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

Frank, Michele B.; Reiner, Alexander P.; Schwartz, Stephen M.; Kumar, Prashanth Ashok; Pearce, Rachel; Arbogast, Patrick G.; Longstreth, W. T.; Rosendaal, Frits R.; Psaty, Bruce M.; Siscovick, David S.

doi:10.1182/blood.v97.4.875

Cited by 50 publications

(39 citation statements)

References 26 publications

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“…28,30,31 The lack of correlation between these platelet GP polymorphisms and ischemic events observed in the present study has been reported in other studies as well. 29,32,33 However, the conclusions of lack of an association between these GP polymorphisms and ischemic events in the present study are not definitive because of our relatively small group of patients.…”

Section: Discussioncontrasting

confidence: 50%

“…30,31 However, other studies have not confirmed these observations. 32,33 A polymorphism in the GP IIIa gene (a single nucleotide change T/C, which causes Leu33Pro transition) has also been associated with coronary artery disease in some studies 34 -36 but not in patients with stroke. 26,27,[35][36][37][38] The aim of the present study was to evaluate whether the development of stroke or TIA in patients with significant (Ն50%) carotid artery stenosis is associated with inherited or acquired thrombophilic factors and/or platelet GP polymorphisms.…”

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confidence: 99%

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Cerebrovascular Events in Patients With Significant Stenosis of the Carotid Artery Are Associated With Hyperhomocysteinemia and Platelet Antigen-1 (Leu33Pro) Polymorphism

Streifler

Rosenberg

Chetrit

et al. 2001

Stroke

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Background and Purpose-Although risk factors for carotid artery stenosis caused by atherosclerosis are known, it is unclear what triggers "activation" of the atherosclerotic plaques and the ensuing thromboembolic cerebral events. The aim of this study was to evaluate whether thrombophilic factors, platelet glycoprotein (GP) polymorphisms, and homocysteine are associated with a risk of ischemic events in patients with significant carotid stenosis. Methods-Consecutive patients with Ն50% carotid stenosis, whether symptomatic (with ipsilateral ischemic events) or asymptomatic, who were evaluated and followed in a neurovascular clinic were tested for plasma levels of homocysteine, C677T mutation in methylenetetrahydrofolate reductase, G20210A mutation of factor II, factor V Leiden, antiphospholipid antibodies, and polymorphisms of platelet membrane GP: human platelet antigen (HPA)-1, GP Ia (C807T), and GP Ib (variable number of tandem repeats, Kozak, and HPA-2). Results-Eighty-six asymptomatic and 67 symptomatic patients were evaluated. The former group was older (73.7Ϯ6.9 versus 69.5Ϯ9.1 years, Pϭ0.02). Major risk factors for stroke were similar in both groups. In symptomatic patients versus asymptomatic patients, hyperhomocysteinemia was 3-fold more frequent (34.3% versus 12.8%, respectively; Pϭ0.002) and HPA-1a/b was almost 2-fold more common (38.8% versus 20.9%, respectively; Pϭ0.01). All other thrombophilic factors and platelet polymorphisms studied did not differ significantly between the 2 groups. Multivariate analysis revealed that hyperhomocysteinemia and the HPA-1a/b genotype conferred a significant risk of cerebral ischemic events, with odds ratios (95% CI) of 4.07 (1.7 to 9.7) and 3.4 (1.5 to 7.8), respectively. Conclusions-Hyperhomocysteinemia and HPA-1a/b are independent risk factors for ischemic events in patients with significant carotid stenosis. (Stroke. 2001;32:2753-2758.)

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Section: Discussioncontrasting

confidence: 50%

mentioning

confidence: 99%

Cerebrovascular Events in Patients With Significant Stenosis of the Carotid Artery Are Associated With Hyperhomocysteinemia and Platelet Antigen-1 (Leu33Pro) Polymorphism

Streifler

Rosenberg

Chetrit

et al. 2001

Stroke

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“…In another study, there was no increase in risk of nonfatal stroke and myocardial infarction in carriers of the Kozak sequence C-allele. 27 This meta-analysis indicates that the Kozak sequence Ϫ5T/C polymorphism demonstrates a strong association with risk of ischemic stroke but that the direction of the association is highly variable. Population variation across ethnicities is one possible interpretation of variability; however, Lohmueller et al 39 showed that stratifying for ethnicity does not necessarily remove or diminish heterogeneity and Ioannides et al 40 showed that although allele frequencies varied, the vast majority of genetic associations were consistent across ethnic groups in terms of magnitude.…”

Section: Platelet Glycoprotein 1b␣ Polymorphismsmentioning

confidence: 99%

Polymorphisms in Platelet Glycoprotein 1bα and Factor VII and Risk of Ischemic Stroke

Maguire

Thakkinstian²,

Sturm³

et al. 2008

Stroke

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Background and Purpose-Platelets and components of the coagulation cascade are known to be instrumental in the pathogenesis of arterial occlusive disorders. The aim of this meta-analysis is to test the hypothesis that genetic variation in the platelet glycoprotein 1b␣ and Factor VII genes influence the occurrence of ischemic stroke. All genetic association studies that examined the R353Q (rs6046) polymorphism of the Factor VII gene and 2 polymorphisms of the platelet glycoprotein (1b␣) gene (Thr/Met rs6065 and Kozak sequence Ϫ5 C/T rs2243093) in relation to ischemic stroke were examined. Methods-Electronic databases Embase, Medline, and HuGEnet were searched for all years up until June 2006 for all studies that evaluated any of these candidate genes and stroke. Results-Pooled ORs were calculated with 95% CIs using both fixed and random effects models. Meta-analysis for Factor VII (R353Q) did not detect any effect on ischemic stroke risk. Further estimation resulted in pooled OR 1 QQ versus RRϭ0.9 (95% CI: 0.4 to 1.9) and pooled OR 2 for RQ versus RRϭ0.9 (95% CI: 0.6 to 1.4). These results were robust and homogeneous. Pooling ORs for the platelet glycoprotein 1b␣ Kozak variant Ϫ5 T/C polymorphism showed extreme heterogeneity with differing effect directions across studies. Fisher's method of pooling was therefore used to calculate a combined probability value, which was highly significant (PϽ0.001). The pooled OR for platelet glycoprotein 1b␣ Met/Met v Thr/Thr was 1.0 to 2.0, depending on the sensitivity analyses, and for Thr/Met versus Thr/Thr, the pooled OR was between 1.3 and 1.4. These results were consistent, reasonably robust, and implied a dominant genetic effect. Conclusion-This analysis provides strong evidence that the Factor VII R353Q gene polymorphism is not associated with ischemic stroke, that the Thr/Met polymorphism of GP1b␣ is associated with ischemic stroke in a dominant genetic model, and that the Kozak sequence polymorphism of GP1b␣ may be close to another causative locus that is associated with ischemic stroke. (Stroke. 2008;39:1710-1716.)

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“…4,5 Similarly, platelet membrane polymorphisms have been linked to stroke in small studies, but the evidence is not strong. [6][7][8][9] Such studies highlight the relevance of identifying additional gene/protein biomarkers that may be causally linked to clinically relevant platelet phenotypes.Platelets retain megakaryocyte-derived mRNA, although the platelet transcriptome is less complex than that of nucleated cells. 10,11 Furthermore, platelets have evolved unique adaptive molecular signals for maintenance of genetic and protein diversity.…”

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Class prediction models of thrombocytosis using genetic biomarkers

Gnatenko¹,

Zhu

et al. 2010

Blood

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Criteria for distinguishing among etiologies of thrombocytosis are limited in their capacity to delineate clonal (essential thrombocythemia [ET]) from nonclonal (reactive thrombocytosis [RT]) etiologies.We studied platelet transcript profiles of 126 subjects (48 controls, 38 RT, 40 ET [24 contained the JAK2V 617 F mutation]) to identify transcript subsets that segregated phenotypes. Cross-platform consistency was validated using quantitative real-time polymerase chain reaction (RT-PCR). Class prediction algorithms were developed to assign phenotypic class between the thrombocytosis cohorts, and by JAK2 genotype. Sex differences were rare in normal and ET cohorts (< 1% of genes) but were male-skewed for approximately 3% of RT genes. An 11-biomarker gene subset using the microarray data discriminated among the 3 cohorts with 86.3% accuracy, with 93.6% accuracy in 2-way class prediction (ET vs RT). Subsequent quantitative RT-PCR analysis established that these biomarkers were 87.1% accurate in prospective classification of a new cohort. A 4-biomarker gene subset predicted JAK2 wild-type ET in more than 85% patient samples using either microarray or RT-PCR profiling, with lower predictive capacity in JAK2V 617 F mutant ET patients. These results establish that distinct genetic biomarker subsets can predict thrombocytosis class using routine phlebotomy. (Blood. 2010;115:7-14) IntroductionPlatelets mediate the initial first step in hemostasis while simultaneously providing the negatively charged phospholipid surface required for contact phase-mediated propagation of the coagulation cascade. Despite these key functions, molecular defects causally implicated in platelet-associated bleeding or thrombotic risk are largely unknown, best characterized by loss of glycoproteins (GP) IIb/IIIa (␣ IIb ␤ 3 ; Glanzmann thrombasthenia) or the GPIb-IX-V complex (Bernard-Soulier syndrome). 1 Similarly, protein overexpression may favor platelet activation and thrombus formation, providing conceptual support for the presence of biomarkers that may confer enhanced thrombosis susceptibility risk. Thus, polymorphisms within the ITGA2 gene encoding the ␣2 polypeptide of the heterodimeric ␣ 2 ␤ 1 collagen receptor increase receptor surface density and are associated with an increased risk of ischemic heart disease in homozygotes (especially smokers), 2,3 although confirmatory results using meta-analyses for a distinct subset of hemostatic proteins have been somewhat disappointing. 4,5 Similarly, platelet membrane polymorphisms have been linked to stroke in small studies, but the evidence is not strong. [6][7][8][9] Such studies highlight the relevance of identifying additional gene/protein biomarkers that may be causally linked to clinically relevant platelet phenotypes.Platelets retain megakaryocyte-derived mRNA, although the platelet transcriptome is less complex than that of nucleated cells. 10,11 Furthermore, platelets have evolved unique adaptive molecular signals for maintenance of genetic and protein diversity. 12 Quiescent platelets...

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

Cited by 50 publications

References 26 publications

Cerebrovascular Events in Patients With Significant Stenosis of the Carotid Artery Are Associated With Hyperhomocysteinemia and Platelet Antigen-1 (Leu33Pro) Polymorphism

Cerebrovascular Events in Patients With Significant Stenosis of the Carotid Artery Are Associated With Hyperhomocysteinemia and Platelet Antigen-1 (Leu33Pro) Polymorphism

Polymorphisms in Platelet Glycoprotein 1bα and Factor VII and Risk of Ischemic Stroke

Class prediction models of thrombocytosis using genetic biomarkers

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