Platelet glycoprotein Ia 807C/T (Phe224) and 873G/A (Thr246) dimorphisms in Turkey

At sites of vascular injury, the platelet collagen receptor Glycoprotein Ia/IIa (GPIa/IIa) acts as an important mediator of platelet adhesion to fibrillar collagens. Two silent polymorphisms (807C/T and 873G/A) within the glycoprotein Ia gene have been implicated in increased risk of developing thrombosis and myocardial infarction in affected individuals. To provide basis for future studies, we examined the frequency of these GPIa polymorphisms for people in Turkey. We analyzed 118 unrelated individuals for their genotypes of the GPIa gene using a multiplexed allele specific-PCR based method. The allelic frequencies were found to be 34% for 807T/873A and 66% for 807C/873G; the genotypic frequencies were 13% for 807TT/873AA, 44% for 807CT/873GA, and 43% for 807CC/873GG.     

Allelic distribution of the glycoprotein Ia (alpha2-integrin) C807T/G873A dimorphisms among caucasian venous thrombosis patients and six racial groups

Two linked silent dimorphisms, 807 C --> T (Phe224) and 873 G --> A (Thr246) within the glycoprotein Ia (GPIa) gene have been correlated with low and high platelet receptor density, respectively, and associated with vascular disease. A multiplexed allele-specific PCR assay was used to determine the GPIa 807T/873A allele frequency among 331 Caucasian venous thrombosis patients and 3571 unrelated individuals belonging to six different racial groups. The 807T/873A allele frequencies were 54%, 51%, 39%, 39%, 38%, 34% and 30% among Native Americans, Hispanics, Caucasians, Caucasian venous thrombosis patients, Asian Indians, African-Americans, and Koreans, respectively. Significant differences in the GPIa allele frequency among racial groups were revealed which emphasized the need for appropriate controls in studies evaluating the association of GPIa genotype to vascular disease.     

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.     

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.     

Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients

Recently, we have shown that two alleles of the glycoprotein (GP) Ia gene, designated C807 and T807, are associated with low or high platelet GPIa-IIa density and consequently with slower or faster rate of platelet adhesion to type I collagen, respectively. This polymorphism could therefore present a genetic predisposition for the development of thrombotic disease and hemostasis. We investigated the relationship of the GPIa C807T dimorphism to the risk of coronary artery disease (CAD) and myocardial infarction (MI). An allele-specific polymerase chain reaction (PCR) was developed for genotyping of C807T polymorphism. DNA samples from 2237 male patients who underwent coronary angiography on account of coronary heart disease as verified illness or presumptive diagnosis were genotyped. The odds ratio was calculated as an estimate of the relative risk by multiple logistic regression. We found a strong association between the T allele and nonfatal MI among individuals younger than the mean age of 62 years (n = 1,057; odds ratio, 1.57; P =.004). The odds ratio of MI increased for T807 carriers with decreasing age. The highest odds ratio was detected within the youngest 10% of the study sample (<49 years; n = 223; odds ratio, 2. 61; P =.009). In contrast, no evidence of an association between C807T dimorphism with CAD was found. Our findings suggest that inherited platelet GP variations might have an important impact on acute thrombotic disease.     

Glycoprotein Ia 807TT/873AA genotype is not associated with myocardial infarction.

OBJECTIVE: The glycoprotein Ia/IIa complex is a major platelet collagen receptor. Its surface expression is influenced by two linked single nucleotide polymorphisms (C807T and G873A) in the glycoprotein Ia (GPIa) gene. In this study we aimed to determine the frequency of GPIa C807T/G873A genotype in patients with myocardial infarction (MI) and healthy controls in Turkish population and association between these dimorphisms and risk factors of MI. METHODS: We examined GPIa (C807T/G873A) genotypes in 158 patients with MI and 145 healthy controls. Distributions of the C807T and G873A dimorphisms were investigated by genotyping DNA using multiplexed allele-specific PCR. RESULTS: There was no association between GPIa genotypes and MI. We further analysed each group for all known risk factors such as plasma lipid levels, cigarette smoking, diabetes, hypertension, gender, age, MI history and body mass index. When compared with other two genotypes for glycoprotein Ia (GT/GA and CC/GG), TT/AA showed an association with higher high-density lipoprotein (HDL) -cholesterol levels in the healthy control group, but none in the group with MI. CONCLUSION: The 807TT/873AA genotype of the GPIa gene alone or in combination with risk factors had no major effect on MI, however, it appears to be associated with higher HDL-cholesterol levels in healthy subjects.     

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.     

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.     

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.     

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.     

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.     

Methionine synthase A2756G and methylenetetrahydrofolate reductase A1298C polymorphisms are not risk factors for idiopathic venous thromboembolism

Hyperhomocysteinemia is a defined risk factor for venous thromboembolism (VTE). Several polymorphisms of genes encoding for enzymes acting in the remethylation pathway of homocysteine metabolism, ie, methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C, can cause increased homocysteine levels particularly in patients with deficiencies of folic acid, vitamin B6, or B12 and hence be potential risk factors for VTE. Indeed, homozygous MTHFR C677T was shown to be a mild risk factor for VTE by some, but not by all, investigators. In this study, we assessed the risk exerted by MS A2756G and MTHFR A1298C in a cohort of patients with idiopathic venous thromboembolism. Homozygosities for MS A2756G and MTHFR A1298C were not found to be statistically significant risk factors for VTE. In addition, no interactions were observed among MS A2756G, MTHFR A1298C and MTHFR C677T in conferring a risk of VTE.     

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.     

Platelet count and venous thromboembolism. A useful test for suspected pulmonary embolism

We have previously reported that patients with deep vein thrombosis (DVT) and scintigraphic evidence of pulmonary embolism (PE) had a fall in platelet count, as compared with their levels before thrombosis had developed. Otherwise, no changes were found in DVT patients without embolism. We recently conducted a prospective study with a larger series of patients and studied platelet count behavior in 189 consecutive patients with acute venous thromboembolism (VTE) in whom a baseline blood cell count was available (obtained before thromboembolism developed). We found no significant differences in baseline platelet counts between groups. However, at the time of VTE diagnosis the analysis of variance demonstrated that mean platelet count was significantly higher in patients without embolism as compared with PE patients (p less than 0.001). On the other hand, no differences were found between patients with silent PE and those with clinically obvious PE. When patients with postoperative VTE and those with nonpostoperative VTE were analyzed separately, mean platelet count increased only in postoperative DVT patients without embolism (p less than 0.001). In the absence of a previous intervention, DVT did not produce any change in platelet count, while PE significantly reduced platelet number (p less than 0.008). In DVT patients without respiratory symptoms of embolism, we suggest that a lung scan should be performed when platelet count is lower than baseline value. For patients with a higher count, the probability of finding PE is very low, and scintigraphy is not cost-effective.     

CTLA-4 gene polymorphisms (-318C/T, +49A/G, +6230A/G) in Iranian patients with multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by multiple regions of demyelination and inflammation along axons with a T cell-mediated autoimmune etiology. While the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene seems to be a strong candidate gene in autoimmune diseases, we investigated its association with a group of patients with MS. One hundred and thirty five patients with relapsing-remitting form of MS and 135 healthy subjects were enrolled in this study. Three single nucleotide polymorphisms (SNPs) (-318C/T, +49A/G, +6230A/G) of the CTLA-4 gene were assessed using PCR-RFLP method. The genotypes -318 CC (82.9% in patients vs. 76.2% in controls) and +49 AA (31.1% in patients vs. 28.1% in controls) were overrepresented in the patient group; however, these differences were not statistically significant. In spite of some previous reports, this study did not confirm any significant association with alleles and genotypes of SNPs of the CTLA4 in Iranian MS patients. Such disparity could be due to genetic background, ethnicity and different forms of the disease.     

Congenital thrombophilia among patients with venous thromboembolism.

During a 3-year period we studied 393 adult patients (382 of whom were unrelated) with a history of acute venous thromboembolism. A congenital deficiency state known to predispose to thrombosis was found in 27.2%. Of these, most were due to deficiencies of protein C (9.2%), protein S (7.6%), antithrombin III (5%) or to increased plasma PAI-1 concentration (3.1%) which, in the absence of any known factor that predisposes towards thrombosis, results in a diminished fibrinolytic activity. There was a characteristic pattern between the age of onset (mean 34 years) of thrombosis and individual protein deficiency. Thrombosis appeared spontaneously in 73% of cases with recurrence in 80%. In contrast, in the remaining unrelated patients, 138 (35.1%) in whom venous thromboembolism was secondary and occurred at a mean age of 43 years, and in the other 140 (35.6%) who suffered thromboembolism spontaneously at a later age (mean age 55), there was no permanent protein deficiency state or alteration in fibrinolytic activity and thrombosis recurrence was lower (53.6% and 20.7% respectively). Of the 393 patients, deep vein thrombosis was the most common manifestation; however, in congenital thrombophilia, thrombosis of visceral vessels and Raynaud's syndrome (6%) were also detected.     

Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism

We determined the prevalence of factor V Leiden and of prothrombin G20210A mutations in a cohort of unselected outpatients (n = 748) referred for suspected deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and a pooled analysis of similar studies was also performed. Based on the clinical presentation, the prevalence of factor V Leiden was 15.7% in the 83 patients with DVT and 14.1% in the 99 patients with PE compared with 5.3% in patients without DVT and/or PE (control group). The prevalence of the prothrombin G20210A mutation did not differ among the three groups (3.9% for controls, 4. 8% for DVT and 3.9% for PE patients). We then divided the 99 patients with PE by separately analysing those with PE but without DVT (n = 57) and those with PE and DVT (n = 42). Compared with the control group, the prevalence of factor V Leiden was 10.5%, odds ratio (OR) 2.10 [95% confidence interval (95% CI) 0.68-5.45] in patients with primary PE and 19.1%, OR 4.20 (95% CI 1.54-10.30) in patients with DVT and PE. For the prothrombin G20210A mutation, no statistically significant differences were found between the control group and the three other groups. In conclusion, our data and the pooled analysis indicate that patients with primary PE are less often affected by the factor V Leiden mutation. No statistically significant differences were observed between patients and controls for the prothrombin G20210A mutation.