons the difference was no longer significant. CONCLUSIONS: We could not confirm the original observation that the Pro33 allele constitutes an independent risk factor for coronary artery disease. Further studies are needed to clarify whether co-occurrence of Pro33 and some unrecognized inherited factor pose an additional risk of vascular disease.     

Role of glycoprotein Ia gene polymorphisms in determining platelet function in myocardial infarction patients undergoing percutaneous coronary intervention on dual antiplatelet treatment

Response variability to antiplatelet treatment has been described and the widespread use of acetylsalicylic acid (ASA) and clopidogrel requires clarification of the residual platelet reactivity (RPR). Various glycoprotein Ia (GpIa) polymorphisms have been investigated, but their influence on platelet reactivity in myocardial infarction (MI) patients undergoing percutaneous coronary intervention (PCI) on dual antiplatelet treatment is not still elucidated. Aim of this study was to evaluate the effect of C807T, G873A and T837C polymorphisms of GpIa on modulating platelet function in MI patients on dual antiplatelet treatment undergoing PCI. We measured platelet function by both a point-of-care assay (PFA100) and platelet-rich-plasma aggregation in 289 MI patients undergoing PCI and receiving dual antiplatelet treatment. Our data show that C807T/G873A polymorphisms, but not T837C, are associated with higher platelet reactivity. Carriers of the 807T/873A allele had significantly higher platelet aggregation values after arachidonic acid (AA) and collagen stimuli and, even if they did not reach the statistical significance, after 2 and 10 microM ADP stimuli; 807T/873A allele carriers had also significantly shorter closure times on PFA100/epinephrine membranes. At the multiple analyses, C807T/G873A polymorphisms resulted an independent risk factor for RPR defined by both AA induced platelet aggregation (OR=3.0, 95%CI 1.17-7.89, p=0.022) or by PFA100/epinephrine (OR=4.1, 95%CI 1.53-10.89, p=0.005). In conclusion, this study shows the 807T/873A allele of the GpIa gene is an independent risk factor for the RPR on dual antiplatelet treatment, and extends, in a larger acute coronary syndrome population, the observation that the 807T/873A allele is associated with higher platelet reactivity.     

Association between ITGA2 C807T polymorphism and gastric cancer risk

AIM:To evaluate the impact of the ITGA2 gene polymorphism on gastric cancer risk.METHODS:A hospital-based case-control study was conducted,including 307 gastric cancer patients and 307 ageand gender-matched control subjects.The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism assay.RESULTS:The frequencies of the wild and variant genotypes in cases were significantly different from those of controls (P=0.019).Compared with individuals with the wild genotype CC,s...     

The GPIa C807T dimorphism associated with platelet collagen receptor density is not a risk factor for myocardial infarction

The platelet collagen receptor, GPIa/IIa, is an important mediator of platelet adhesion to fibrillar collagens at sites of vascular injury. Recently, a dimorphism at nucleotide 807 of the GPIa cDNA (TTC/TTT in codon 224) was shown to be associated with variation in GPIa/IIa receptor density on the platelet surface. We conducted a case-control study to determine if the 807T allele, linked with increased GPIa/IIa density, contributed to risk of myocardial infarction (MI). DNA from 546 acute MI cases and 507 controls, all aged <75 years, was genotyped for the C807T dimorphism using the TaqManTM system of allelic discrimination. The allelic odds ratio (OR) for MI in the complete cohort was 0.88 (95% CI 0.74-1.05, P = 0.17), indicating that the 807T allele was not associated with an increased risk of MI. There was also no increased risk of MI associated with the homozygous 807TT (P = 0.22) or heterozygous 807CT (P = 0.24) genotypes or for carriers of the 807T allele in any cohort subgroup analysed. We conclude that the GPIa 807T allele is not a risk factor for MI in our population either alone or in combination with other major cardiovascular risk factors.     

Association of the GPIa C807T and GPIIIa PlA1/A2 polymorphisms with premature myocardial infarction in men.

Aims Recent studies have reported an association between the platelet glycoprotein (GP) Ia C807T polymorphism and myocardial infarction, whereas other studies have reported contradictory results concerning the platelet GPIIIa PlA1/A2 polymorphism. In most of these studies the patients were older than 45 years. Thus we decided to examine both genotypes in 287 men who had their first myocardial infarction before age 45, and a group of 138 healthy controls.Methods and Results The frequency of T807 allele carriers was similar among myocardial infarction patients and among controls (54.6% vs 62.3%; odds ratio (OR) 0.73; 95% confidence interval (CI), 0.47-1.12). The frequency of PlA2 carriers was higher in cases than in controls (26.5% vs 15.2%; OR 1.65; CI, 1.09-2.54). After performing a logistic regression analysis, taking into account other cardiovascular risk factors, this difference did not remain significant. The combination of the risk alleles of both genotypes had no major effect on the myocardial infarction risk.Conclusions The GPIIIa PlA2 allele is not independently associated with the risk of premature myocardial infarction. The T807 allele of the GPIa gene alone or in combination with the PlA2 allele had no major effect on premature myocardial infarction risk.     

Association of the Platelet Glycoprotein Ia C807T Gene Polymorphism With Risk of Myocardial Infarction in Chinese

Objectives To investigate the relationship of the GPIa C807T dimorphism to the risk of myocardial infarction （MI） in Chinese. Methods We did a case-control study including 100 patients and 110 controls with same race. An allele-specific polymerase chain reaction （PCR） was used for genotyping of C807T polymorphism. Results An apparent association was found between the T807 allele and MI among individuals younger than the mean age of 60 years （odds ratio, 2. 49 ; 95 % confidence interval, 1.08 - 6.22 ）. The T807 allele remained an independent risk factor for MI when age, sex, smoking, hypertension, diabetes, bodymass index, LDL-cholesterol and HDL-cholesterol were adjusted by logistic regression. Conclusions GPIa T807 appears to be an independent risk factor for MI.