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

Schie, Marianne C. van; Maat, Moniek P.M. de; Isaacs, Aaron; Duijn, Cornelia M. van; Deckers, Jaap W.; Dippel, Diederik W.J.; Leebeek, Frank W.G.

doi:10.1182/blood-2010-03-273961

Cited by 58 publications

(58 citation statements)

References 26 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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“…More recent evidence shows that these plasma hemostatic proteins are also risk factors for other cardiovascular diseases (CVD) [4][5][6][7][8]. The broader role of FVIII and vWF is further supported by studies showing that genetic factors modulating the variability of these proteins are also associated with CVD.…”

Section: Introductionmentioning

confidence: 70%

Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

Antoni¹,

Oudot-Mellakh²,

Dimitromanolakis³

et al. 2014

Bioinformatics

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Background: Elevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs) that could influence the variability of these traits. Methods: Three independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects.

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“…Van Schie et al (2010) report an association study for 421 acute CHD patients and 409 healthy controls using tagging SNPs in the VWF gene. They report a novel association between SNP rs4764478 and vWF levels.…”

Section: Previously Reported Associations and Functional Candidatesmentioning

confidence: 99%

Genetic Variants Associated with von Willebrand Factor Levels in Healthy Men and Women Identified Using the HumanCVD BeadChip

Zabaneh

Gaunt²,

Drenos³

et al. 2011

Annals of Human Genetics

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SummaryWe have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women.The Whitehall II (WHII) study (n = 5592) and the British Women's Heart and Health Study (BWHHS) (n = 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n = 3897) and 1958 Birth Cohort (n = 5048).We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10 −4 . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P = 9.7 × 10 −233 ). The lead variant in the 24 VWF SNPs was rs1063856 (P = 2.3 × 10 −20 ). SNPs at ESR1 (rs6909023) and NRG1( rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.

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

Cited by 58 publications

References 26 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

Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

Genetic Variants Associated with von Willebrand Factor Levels in Healthy Men and Women Identified Using the HumanCVD BeadChip

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