Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

Heit, John A.; Cunningham, J. M.; Petterson, Tanya M.; Armasu, Sebastian M.; Rider, David N.; Andrade, Mariza de

doi:10.1111/j.1538-7836.2011.04272.x

Cited by 65 publications

(88 citation statements)

References 56 publications

(58 reference statements)

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“…prothrombin 20210A) of proteins and are predominately located in or near genes encoding for proteins in the coagulation or fibrinolytic pathways. 15 Activated factor V (FV) acts as an important cofactor in the coagulation cascade by facilitating conversion of prothrombin to thrombin and by promoting degradation of activated factor VIII together with activated protein C (APC) and protein S. 16,17 Variations in the factor 5 gene (F5) commonly result in attenuated down-regulation of activated FV by APC. 18 The rs4524 single nucleotide polymorphism (169542517T>C) is the result of a missense mutation (lysine to arginine) at position 2684 in the B-domain of F5 which is thought to result in APC resistance.…”

Section: Introductionmentioning

confidence: 99%

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

et al. 2016

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Section: Introductionmentioning

confidence: 99%

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

et al. 2016

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“…Genotypic markers of procoagulant activity of the blood such as factor V Leiden and prothrombin G20210A have been evaluated almost exclusively in the context of defining risk for venous thrombosis and not cardiovascular disease in general, even though both arterial and venous thromboses have been linked to estrogen therapy. Epidemiology of coronary disease and stroke also has established familial risk factors for occurrence of events (30). Thus, linking genetic variation in estrogen (or other sex-steroid) receptors to genetic variation in proteins of the coagulation cascade could help identify an at-risk thrombotic genotype.…”

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confidence: 99%

Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos Early Estrogen Prevention Study

Miller

Petterson

Jeavons

et al. 2013

Physiological Genomics

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Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, P value = 2.36 × 10(-06)) and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, P value = 5.02 × 10(-05)), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = -0.043, P value = 3.59 × 10(-05); rs2291299, β = -0.032, P value = 5.59 × 10(-05)) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10(-04); and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10(-04)) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10(-04)) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

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“…(150 ng/mL) or a higher concentration (data now shown) within the range of elevated plasma SCUBE1 levels observed in patients experiencing acute coronary syndrome or acute ischemic stroke 20 further enhanced platelet aggregation of +/+ PRP and possibly promoted pathological thrombosis ( Figure XIIA in the online-only Data Supplement). In addition, a recent study showed a significant association of SCUBE1 polymorphism and venous thromboembolism, 23 which underscores SCUBE1 as a promising susceptible candidate gene for this type of disease.…”

Section: Discussionmentioning

confidence: 99%

“…13 Similar to the known functions of the EGF-like domains in mediating homophilic protein-protein interactions as well as cell adhesion,Furthermore, a genetic variant of SCUBE1 gene is associated with enhanced risk of venous thromboembolism. 23 However, the precise functions of soluble SCUBE1 in thromboembolic vascular diseases remain largely unknown.…”

mentioning

confidence: 99%

Inhibition of the Plasma SCUBE1, a Novel Platelet Adhesive Protein, Protects Mice Against Thrombosis

Lin

Liao

et al. 2014

ATVB

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14,15 the NH 2 -terminal EGF-like domain repeats of SCUBE1 are also capable of promoting platelet-platelet interaction or supporting platelet-matrix adhesion in vitro. 13,16 Platelet activation and aggregation are primary reactions in arterial thrombosis and, accordingly, are responsible for the ischemic complications of acute thromboembolic diseases. [17][18][19] Our recent clinical study showed that plasma SCUBE1 concentration is significantly elevated and is a potential biomarker of platelet activation in acute coronary syndrome and acute ischemic stroke. 20 In addition, plasma SCUBE1 levels are higher in hemodialysis or hypertensive patients. Objective-Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1), a secreted and surface-exposed glycoprotein on activated platelets, promotes platelet-platelet interaction and supports platelet-matrix adhesion. Its plasma level is a biomarker of platelet activation in acute thrombotic diseases. However, the exact roles of plasma SCUBE1 in vivo remain undefined. Approach and Results-We generated new mutant (Δ) mice lacking the soluble but retaining the membrane-bound form of SCUBE1. Plasma SCUBE1-depleted Δ/Δ mice showed normal hematologic and coagulant features and expression of major platelet receptors, but Δ/Δ platelet-rich plasma showed impaired platelet aggregation in response to ADP and collagen treatment. The addition of purified recombinant SCUBE1 protein restored the aggregation of platelets in Δ/Δ platelet-rich plasma and further enhanced platelet aggregation in +/+ platelet-rich plasma. Plasma deficiency of SCUBE1 diminished arterial thrombosis in mice and protected against lethal thromboembolism induced by collagen-epinephrine treatment. Last, antibodies directed against the epidermal growth factor-like repeats of SCUBE1, which are involved in trans-homophilic protein-protein interactions, protected mice against fatal thromboembolism without causing bleeding in vivo. Conclusions-We

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Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

Cited by 65 publications

References 56 publications

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos Early Estrogen Prevention Study

Inhibition of the Plasma SCUBE1, a Novel Platelet Adhesive Protein, Protects Mice Against Thrombosis

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