Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review

Schie, Marianne C. van; Loon, Janine E. van; Maat, Moniek P.M. de; Leebeek, Frank W.G.

doi:10.1111/j.1538-7836.2011.04243.x

Cited by 69 publications

(52 citation statements)

References 94 publications

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“…It has been well established that common genetic polymorphisms in the VWF gene contribute to the variability in VWF:Ag levels. [35][36][37] The most significant SNP that marked the VWF locus was rs216303:T4C, which is located within an intronic region. Until recently, intronic polymorphisms were often considered less relevant for disease development and regulating protein levels in plasma.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

et al. 2015

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Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10 − 8 and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10 − 10 ), 9q34 (2.4 × 10 − 64 ), 12p13 (5.3 × 10 − 22 ), 12q23 (1.2 × 10 − 8 ) and 13q13 (2.6 × 10 − 8 ). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

et al. 2015

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“…Excessive thrombus formation after plaque rupture remains difficult to predict and can be linked to hyperactive platelet function. 1,2 Therefore, low-dose aspirin to inhibit platelet cyclooxygenase-1 (COX-1) and clopidogrel to inhibit platelet P2Y 12 signaling are used widely in patients with cardiovascular risks, although patient response to these drugs can vary.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Similarly, platelet dysfunction or antiplatelet therapy can be associated with bleeding risks. [5][6][7] Furthermore, the function of blood is highly dependent on hemodynamic forces; examples include shear-induced platelet activation at Ͼ 5000/s shear rate, 8,9 requirement of VWF in arterial thrombosis, [10][11][12] shear effects on VWF structure/function and GPIb-VWF A1 domain-bonding dynamics, [13][14][15][16][17] RBC-dependent platelet migration toward the wall, 18,19 and convection-enhanced mass transfer to and from local zones of clotting or bleeding. 20,21 Defining, quantifying, and linking a patient's unique platelet phenotype or coagulation phenotype under hemodynamic conditions to clinical risk remains a diagnostic challenge.…”

Section: Introductionmentioning

confidence: 99%

Multiscale prediction of patient-specific platelet function under flow

Flamm¹,

Colace²,

Chatterjee³

et al. 2012

Blood

107

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During thrombotic or hemostatic episodes, platelets bind collagen and release ADP and thromboxane A 2 , recruiting additional platelets to a growing deposit that distorts the flow field. Prediction of clotting function under hemodynamic conditions for a patient's platelet phenotype remains a challenge. A platelet signaling phenotype was obtained for 3 healthy donors using pairwise agonist scanning, in which calcium dye-loaded platelets were exposed to pairwise combinations of ADP, U46619, and convulxin to activate the P2Y 1 /P2Y 12 , TP, and GPVI receptors, respectively, with and without the prostacyclin receptor agonist iloprost. A neural network model was trained on each donor's pairwise agonist scanning experiment and then embedded into a multiscale Monte Carlo simulation of donor-specific platelet deposition under flow. The simulations were compared directly with microfluidic experiments of whole blood flowing over collagen at 200 and 1000/s wall shear rate. The simulations predicted the ranked order of drug sensitivity for indomethacin, aspirin, MRS-2179 (a P2Y 1 inhibitor), and iloprost. Consistent with measurement and simulation, one donor displayed larger clots and another presented with indomethacin resistance (revealing a novel heterozygote TP-V241G mutation). In silico representations of a subject's platelet phenotype allowed prediction of blood function under flow, essential for identifying patientspecific risks, drug responses, and novel genotypes. IntroductionDuring a clotting event, platelets respond to combinatorial stimuli, including collagen, adenosine diphosphate (ADP), thromboxane A 2 (TXA 2 ), thrombin, epinephrine, and serotonin, as well as endothelialderived inhibitors such as nitric oxide and prostacyclin (PGI 2 ). Excessive platelet buildup at the site of cardiovascular disease and plaque rupture causes more than 1 million heart attacks and strokes in the United States each year. Excessive thrombus formation after plaque rupture remains difficult to predict and can be linked to hyperactive platelet function. 1,2 Therefore, low-dose aspirin to inhibit platelet cyclooxygenase-1 (COX-1) and clopidogrel to inhibit platelet P2Y 12 signaling are used widely in patients with cardiovascular risks, although patient response to these drugs can vary.Interindividual variations in platelet reactivity, even in the healthy population, have been associated with several factors, including female sex, fibrinogen level, ethnicity, inherited variations, and polymorphisms. 3,4 Similarly, platelet dysfunction or antiplatelet therapy can be associated with bleeding risks. [5][6][7] Furthermore, the function of blood is highly dependent on hemodynamic forces; examples include shear-induced platelet activation at Ͼ 5000/s shear rate, 8,9 requirement of VWF in arterial thrombosis, 10-12 shear effects on VWF structure/function and GPIb-VWF A1 domain-bonding dynamics, 13-17 RBC-dependent platelet migration toward the wall, 18,19 and convection-enhanced mass transfer to and from local zones of clotting or bleeding....

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“…13,14 Non-O blood types are associated with higher levels of vWF and FVIII, procoagulant proteins that circulate as a complex in blood, 11,12 because the ABO antigen affects clearance of vWF. 15 Levels of both vWF and FVIII are associated with thrombosis, 16 and were recently linked to dementia risk. 17 A recent report demonstrating an association between blood type AB and stroke risk found that 60% of that association was mediated by differences in FVIII level.…”

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confidence: 99%

ABO blood type, factor VIII, and incident cognitive impairment in the REGARDS cohort

et al. 2014

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Objective: To assess the relationships among ABO group, factor VIII (FVIII), and incident cognitive impairment in a large, prospective cohort study of black and white adults in the United States using a nested case-control design.Methods: Incident cognitive impairment was defined using cognitive domain tests over a mean follow-up of 3.4 years. ABO blood group was measured by genotyping in a nested case-control sample of 495 cases with cognitive impairment and 587 controls.Results: Those with blood group AB and those with higher FVIII had an increased risk of cognitive impairment, adjusting for age, race, region, and sex (respective odds ratios 1.82, 95% confidence interval [CI] 1.15-2.90; and 1.24, 95% CI 1.10-1.38 for 40 IU/dL higher FVIII). Mean FVIII was higher in those with blood type AB (142 IU/dL; 95% CI 119-165) compared with O (104 IU/dL; 95% CI 101-107), and FVIII mediated 18% of the association between AB group and incident cognitive impairment (95% CI for mediation 230% to 68%).Conclusions: Blood group AB and higher FVIII were associated with increased incidence of cognitive impairment in this prospective study. The association of blood group AB with incident cognitive impairment was not significantly mediated by FVIII levels. There is a growing understanding that cardiovascular disease (CVD) and cognitive impairment share many common risk factors. Hypertension, 1,2 elevated cholesterol, 3 hyperglycemia, 2,4 and obesity 4,5 are all associated with longitudinal declines in cognitive function and dementia. Higher levels of the hemostatic markers von Willebrand factor (vWF), coagulation factor VIII (FVIII), and D-dimer have also been related to risk of cognitive impairment and dementia. [6][7][8][9] ABO blood group is associated with many forms of CVD, including coronary heart disease (CHD), stroke, and venous thromboembolism. [10][11][12] In general, individuals with blood group O have a reduced risk of CVD.13,14 Non-O blood types are associated with higher levels of vWF and FVIII, procoagulant proteins that circulate as a complex in blood, 11,12 because the ABO antigen affects clearance of vWF.15 Levels of both vWF and FVIII are associated with thrombosis, 16 and were recently linked to dementia risk. 17 A recent report demonstrating an association between blood type AB and stroke risk found that 60% of that association was mediated by differences in FVIII level. 18Although ABO blood group is a CVD risk factor, we are not aware of studies on its relationship with cognitive impairment. In this study, we examined the relationships among ABO group, FVIII, and incident cognitive impairment in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We hypothesized that blood group A, B, or AB would be associated with an increased risk of cognitive impairment relative to group O.

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Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review

Abstract: To cite this article: van Schie MC, van Loon JE, de Maat MPM, Leebeek FWG. Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease. A review. J Thromb Haemost 2011; 9: 899-908.

Cited by 69 publications

References 94 publications

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

Multiscale prediction of patient-specific platelet function under flow

ABO blood type, factor VIII, and incident cognitive impairment in the REGARDS cohort

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