Dataset Information

Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis.

ABSTRACT: In a recent genome-wide association study, variants in 8 genes were associated with VWF level, a risk factor for venous thrombosis (VT). In an independent, population-based, case-control study of incident VT, we tested hypotheses that variants in these genes would be associated with risk. Cases were 656 women who experienced an incident VT, and controls comprised 710 women without a history of VT. DNA was obtained from whole blood. Logistic regression was used to test associations between incident VT and single nucleotide polymorphisms (SNPs) in 7 genes not previously shown to be associated with VT. Associations with P < .05 were candidates for replication in an independent case-control study of VT in both sexes. Two of the 7 SNPs tested yielded P < .05: rs1039084 (P = .005) in STXBP5, a novel candidate gene for VT, and rs1063856 (P = .04) in VWF, a gene whose protein level is associated with VT risk. Association results for the remaining 5 variants in SCARA5, STAB2, STX2, TC2N, and CLEC4M were not significant. Both STXBP5 and VWF findings were replicated successfully. Variation in genes associated with VWF levels in the genome-wide association study was found to be independently associated with incident VT.

SUBMITTER: Smith NL

PROVIDER: S-EPMC3112044 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis.

Smith Nicholas L NL Rice Kenneth M KM Bovill Edwin G EG Cushman Mary M Bis Joshua C JC McKnight Barbara B Lumley Thomas T Glazer Nicole L NL van Hylckama Vlieg Astrid A Tang Weihong W Dehghan Abbas A Strachan David P DP O'Donnell Christopher J CJ Rotter Jerome I JI Heckbert Susan R SR Psaty Bruce M BM Rosendaal Frits R FR

Blood 20101216 22

In a recent genome-wide association study, variants in 8 genes were associated with VWF level, a risk factor for venous thrombosis (VT). In an independent, population-based, case-control study of incident VT, we tested hypotheses that variants in these genes would be associated with risk. Cases were 656 women who experienced an incident VT, and controls comprised 710 women without a history of VT. DNA was obtained from whole blood. Logistic regression was used to test associations between incide ...[more]

PMID: 21163921

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Project description:Essentials von Willebrand factor (VWF) is synthesized in endothelial cells and platelet precursors. Type 3 patients with Pro2808Leufs*24 have lower bleeding scores than other type 3s. The Pro2808Leufs*24 variant was examined in patient platelets and endothelial cells. Type 3s with this variant contain releaseable VWF, possibly reducing bleeding.SummaryBackground A novel variant, p.Pro2808Leufs*24, in the von Willebrand factor (VWF) gene was previously identified in the Canadian von Willebrand disease (VWD) patient population. Clinical observations of type 3 VWD patients with this variant indicate a milder bleeding phenotype compared with other type 3 patients. Objective To assess the effect of the Pro2808Leufs*24 variant on the molecular pathogenesis of VWD and correlate this with the phenotype observed in patients. Patients/Methods Phenotypic data from individuals in the Canadian type 3 VWD study were analyzed. VWF expression in platelets and plasma was assessed via immunoblotting. Cellular expression of VWF in platelets and blood outgrowth endothelial cells (BOEC) was examined via immunofluorescence microscopy and biochemical analysis in a type 3 index case and family member with Pro2808Leufs*24. Results Twenty-six individuals with the Pro2808Leufs*24 variant (16 type 3 VWD homozygous or compound heterozygous and 10 heterozygous family members) were studied. Bleeding scores were lower in type 3 patients with Pro2808Leufs*24 compared with type 3 patients with other variants, confirming a milder bleeding phenotype. Immunoblotting of platelet lysates detected VWF in the platelets of type 3 patients with Pro2808Leufs*24. Examination of an index case detected VWF within platelets via immunofluorescence microscopy, and in vitro experiments showed that this VWF was released upon platelet activation. Patient BOECs showed decreased VWF synthesis and secretion, although some VWF-containing granules were observed. Conclusion Type 3 VWD patients with the Pro2808Leufs*24 have bioavailable platelet-derived VWF that may produce a milder bleeding phenotype than other type 3s.

Dataset Information

Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis.

Publications

Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis.

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