Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study

Campos, Marco; Buchanan, Ashley; Barbalić, Maja; Xiao, Yang; Chambless, Lloyd E.; Wu, Kenneth W.; Folsom, Aaron R.; Boerwinkle, Eric; Dong, Jing‐fei

doi:10.1182/blood-2011-10-383661

Cited by 26 publications

(25 citation statements)

References 35 publications

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“…Although we were able to detect the association of the A2 allele (minor allele frequency 0.05) after a conditional analysis, we were unable to detect several other less common alleles at ABO (30), likely because of their lower allele frequencies. The significantly associated SNPs at the VWF locus tag three of seven haplotype blocks, consistent with a similar analysis of the ARIC cohort (38,39). Although the causative SNPs are not yet at this point, they likely act via alterations in VWF biosynthesis, secretion, or clearance from plasma (40).…”

Section: Discussionsupporting

confidence: 79%

Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Desch

Ozel²,

Siemieniak

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

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The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits.genome-wide association study | linkage study | venous thromboembolic disease | von Willebrand disease | quantitative trait loci V on Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in hemostasis by acting as a molecular bridge tethering platelets to injured endothelium and as a carrier molecule for coagulation factor VIII (1). Quantitative or qualitative deficiencies in VWF lead to von Willebrand Disease (VWD), the most common inherited bleeding disorder, with an estimated prevalence of 0.002-0.01% worldwide (1, 2). Type I VWD is characterized by mild to moderate bleeding and low circulating VWF levels. This form of VWD is generally associated with haploinsufficiency for VWF and is characterized by incomplete penetrance. In contrast, elevated levels of plasma VWF are an independent risk factor for venous thromboembolic disease (3), myocardial infarction (4), stroke (5, 6), and also complicate anticoagulant management (7).Plasma VWF levels vary by approximately fivefold in healthy populations and are influenced by both environmental and inherited factors. Increased levels of VWF occur with advancing age (8), may rise acutely because of inflammation or infection, and may serve as a surrogate marker for endothelial dysfunction and atherosclerosis (9-11). Estimates for the heritability of plasma VWF levels in the general population from previous family-based studies range from 32-75%. A 1985 study in Norwegian twins reported the heritability of VWF at 66%, with 30% of this effect attributable to ABO blood type (12). More recent studies estimated the heritabil...

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Section: Discussionsupporting

confidence: 79%

Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Desch

Ozel²,

Siemieniak

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

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“…Nevertheless, an independent case-control study subsequently demonstrated that a SNP in STXBP5 also constituted a novel candidate risk factor for VTE (Smith et al, 2011). Furthermore, Campos et al (2012) recently reported that four intronic SNPs within the F8 gene also significantly associated with plasma FVIII activity levels. Further studies will be required in order to define how such non-coding F8 gene polymorphisms influence FVIII levels.…”

Section: Alternate Possible Determinants Of Elevated Fviii:cmentioning

confidence: 99%

Elevated factor VIII levels and risk of venous thrombosis

et al. 2012

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SummaryModern thrombophilia testing fails to identify any underlying prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous thromboemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human thrombophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candidates remains weak. In contrast, an increasing body of work supports the hypothesis that increased plasma factor VIII (FVIII) levels may be important in this context. An association between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subsequently, these conclusions have been supported by an increasing number of independent case-control studies. Cumulatively, these studies have clearly demonstrated that high FVIII levels constitute a prevalent, dose-dependent risk factor for VTE. Furthermore, more recent studies have shown that the risk of recurrent venous thrombosis is also significantly increased in patients with high FVIII levels. In this review, we present the evidence supporting the hypothesis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mechanisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk.

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“…The ISTH-SSC VWF Online Database (http:// www.vwf.group.shef.ac.uk/vwd.html) lists~500 mutations and polymorphic variants that were associated with VWD [11]. Single nucleotide polymorphisms (SNPs) in exons, 5′ regulatory region and introns are also reported to influence levels of VWF antigen and FVIII activity in healthy subjects [12][13][14][15]. Some of these VWF SNPs are associated with an elevated risk of thrombosis [5,16].…”

Section: Introductionmentioning

confidence: 99%

Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes

Wang

Song

Gibbs

et al. 2013

Journal of Thrombosis and Haemostasis

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Background The von Willebrand factor (VWF) gene is highly polymorphic, with variants correlated with VWF antigen levels, adhesion activity, clearance, and factor VIII binding. VWF mutations are detected in patients with von Willebrand disease (VWD), whereas polymorphic variants could be associated with thrombosis. However, information on the ethnic diversity of VWF variants and their association with diseases is limited. Objectives To characterize novel VWF variants from different ethnicities in the general population. Patients/Methods We analyzed samples from 1,092 subjects of 14 ethnicities available in the 1000 Genomes database for VWF variants and their potential functional impacts. Results We identified 2,728 SNPs and 91 insertions and deletions that had a high level of ethnic diversity, with Africans having the highest number of variants. The highest level of diversity was found in the D′ and D2 domains. Among 94 non-synonymous variants, 31 were predicted to be deleterious, including 19 that were previously associated with VWD. Most of these “VWD variants” had allele frequencies consistent with disease incidence in European subjects; but some had a significantly higher frequency in other ethnicities. The mutation R2185Q, H817Q and M740I associated with type 1 and type 2N VWD were present in more than 13% of African subjects. Conclusions These results highlight the complexity of VWF variations in different ethnic groups and emphasize the importance of interrogating variations on multiple ethnic backgrounds for associations with bleeding and thrombosis.

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Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study

Cited by 26 publications

References 35 publications

Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

Elevated factor VIII levels and risk of venous thrombosis

Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes

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