Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polymorphisms C807T and G873A of the platelet integrin alpha2beta1 (collagen receptor glycoprotein [GP] Ia-IIa) are linked to the expression density of this receptor. The GPIa T807/A873 allele causes a higher receptor expression, enhancing platelet binding to collagen. This might present a genetic predisposition for the development of thromboembolic complications. In this case-control study, the genotypes of the GPIa C807T polymorphism and presence of conventional risk factors (hypertension, diabetes mellitus, and smoking) were compared in stroke patients and patients without cerebrovascular disease (non-CVD patients) </=50 years of age (n = 45 and 41, respectively) and in stroke patients and non-CVD patients more than 50 years of age (n = 182 and 129, respectively. In patients </=50 years of age, the T807 allele was the only overrepresented variable (P =.023; odds ratio, 3.02; 95% confidence interval, 1.20 to 7.61) and an independent risk factor, whereas the presence of conventional risk factors was similar between stroke patients </=50 years of age and non-CVD patients </=50 years of age. Large epidemiological studies should prove whether the platelet collagen receptor GPIa-IIa T807 allele is an independent risk factor for the development of stroke in younger patients.
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PMID:The alpha2 gene coding sequence T807/A873 of the platelet collagen receptor integrin alpha2beta1 might be a genetic risk factor for the development of stroke in younger patients. 1033 62

This review summarises some of the key developments that have taken place in our understanding of platelet-collagen interactions within the last 18 months. Within this time, the major activatory collagen receptor glycoprotein VI (GPVI) has been sequenced and shown to reconstitute collagen responses in a megakaryocytic cell line. It is a member of the Ig superfamily of proteins, with two extracellular Ig domains, and is constitutively associated with the Fc receptor gamma-chain (FcR gamma-chain). GPVI signals through a pathway that shares many features with those of immune receptors, with critical roles for Syk and the adapters LAT and SLP-76 in the activation of PLCgamma2. Significant developments have also taken place in regard to the role of the major adhesion receptor for collagen, the integrin alpha2beta1 (also known as GPIa-IIa). An alpha2beta1-selective collagen-based peptide has been developed and co-crystallised with the I-domain of the alpha2 subunit. Polymorphisms in alpha2 have been shown to cause wide variation in expression of alpha2beta1, with the alpha2 allele T807/A873 leading to a high level of the integrin and increased risk of stroke in young people. Activation of platelets by a wide range of agonists has been shown to increase the affinity of alpha2beta1 to intermediate or high affinity states. This has important implications for the two-site, two-state model of collagen-platelet interactions. A new model is proposed in which collagen binds initially to either alpha2beta1 or GPVI, leading to subsequent binding to the other receptor and conversion of the integrin to a high affinity state. In this model, both receptors generate intracellular signals which support platelet activation.
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PMID:Update on collagen receptor interactions in platelets: is the two-state model still valid? 1103 Apr 59

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90

Thromboangiitis obliterans or Buerger's disease is an episodic and segmental inflammatory and thrombotic process of the medium and small arteries of the lower extremities. Even though the disease was described 90 years ago, the etiopathogenesis is still under consideration. Afflicted patients are mostly young male cigarette smokers without signs of atherosclerosis or other risk factors for peripheral arterial occlusive disease. This indicates that hereditary thrombophilic factors could play a role in the etiopathogenesis. Recently, increasing evidence shows that platelet receptor polymorphisms (HPA-1 polymorphism of beta3 subunit of alphaIIbbeta3 and 807 C/T polymorphism alpha2beta1) are associated with early onset of arterial thrombosis (myocardial infarction, stroke). This case-control study was designed to assess whether the 807 C/T polymorphism or the HPA-1 polymorphism is involved in the pathogenesis of Buerger's disease or has any influence on the clinical course of Buerger's disease. Eighteen patients with Buerger's disease and 81 (sex and age matched) healthy control subjects (mean age 44 +/- 10 vs 45 +/- 8 years, respectively) were genotyped for platelet receptor HPA-1 and GPIa 807 C/T polymorphism. The gene frequency of HPA-1 and GPIa 807 C/T polymorphisms was identical in both groups. Prevalence of hetero- and homozygous carriers of the HPA-1b allel (1a1b and 1b1b genotype) as well as the prevalence of the 807 C/T and 807 T/T carriers did not differ significantly between the two groups, p >0.05. The grade of clinical disease manifestation as well as disease progression did not reveal any significant relationship with HPA-1 and 807 C/T polymorphisms. A relationship between the age at onset of the disease and HPA-1 polymorphism was not found. Otherwise analysis of the GPIa 807 C/T platelet receptor polymorphism showed that the average age of patients who are carriers of the T allele at early onset of disease was 32 +/- 6 years (range 27-48 years) compared to 42 +/- 6 years (range 34-53 years) of the C/C carriers (p <0.05). This indicates that the GPIa 807 C/T polymorphism does not represent a risk factor for Buerger's disease itself, but could be associated with premature onset of this disorder in predisposed individuals.
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PMID:Platelet receptor HPA-1 polymorphism of alphaIIbbeta3 and 807 C/T polymorphism of alpha2beta1 and Buerger's disease. 1749 65

Polymorphisms in human platelet alloantigen (HPA)-1 and HPA-3 (GPIIb/IIIa), HPA-2 (GPIb/IX), HPA-4 (GPIIIa) and HPA-5 (GPIa/IIa) were investigated in 216 stroke patients and 318 matched control subjects. HPA genotyping was done by the polymerase chain reaction method using sequence-specific primers. Higher frequencies of the HPA-1 a/b (p < 0.001) and HPA-5 a/b (p < 0.001) allele, together with HPA-1 b/b, HPA-5 a/b and HPA-5 b/b genotypes were seen in patients, which was confirmed by regression analysis after controlling for a number of confounding variables. Furthermore, HPA-1 b/b and HPA-5 b/b were significantly associated with the extent of neurological symptoms, and with the recurrence of stroke. Both susceptible (1a/ b -2a/a-3a/ b -4a/a-5a/ b ) and protective (1a/a-2a/a-3a/a-4a/a-5a/a; 1a/a-2a/a-3a/ b -4a/a-5a/a; 1a/ b -2a/a-3a/a-4a/a-5a/a; 1a/ b -2a/a-3a/ b -4a/a-5a/a) HPA genotypes were identified. This is the first evidence demonstrating differential association of the common 5 HPA gene variants with stroke, with HPA-1b and HPA-5b representing strong genetic risk factors.
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PMID:Association of human platelet alloantigen 1 through 5 polymorphisms with ischemic stroke. 1805 77

Polymorphism in human platelet antigen (HPA)-1 and HPA-3 (GPIIb/IIIa), HPA-2 (GPIb/IX), HPA-4 (GPIIIa), and HPA-5 (GPIa/IIa) was investigated in 329 stroke patients and 444 matched control subjects. HPA genotyping was done by PCR-SSP method. Lower HPA-1a (P < 0.001) and higher HPA-1b (P < 0.001) allele frequencies were seen in patients than control subjects, and homozygosity for HPA-1b (P < 0.001) alleles was more prevalent in stroke cases than in controls. The allele and genotype distributions of the other HPA polymorphic variants were similar between cases and controls. Select HPA combined genotypes comprising the 2121 (Pc = 0.008) and 2221 (Pc = 0.018) genotypes, which were positively associated, and the 1111 (Pc < 0.001), which was negatively associated with stroke, thereby conferred a disease susceptibility and protective nature to these genotype combinations. Multivariate analysis confirmed the negative association of the 1111 (P < 0.001) and the positive association of the 2121 (P = 0.017) combined genotypes with stroke, after adjustment for a number of covariates. This is the first evidence demonstrating differential association of the common 4 HPA gene variants and specific HPA genotype combinations with stroke.
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PMID:Polymorphisms of the human platelet alloantigens HPA-1, HPA-2, HPA-3, and HPA-4 in ischemic stroke. 1838 24

Aspirin is a key player in the management and prevention of stroke and myocardial infarction in patients with atherothrombosis. About 12% of Pakistanis suffering from coronary artery disease are resistant to aspirin's effects. Clinical, biochemical and genetic factors are known to be responsible for this phenomenon. We conducted this study to investigate whether previously studied polymorphisms in COX-1, GPIIIa, GPIa and P2RYI genes could be the cause of aspirin resistance in our population. Blood samples were collected from 29 aspirin non-responders and 60 ethnically matched responders. Aspirin response assay was performed on IMPACT-R and DNA prepared from blood using the phenol: chloroform method. Genotyping was carried out for four SNPS including COX-1 C50T (rs3842787), GPIIIA PIA1/A2 polymorphism (rs5918), GPIA C807T (rs1126643) and p2RY1 C893T (rs1065776). No statistically significant differences were observed in the allele or genotype frequencies between the aspirin non responders and responders indicating the possible involvement of different genetic determinants of aspirin resistance in our population. This study paves the way for further research into the field of aspirin resistance in Pakistan.
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PMID:A study into the genetic basis of aspirin resistance in Pakistani patients with coronary artery disease. 2739 50