Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group

Davies, James A.; Collins, Peter William; Hathaway, Lee Sarah; Bowen, Derrick John

doi:10.1182/blood-2006-07-035105

Cited by 35 publications

(35 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[33][34][35] Our large sample set allowed us to construct a VWF haplomap that included rare SNPs to identify specific SNPs that are transmitted together. We found 9 separate blocks that are in LD in the VWF gene ( Figure 3).…”

Section: Haplotype Construction and Correlation With Vwf Antigen Levelsmentioning

confidence: 99%

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Campos

Sun

et al. 2011

Blood

View full text Add to dashboard Cite

IntroductionThe von Willebrand factor (VWF) is an essential component of hemostasis at sites of vascular injury. This hemostatically active adhesion ligand also plays a critical role in thrombus formation at the site of a ruptured atherosclerotic plaque and in platelet aggregation induced by high fluid shear stress in areas of severe vascular stenosis. The former results in myocardial infarction when it occurs in coronary arteries, whereas the latter is a major cause of thromboembolism associated with ischemic stroke. 1 VWF is the largest multimeric glycoprotein in the plasma. It is exclusively synthesized in endothelial cells and megakaryocytes initially as a monomeric glycoprotein. In the endoplasmic reticulum and Golgi apparatus of these cells, the monomers form C-terminal disulfide-linked dimers. A various number of dimers subsequently form multimers through N-terminal disulfide linkages, a process assisted by the proteolytic release of a 714-amino acid propeptide. 2,3 The newly synthesized VWF multimers are either constitutively released into the circulation or stored in the Weibel-Palade bodies of endothelial cells and ␣-granules of megakaryocytes/platelets. 4,5 On stimulation, these granules secrete the stored VWF multimers that are rich in ultra-large and hemostatically hyperactive forms. 4,6 Ultra-large VWF multimers are also secreted under endothelial stress caused by inflammation but are rapidly and partially cleaved by the zinc metalloprotease AD-AMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) into smaller, variable-sized multimers. 7-9 The hemostatic activity of VWF multimers is determined not only by multimer size, 4,10 but also by the quantity of VWF antigen in the circulation. The plasma level of VWF multimers is determined by a dynamic balance between the rate of production and that of clearance. Although acquired conditions are known to affect synthesis and secretion, 11 genetic factors play a major role in regulating VWF synthesis and clearance. It has been reported that genetic factors are responsible for up to 66% of variation in plasma VWF antigen level, of which 30% is related to ABO blood type. 12,13 The human VWF gene is located on chromosome 12. 14,15 It spans approximately 180 kb of nucleotides and contains 52 exons that encode a multidomain prepolypeptide of 2791 amino acids. [14][15][16] The VWF gene is highly polymorphic. 17 Single nucleotide polymorphisms (SNPs) of the coding and promoter sequences in the VWF gene have been extensively studied and found to influence the levels of VWF in the circulation. Furthermore, as a heavily glycosylated polypeptide, 16,18 the level of circulating VWF is also affected by the structure of its carbohydrate side chains, which are associated with ABO blood group, primarily because of the presence or absence of a functional glycosyltransferase that adds either a N-acetylgalactosamine or a D-galactose to a D-galactose side chain on the H antigen. 19 This structural variation in glycosylation has been reported to directly...

show abstract

Section: Haplotype Construction and Correlation With Vwf Antigen Levelsmentioning

confidence: 99%

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Campos

Sun

et al. 2011

Blood

View full text Add to dashboard Cite

show abstract

“…12,13 Although VWF multimeric composition is a strong determinant of its functional activity, 14 the limited studies available on coding regions of the VWF gene mainly focused on the contribution of common variants to VWF:Ag levels and not on their contribution to VWF activity or CVD. 12,13 We investigated the association between common variation spanning the total VWF gene (including 12kb of the 5Јand 3Ј flanking regions), VWF:Ag levels, VWF collagen-binding activity (VWF:CB), and the risk for CVD. A total of 27 haplotypetagging SNPs (ht-SNPs) representing common variation in the VWF gene were selected and were subsequently genotyped in young patients with a first event of acute CHD or IS and in healthy control participants.…”

Section: Introductionmentioning

confidence: 99%

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

Schie¹,

Maat²,

Isaacs

et al. 2011

Blood

View full text Add to dashboard Cite

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 (

show abstract

“…Preliminary estimates of frequency suggested that 1 in 100 individuals were heterozygous Y/C1584 [1, 2], and power calculations indicated that a cohort of 50 heterozygotes would permit statistical analysis of relevant phenotypic parameters. A cohort of 5,052 blood donors was recruited and genotyped for C1584, this yielded 50 Y/C1584 heterozygous individuals and 5,002 Y/Y1584 homozygous individuals; no C/C1584 homozygous individuals were detected [8]. The findings indicated a rate of heterozygosity of 1% for Y/C1584 in the population.…”

Section: Properties Of C1584mentioning

confidence: 99%

“…The findings indicated a rate of heterozygosity of 1% for Y/C1584 in the population. The following paragraphs summarise the data obtained from the large blood donor cohort study [8]. …”

Section: Properties Of C1584mentioning

confidence: 99%

C1584: Effect on von Willebrand Factor Proteolysis and von Willebrand Factor Antigen Levels

Davies¹,

Collins²,

Hathaway³

et al. 2009

Acta Haematol

Self Cite

View full text Add to dashboard Cite

The present review provides a clearer picture of the effect of C1584 on the level and properties of von Willebrand factor (VWF). The C1584 variant is associated with decreased VWF levels (especially in combination with blood group O) and VWF function, and with slightly enhanced VWF proteolysis, and there is evidence to support its association with enhanced VWF clearance. These properties help explain the enrichment for C1584 in mild type 1 VWD and the observed marked association of the variant and blood group O in this mild bleeding disorder. It has been proposed that the mildly enhanced VWF proteolysis associated with C1584 (and also with blood group O) may compromise clot formation, offering a further rationale for the enrichment of the variant in type 1 VWD. C1584 shows variable penetrance and this is still not fully understood. It reflects the interaction of C1584 with other variables, one of which is clearly blood group O. Genome-wide association studies aimed at identifying loci involved in the control of the VWF level may provide further insights into C1584 penetrance and, more generally, into mechanisms underlying type 1 VWD and also cardiovascular disease.

show abstract

Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group

Cited by 35 publications

References 35 publications

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

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

C1584: Effect on von Willebrand Factor Proteolysis and von Willebrand Factor Antigen Levels

Contact Info

Product

Resources

About