Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1393-1399 ◽  
Author(s):  
Marianne C. van Schie ◽  
Moniek P. M. de Maat ◽  
Aaron Isaacs ◽  
Cornelia M. van Duijn ◽  
Jaap W. Deckers ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Von Willebrand Factor ◽  
Young Patients ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Cvd Risk ◽  
New Associations ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (IS), and 409 healthy control participants (men aged ≤ 45 years, women aged ≤ 55 years), 27 haplotype-tagging single-nucleotide polymorphisms (ht-SNPs), covering the total common VWF gene variation, were selected and genotyped. The associations between these SNPs, VWF antigen (VWF:Ag) levels, VWF collagen-binding (VWF:CB) activity, and CVD risk was investigated. Two new associations were identified. For ht-SNP rs4764478 (intron 45), the increase in VWF:Ag levels and VWF:CB activity per minor allele was 0.082 (± 0.026) IU/mL (P = .001) and 0.096 (± 0.030) IU/mL (P = .002), respectively. ht-SNP rs216293 (intron 17) was associated with CVD risk (odds ratio, 1.44; 95% confidence interval [CI], 1.12-1.86 per minor allele). We confirmed the association between rs1063857 and CVD risk. Our data show that common variants in the VWF gene are associated with VWF levels and with the risk for CVD.

Effects of Low ADAMTS 13 Levels and the Role of Von Willebrand Factor in Cardiovascular Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5320-5320
Author(s):  
Giorgio Corinaldesi
Keyword(s):  
Cardiovascular Disease ◽  
Shear Stress ◽  
Relative Risk ◽  
Von Willebrand Factor ◽  
Conflicts Of Interest ◽  
High Shear ◽  
High Shear Stress ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract 5320 Von Willebrand factor (vWF) is a large multimeric glycoprotein that plays an important role as a co-factor in platelet adhesion and aggregation and as the circulating carrier for factor VIII; increased vWF levels, and the persistence of unprocessed ultra-large vWF multimers (ULVWF) that are hyperactive to binding GPIb-IX-V complex with high-strength bonds, precipitate platelet clumping in arterioles and capillaries, causing platelet aggregation and thrombotic microangiopathy resulting in tissue ischemia with an increased risk of CAD and stroke. vWF is the major ligand binding the subunit of trombospondin, P-selectin, collagen and SLAM family (signaling lymphocytic activation molecule), mediates platelet translocation, tethering and rolling under high shear stress and adhesion. The activity of VWF is modulated by ADAMTS-13 a Zn2+/Ca2+ dependent metalloprotease that cleaves vWF to smaller and less active forms at the tyr842/met843 within the A2 domain, and cleaves the tyr 1605/met 1606; this mechanism reduces the molecular weight and platelet-tethering function of vWF to the sub endothelium at high shear stress. ADAMTS-13 levels also correlate positively with cholesterol, triglycerides and body mass index (BMI). In addition, we have observed a negative association with fibrinogen, C-reactive protein, and ion trasport K+dependent Na+/Ca2+ exchange (SLC24A3); the phosphorylation of tyrosine 1605 and threonine/serine kinase inhibitors have negative effects on integrin GPIIb-IIIa that showed decrease expression. In patients with a level of ADAMTS-13 below 38%, the presence of ultra large vWF multimers is high and the relative risk of ischemic heart disease was 18.2% (95% CI, 0.8 to 4.2), and the relative risk of stroke was 11.5 % (95% CI, 0.6 to 3.9). We investigated the relation between the low activity of ADAMTS-13 and AMI or stroke; we measured VWF and ADAMTS-13 antigen levels in 16 patients with AMI, in 10 patients with stroke, and in 16 control subjects. We demonstrated that vWF levels are significantly higher in patients with AMI or stroke, while a severe decrease of ADAMTS-13 activity augments the risk of cardiovascular disease, and cerebral ischemia; measurement of both VWF and ADAMTS-13 may provide a good indicator for the likelihood of AMI and stroke. Disclosures: No relevant conflicts of interest to declare.

Combined effects of plasma von Willebrand factor and platelet measures on the risk of incident venous thromboembolism

Blood ◽  
2021 ◽  
Author(s):  
Magnus Sandvik Edvardsen ◽  
Ellen-Sofie Hansen ◽  
Kristian Hindberg ◽  
Vânia Maris Morelli ◽  
Thor Ueland ◽  
...  
Keyword(s):  
Platelet Count ◽  
Venous Thromboembolism ◽  
Von Willebrand Factor ◽  
Platelet Reactivity ◽  
High Plasma ◽  
Combined Effects ◽  
Exposure Group ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma von Willebrand factor (VWF) and platelet reactivity are both risk factors for venous thromboembolism (VTE), and VWF can promote hemostasis by interaction with platelets. In this study, we explored the combined effects of plasma VWF and platelet measures on the risk of incident VTE. A population-based nested case-control study with 403 cases and 816 controls was derived from the Tromsø Study. VWF, platelet count and mean platelet volume (MPV) were measured in blood samples drawn at baseline. Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across VWF tertiles, within predefined MPV (<8.5, 8.5-9.5, ≥9.5 fL) and platelet count (<230, 230-299, ≥300·109 L-1) strata. Here, participants with VWF levels in the highest tertile and MPV ≥9.5 fL had an OR of 1.98 (95% CI 1.17-3.36) for VTE compared with those in the lowest VWF tertile and with MPV <8.5 fL in the age- and sex-adjusted model. In the joint exposure group, 48% (95% CI 15% to 96%) of VTEs were attributable to the biological interaction between VWF and MPV. Similarly, individuals with VWF in the highest tertile and platelet count ≥300·109 L-1 had an OR of 2.91 (95% CI 1.49-5.67) compared with those with VWF in the lowest tertile and platelet count <230, and 39% (95% CI -2% to 97%) of VTEs in the joint exposure group were explained by the interaction. Our results suggest that both platelet reactivity and platelet count interact biologically with high plasma VWF, resulting in an increased risk of incident VTE.

Effect of the Antioxidants Selenium and Beta-carotene on HIV-related Endothelium Dysfunction

1998 ◽  
Vol 80 (12) ◽  
pp. 1015-1017 ◽  
Author(s):  
M. Seigneur ◽  
A. D. Blann ◽  
M. Renard ◽  
F. Resplandy ◽  
J. Amiral ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Von Willebrand Factor ◽  
Inflammatory Markers ◽  
Beta Carotene ◽  
Soluble Thrombomodulin ◽  
Endothelium Dysfunction ◽  
Increased Risk ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryPatients infected with HIV are at increased risk of atherosclerosis, and have evidence of endothelium dysfunction. The hypothesis was tested that HIV-related endothelium dysfunction is related to loss of antioxidants. This was done by the supplementation of the antioxidants selenium and beta-carotene. We supplemented the diet of 10 HIV-sero-positive subjects with 100 μg selenium daily, 11 subjects with 30 mg beta-carotene twice daily while 15 subjects were not supplemented. Plasma was obtained at outset and after a year, and tested by ELISA for endothelial cell, platelet and inflammatory markers.The non-supplemented patients experienced increases in von Wille-brand factor and soluble thrombomodulin (both p < 0.01). There were no changes in any of the indices in the patients taking selenium or beta-carotene.Increased von Willebrand factor and soluble thrombomodulin in the non-supplemented patients imply increased damage to the endothelium over the year of the study. Therefore we interpret the lack of increase in the patients taking antioxidants as evidence of the protection of the endothelium by these agents.

Variation at the von Willebrand Factor (vWF) Gene Locus Is Associated With Plasma vWF:Ag Levels: Identification of Three Novel Single Nucleotide Polymorphisms in the vWF Gene Promoter

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4277-4283 ◽  
Author(s):  
Angela M. Keightley ◽  
Y. Miu Lam ◽  
Jolene N. Brady ◽  
Cherie L. Cameron ◽  
David Lillicrap
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Von Willebrand Factor ◽  
Gene Locus ◽  
Strong Linkage Disequilibrium ◽  
Nucleotide Polymorphisms ◽  
Polymorphic Variation ◽  
Single Nucleotide ◽  
Haplotype 1 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Both genetic and environmental factors contribute to the normal population variability of plasma von Willebrand Factor (vWF) levels, however, regulatory mechanisms at the vWF gene locus itself have not yet been identified. We have investigated the association between polymorphic variation in the 5′-regulatory region of the vWF gene and levels of plasma vWF:Ag in a study of 261 group O blood donors. Three novel single nucleotide polymorphisms (SNPs) were identified in the vWF promoter: C/T at -1234, A/G at -1185, and G/A at -1051. These SNPs had identical allele frequencies of 0.36 for the -1234C, -1185A, and -1051G alleles and 0.64 for the -1234T, -1185G, and -1051A alleles and were in strong linkage disequilibrium. In fact, these polymorphisms segregated as two distinct haplotypes: -1234C/-1185A/-1051G (haplotype 1) and -1234T/-1185G/-1051A (haplotype 2) with 12.6% of subjects homozygous for haplotype 1, 40.6% homozygous for haplotype 2, and 42.5% of subjects heterozygous for both haplotypes. Only 4.3% of individuals had other genotypes. A significant association between promoter genotype and level of plasma vWF:Ag was established (analysis of covariance [ANCOVA], P = .008; Kruskal-Wallis test,P = .006); individuals with the CC/AA/GG genotype had the highest mean vWF:Ag levels (0.962 U/mL), intermediate values of vWF:Ag (0.867 U/mL) were observed for heterozygotes (CT/AG/GA), and those with the TT/GG/AA genotype had the lowest mean plasma vWF:Ag levels (0.776 U/mL). Interestingly, when the sample was subgrouped according to age, the significant association between promoter genotype and plasma vWF:Ag level was accentuated in subjects &gt; 40 years of age (analysis of variance [ANOVA], P = .003; Kruskal-Wallis test, P= .001), but was not maintained for subjects ≤ 40 years of age (ANOVA, P &gt; .4; Kruskal-Wallis test, P &gt; .4). In the former subgroup, mean levels of plasma vWF:Ag for subjects with the CC/AA/GG, CT/AG/GA, and TT/GG/AA genotypes were 1.075, 0.954, and 0.794 U/mL, respectively. By searching a transcription factor binding site profile database, these polymorphic sequences were predicted to interact with several transcription factors expressed in endothelial cells, including Sp1, GATA-2, c-Ets, and NFκB. Furthermore, the binding sites at the -1234 and -1051 SNPs appeared to indicate allelic preferences for some of these proteins. Electrophoretic mobility shift assays (EMSAs) performed with recombinant human NFκB p50 showed preferential binding of the -1234T allele (confirmed by supershift EMSAs), and EMSAs using bovine aortic endothelial cell (BAEC) nuclear extracts produced specific binding of a nuclear protein to the -1051A allele, but not the -1051G allele. These findings suggest that circulating levels of vWF:Ag may be determined, at least in part, by polymorphic variation in the promoter region of the vWF gene, and that this association may be mediated by differential binding of nuclear proteins involved in the regulation of vWF gene expression.

scholarly journals Cerebral Sinus and Venous Thrombosis Associated with von Willebrand Factor, Independently of Factor VIII

2008 ◽  
Vol 1 ◽  
pp. CCRep.S737
Author(s):  
Mari Terashima ◽  
Hiroshi Kataoka ◽  
Hirosei Horikawa ◽  
Hiroyuki Nakagawa ◽  
Toshiaki Taoka ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Transluminal Angioplasty ◽  
Right Hand ◽  
Increased Risk ◽  
Cerebral Sinus ◽  
The Right ◽  
Von Willebrand ◽  
Willebrand Factor

Background and purpose Previous studies have linked procoagulant factor VIII (F VIII) to an increased risk of venous thrombosis, whereas the relation between plasma von Willebrand factor (VWF) and venous thrombosis remains poorly understood. Elevated VWF levels are frequently found in patients with cerebral sinus and venous thrombosis (CSVT), always in association with high F VIII levels. We describe a patient with CSVT accompanied by elevated VWF levels without high F VIII levels. Case description A 23-year-old healthy man who had headache noticed difficulty in moving the right hand. On the following day, he lost consciousness and had partial seizures of the right hand. After regaining consciousness, weakness of the right extremities developed. The cranial angiogram confirmed occlusion of the superior sagittal sinus. The levels of VWF and F VIII were 238% and 101.9 IU/dl, respectively. We performed balloon percutaneous transluminal angioplasty and mechanical thrombectomy, leading to successful recanalization of the intracranial sinuses. VWF levels were decreased along with radiographic improvement, independently of F VIII. Conclusion VWF may contribute to CSVT and that inhibition of VWF activity potentially has a role in the future treatment of pathological conditions related to venous thrombosis.

scholarly journals Influence of ABO Locus on PFA-100 Collagen-ADP Closure Time Is Not Totally Dependent on the Von Willebrand Factor. Results of a GWAS on GAIT-2 Project Phenotypes

2019 ◽  
Vol 20 (13) ◽  
pp. 3221 ◽  
Author(s):  
Núria Pujol-Moix ◽  
Angel Martinez-Perez ◽  
Maria Sabater-Lleal ◽  
Dolors Llobet ◽  
Noèlia Vilalta ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Genome Wide Association Study ◽  
Platelet Reactivity ◽  
Coagulation Factor ◽  
Nucleotide Polymorphisms ◽  
Closure Time ◽  
A Genome ◽  
Abo Genotype ◽  
Von Willebrand ◽  
Willebrand Factor

(1) Background: In a previous study, we found that two phenotypes related to platelet reactivity, measured with the PFA-100 system, were highly heritable. The aim of the present study was to identify genetic determinants that influence the variability of these phenotypes: closure time of collagen-ADP (Col-ADP) and of collagen-epinephrine (Col-Epi). (2) Methods: As part of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia (2) Project, 935 individuals from 35 large Spanish families were studied. A genome-wide association study (GWAS) with ≈ 10 M single nucleotide polymorphisms (SNPs) was carried out with Col-ADP and Col-Epi phenotypes. (3) Results: The study yielded significant genetic signals that mapped to the ABO locus. After adjusting both phenotypes for the ABO genotype, these signals disappeared. After adjusting for von Willebrand factor (VWF) or for coagulation factor VIII (FVIII), the significant signals disappeared totally for Col-Epi phenotype but only partially for Col-ADP phenotype. (4) Conclusion: Our results suggest that the ABO locus exerts the main genetic influence on PFA-100 phenotypes. However, while the effect of the ABO locus on Col-Epi phenotype is mediated through VWF and/or FVIII, the effect of the ABO locus on Col-ADP phenotype is partly produced through VWF and/or FVIII, and partly through other mechanisms.

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