A Common Thrombomodulin Amino Acid Dimorphism Is Associated with Myocardial Infarction

Norlund, Lena; Holm, Johan; Zöller, Bengt; Öhlin, Ann-Kristin

doi:10.1055/s-0038-1655947

Cited by 97 publications

(71 citation statements)

References 16 publications

(22 reference statements)

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“…Table 2 shows the genotype distribution. Among the 1262 healthy subjects, the frequency of the 1418T allele was 0.175, which is similar to that reported in previous studies (0.180, 19 0.169, 23 and 0.184 27 ) but lower than in other studies (0.261 20 and 0.280 25 ). Given that the control subjects were recruited in 3 different geographical areas of Spain, we analyzed the 1418T allele frequency in the 3 control populations.…”

Section: Thbd C1418c>t Polymorphism and Vte Risksupporting

confidence: 79%

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Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

Navarro

Medina

Bonet

et al. 2013

ATVB

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Objective— To investigate the association of the THBD c.1418C>T polymorphism, which encodes for the replacement of Ala455 by Val in thrombomodulin (TM), with venous thromboembolism (VTE), plasma soluble TM, and activated protein C levels. In addition, human umbilical vein endothelial cells (HUVEC) isolated from 100 umbilical cords were used to analyze the relation between this polymorphism and THBD mRNA and TM protein expression. Approach and Results— The THBD c.1418C>T polymorphism was genotyped in 1173 patients with VTE and 1262 control subjects. Levels of soluble TM and activated protein C were measured in 414 patients with VTE (not on oral anticoagulants) and 451 controls. HUVECs were genotyped for the polymorphism and analyzed for THBD mRNA and TM protein expression and for the ability to enhance protein C activation by thrombin. The 1418T allele frequency was lower in patients than in controls ( P <0.001), and its presence was associated with a reduced VTE risk, reduced soluble TM levels, and increased circulating activated protein C levels ( P <0.001). In cultured HUVEC, the 1418T allele did not influence THBD expression but was associated with increased TM in cell lysates, increased rate of protein C activation, and reduced soluble TM levels in conditioned medium. Conclusions— The THBD 1418T allele is associated with lower soluble TM, both in plasma and in HUVEC-conditioned medium, and with an increase in functional membrane–bound TM in HUVEC, which could explain the increased activated protein C levels and the reduced VTE risk observed in individuals carrying this allele.

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Section: Thbd C1418c>t Polymorphism and Vte Risksupporting

confidence: 79%

“…However, its association with venous [19][20][21][22][23] and arterial thrombosis [24][25][26] is not consistent. In the present study, we investigated the association of this polymorphism with VTE and plasma TM and activated PC (APC) levels.…”

mentioning

confidence: 99%

Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

Navarro

Medina

Bonet

et al. 2013

ATVB

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“…46 Two polymorphisms have been identified in the thrombomodulin gene that code for Ala455Val and Ala25Thr amino acid substitutions. One report suggested an association between the former and MI, 47 but this has not been confirmed. In the Study of Myocardial Infarctions Leiden (SMILE), the Ala25Thr substitution was found to increase the risk of MI, particularly in smokers (OR, 8.8; 95% CI, 1.8 to 42.2) 48 ; however, there is no biologic evidence that the 25Thr isoform alters protein function.…”

Section: Thrombomodulinmentioning

confidence: 94%

Genetic Determinants of Arterial Thrombosis

Voetsch

Loscalzo

2004

ATVB

158

112

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Abstract-Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.

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“…In conjunction with its cofactor protein S, activated protein C degrades coagulation cofactors Va and VIIa, thereby attenuating the coagulation cascade (5,6). The importance of the anticoagulant properties of activated protein C is highlighted by the fact that patients with congenital or acquired deficiencies in the activated protein C anticoagulant pathway are prone to venous and arterial thrombosis (7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant

Stephenson¹,

Toltl²,

Beaudin

et al. 2006

The Journal of Immunology

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Activated protein C is the first effective biological therapy for the treatment of severe sepsis. Although activated protein C is well established as a physiological anticoagulant, emerging data suggest that it also exerts anti-inflammatory and antiapoptotic effects. In this study, we investigated the ability of activated protein C to modulate monocyte apoptosis, inflammation, phagocytosis, and adhesion. Using the immortalized human monocytic cell line THP-1, we demonstrated that activated protein C inhibited camptothecin-induced apoptosis in a dose-dependent manner. The antiapoptotic effect of activated protein C requires its serine protease domain and is dependent on the endothelial cell protein C receptor and protease-activated receptor-1. In primary blood monocytes from healthy individuals, activated protein C inhibited spontaneous apoptosis. With respect to inflammation, activated protein C inhibited the production of TNF, IL-1β, IL-6, and IL-8 by LPS-stimulated THP-1 cells. Activated protein C did not influence the phagocytic internalization of Gram-negative and Gram-positive bioparticles by THP-1 cells or by primary blood monocytes. Activated protein C also did not affect the expression of adhesion molecules by LPS-stimulated blood monocytes nor the ability of monocytes to adhere to LPS-stimulated endothelial cells. We hypothesize that the protective effect of activated protein C in sepsis reflects, in part, its ability to prolong monocyte survival in a manner that selectively inhibits inflammatory cytokine production while maintaining phagocytosis and adherence capabilities, thereby promoting antimicrobial properties while limiting tissue damage.

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A Common Thrombomodulin Amino Acid Dimorphism Is Associated with Myocardial Infarction

Cited by 97 publications

References 16 publications

Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

Genetic Determinants of Arterial Thrombosis

Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant

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