Association of two silent polymorphisms of platelet glycoprotein la/lla receptor with risk of myocardial infarction: a case-control study

Moshfegh, Khatereh; Wuillemin, Walter A.; Redondo, Maurice; Lämmle, Bernhard; Beer, Jürg H.; Liechti‐Gallati, Sabina; Meyer, Beat J.

doi:10.1016/s0140-6736(98)06448-4

Cited by 188 publications

(144 citation statements)

References 29 publications

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“…The highdensity GPIa 807T/873A allele frequency was not reported to be a risk factor for venous thrombosis among this patient cohort [6]. The high-density allele 807T/873A has been found to be associated with increased risk of myocardial infarction in two independent studies [3,7], whereas was reported by another group [8].…”

Section: Introductionmentioning

confidence: 57%

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

Komurcu

Erginel-Unaltuna

2001

American J Hematol

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At sites of vascular injury, the platelet collagen receptor Glycoprotein Ia/IIa (GPIa/IIa) acts as an important mediator of platelet adhesion to ®brillar 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 speci®c-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. Am.

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Section: Introductionmentioning

confidence: 57%

“…Individuals with low receptor densities are homozygous for the 807C/873G allele, whereas individuals homozygous for the 807T/873A allele have high receptor densities [1,3]. This polymorphism could therefore present a genetic predisposition for the development of thrombotic disease and hemostasis.…”

Section: Introductionmentioning

confidence: 99%

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

Komurcu

Erginel-Unaltuna

2001

American J Hematol

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“…Given the importance of GpIa/IIa in primary haemostasis, several studies have assessed the roles of these polymorphisms in both large vessel venous and arterial thrombosis including myocardial infarction (MI), stroke, deep venous thrombosis, and pulmonary embolism. [18][19][20][21][22][23] Although results are conflicting, it appears that GpIa/IIa polymorphisms may play a role in large vessel arterial but not venous thrombosis and its role in microvascular disease is unknown. We know however that GpIa/IIa polymorphisms play a major role in retinal vessel disease.…”

Section: Introductionmentioning

confidence: 99%

The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion

Dodson

Haynes

Starczynski

et al. 2003

Eye

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Retinal vein occlusion (RVO) is associated with hyperhomocysteinaemia and the antiphospholipid syndromeFdisorders known to contribute to both arterial and venous thrombosis. In both of these conditions and RVO, platelet activation occurs. Aspirin, not warfarin, is the most effective antithrombotic agent in RVO and, taken together, these observations suggest an important role for platelets in this common ocular thrombotic condition. Platelet glycoprotein Ia/IIa (GpIa/IIa) is an adhesion molecule mediating platelet-collagen interactions and is key to the initiation of thrombosis. Recently, the cellular density of this molecule was shown to be determined by two silent, linked polymorphisms (C807T/ G873A) within the GpIa/IIa gene. There is evidence that some of the resulting genotypes are associated with thrombo-embolic disease. This study therefore aimed to establish the prevalence of the GpIa/IIa polymorphisms and the three commonest hereditary thrombophilic disorders (prothrombin gene G20210A (PT) mutation, Factor V Leiden (FVL), and the thermolabile methylene tetrahydrofolate reductase C677T (MTHFR) mutation) in patients with RVO and normal controls. The GpIa/IIa polymorphisms and thrombophilic abnormalities were all identified using the polymerase chain reaction. Our results show that the frequency of the GpIa/IIa polymorphisms was similar in our normal control population to previously published series. Patients with RVO, however, had only a 10% (4/40) frequency of the lowest risk subtype (CC/GG) compared to 37.5% (15/40) in the control groupFP 0.0039.The incidence of the PT, FVL, and MTHFR thrombophilic mutations was not different between the two groups, but interestingly none of the 7/40 RVO cases with a PT, FVL, or MTHFR mutation had the low-risk GpIa/IIa genotype while all but one of the controls didFPo0.05. Thus, 17.5% of RVO patients harboured more than one prothrombotic abnormality. The principal difference between the RVO and control group was the very high incidence of the intermediate-risk GpIa/IIa subtype (CT/GA)F82.5 vs 50%, Po0.05. These results suggest a major role for GpIa/IIa polymorphisms in the pathogenesis of RVO.

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“…GpVI, recently cloned (11), acts with the Fc receptor ␥-chain (12, 13) as a crucial signaling receptor complex, and platelets deficient in GpVI fail to aggregate in response to collagen, although the tyrosine kinase c-Src, but not p72 syk , is activated (14). The role of ␣ 2 ␤ 1 in platelet signaling is unclear: ␣ 2 ␤ 1 -reactive snake venoms fuel the debate on the integrin's role in platelet signaling (15, 16), and overexpression of ␣ 2 ␤ 1 has recently been advanced as a risk factor in myocardial infarction and stroke (17,18).We have synthesized a collagen-related peptide (CRP) recognized by GpVI, which shares both the triple-helical structure and activatory characteristics of collagen (19). CRP comprises a repeating GPO motif, a sequence representing about 10% of the primary structure of collagen.…”

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confidence: 99%

Integrin-independent Tyrosine Phosphorylation of p125fak in Human Platelets Stimulated by Collagen

Achison

Elton

Hargreaves

et al. 2001

Journal of Biological Chemistry

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Collagen fibers or a glycoprotein VI-specific collagenrelated peptide (CRP-XL) stimulated tyrosine phosphorylation of the focal adhesion kinase, p125 fak (FAK), in human platelets. An integrin ␣ 2 ␤ 1 -specific triple-helical peptide ligand, containing the sequence GFOGER (single-letter nomenclature, O ‫؍‬ Hyp) was without effect. Antibodies to the ␣ 2 and ␤ 1 integrin subunits did not inhibit platelet FAK tyrosine phosphorylation caused by either collagen fibers or CRP-XL. Tyrosine phosphorylation of FAK caused by CRP-XL or thrombin, but not that caused by collagen fibers, was partially inhibited by GR144053F, an antagonist of integrin ␣ IIb ␤ 3 . The intracellular Ca 2؉ chelator, BAPTA, and the protein kinase C inhibitor, Ro31-8220, were each highly effective inhibitors of the FAK tyrosine phosphorylation caused by collagen or CRP-XL. These data suggest that, in human platelets, 1) occupation or clustering of the integrin ␣ 2 ␤ 1 is neither sufficient nor necessary for activation of FAK, 2) the fibrinogen receptor ␣ IIb ␤ 3 is not required for activation of FAK by collagen fibers, and 3) both intracellular Ca 2؉ and protein kinase C activity are essential intermediaries of FAK activation.Hemostasis, prevention of blood loss from damaged blood vessels, is dependent upon the activation of platelets by subendothelial collagens (types I and III) of the vessel wall. Platelet activation involves shape change, adhesion, aggregation, and secretion of granule contents. These events lead to the formation of a clot at the site of injury (1).Platelets possess several receptors for collagen, recently reviewed (2-4), including the integrin ␣ 2 ␤ 1 (glycoproteins IaIIa), CD36 1 (glycoprotein IV), and glycoprotein VI (GpVI). Platelet activation by collagen is a two-stage process involving sites in collagen, which support platelet adhesion, and others, which support both platelet adhesion and activation (5, 6). At present, ␣ 2 ␤ 1 is considered primarily an adhesive co-receptor (7), whereas other collagen receptors, notably glycoprotein VI, activate platelets (8). This study was designed to clarify which collagen receptors transmit signals to the platelet interior, information which is crucial for the development of anti-platelet therapy based on collagen receptor antagonism (9).Recent evidence suggests that CD36, ␣ 2 ␤ 1 , and GpVI each contribute to both signaling and adhesion to collagen (10). GpVI, recently cloned (11), acts with the Fc receptor ␥-chain (12, 13) as a crucial signaling receptor complex, and platelets deficient in GpVI fail to aggregate in response to collagen, although the tyrosine kinase c-Src, but not p72 syk , is activated (14). The role of ␣ 2 ␤ 1 in platelet signaling is unclear: ␣ 2 ␤ 1 -reactive snake venoms fuel the debate on the integrin's role in platelet signaling (15, 16), and overexpression of ␣ 2 ␤ 1 has recently been advanced as a risk factor in myocardial infarction and stroke (17,18).We have synthesized a collagen-related peptide (CRP) recognized by GpVI, which shares both the triple-helica...

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Association of two silent polymorphisms of platelet glycoprotein la/lla receptor with risk of myocardial infarction: a case-control study

Cited by 188 publications

References 29 publications

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

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

The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion

Integrin-independent Tyrosine Phosphorylation of p125fak in Human Platelets Stimulated by Collagen

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