Genetic regulation of plasma von Willebrand factor levels in health and disease

Swystun, Laura L.; Lillicrap, David

doi:10.1111/jth.14304

Cited by 58 publications

(62 citation statements)

References 129 publications

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“…It is estimated that variability at the VWF locus accounts for 5% VWF heritability, whereas that at the ABO blood group locus accounts for approximately 25% VWF heritability. 73 An interesting example of somatic mosaicism of VWF gene mutations has been described by Shen et al in a large family with type 2A VWD. The father carried a mutated VWF gene, p. Arg1597Trp, and transmitted this mutation to his nine offspring.…”

Section: Genotype Versus Phenotypementioning

confidence: 96%

“…Type 1 patient analysis in the Netherlands study demonstrated the association of STXBP5 with a VWF:Ag level reduction of -3 IU/dL per allele and of CLEC4M with a VWF: Ag level of -4.3 IU/dL and VWF activity of -5.75 IU/dL per allele. 31,73 Eleven additional quantitative trait loci were found to associate with plasma VWF levels: ARSA, C2CD4B, DAB2IP, FCHO2, GIMAP7, HLA-DGA1, OR13C5, PDHB, RAB5C, ST3GAL4, and TAB1/SYNGR1. 73 Sabater-Lleal et al identified 11 loci associated with VWF levels: PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPS-NAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Žolková

Sokol

Šimurda

et al. 2019

Semin Thromb Hemost

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Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

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Section: Genotype Versus Phenotypementioning

confidence: 96%

Section: Future Perspectivesmentioning

confidence: 99%

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Žolková

Sokol

Šimurda

et al. 2019

Semin Thromb Hemost

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“…This is supported by the observation of a strong association between VWF levels and the degree of loading of VWF with A and B antigens 10,11 . This would explain the robust association found between the ABO blood group and circulating concentrations of VWF 12 and factor VIII (FVIII) of which VWF is the transport protein. Individuals with A1 and B blood groups have on average 20% higher circulating VWF and FVIII levels than those with O or A2 13,14 groups, high plasma levels of VWF and FVIII being associated with increased VT risk [15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

ABO blood group, glycosyltransferase activity and risk of Venous Thrombosis

Kosta

Bailly

Silvy

et al. 2020

Preprint

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Introduction: ABO blood group influence the risk of venous thrombosis (VT) by modifyingA and B glycosyltransferases (AGT and BGT) activities that further modulates Factor VIII (FVIII) and von Willebrand Factor (VWF) plasma levels. The aim of this work was to evaluate the association of plasma GTs activities with VWF/FVIII plasma levels and VT risk in a casecontrol study.Materials and Methods: 420 cases were matched with 420 controls for age and ABO blood group. GT activities in plasma were measured using the quantitative transfer of tritiated Nacetylgalactosamine or galactose to the 2'-fucosyl-lactose and expressed in disintegration per minute/30µL of plasma and 2 hours of reaction (dpm/30µL/2H). FVIII and VWF plasma levels were respectively measured using human FVIII-deficient plasma in a 1-stage factor assay and STA LIATEST VWF (Diagnostica Stago). Results:A and B GT activities were significantly lower in cases than in controls (8119±4027 vs 9682±4177 dpm/30µL/2H, p=2.03 x 10 -5 , and 4931±2305 vs 5524±2096 dpm/30µL/2H, p=0.043 respectively). This association was observed whatever the ABO blood groups. The ABO A1 blood group was found to explain~80% of AGT activity. After adjusting for ABO blood groups, AGT activity was not correlated to VWF/FVIII plasma levels. Conversely, there was a moderate correlation (ρ~0.30) between BGT activity and VWF/ FVIII plasma levels in B blood group carriers. Conclusion:This work showed, for the first time, that GT activities were decreased in VT patients in comparison to controls with the same ABO blood group. The biological mechanisms responsible for this association remained to be determined.

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“…Numerous other non-VWF and non-ABO genes have been implicated to influence VWF through multiple mechanisms including secretion, glycosylation, and clearance. However, a proportion of VWF variation remains unexplained [135][136][137].…”

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confidence: 99%

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

Ward

Andrews

2019

Research and Practice in Thrombosis and Haemostasis

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The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6‐10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or ‘Capsules’ consisting of short text, three references and a figure, with topics including stroke, cancer‐associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure‐function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

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Genetic regulation of plasma von Willebrand factor levels in health and disease

Cited by 58 publications

References 129 publications

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

ABO blood group, glycosyltransferase activity and risk of Venous Thrombosis

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

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